CN118139868A

CN118139868A - Orally bioavailable nucleoside analogs

Info

Publication number: CN118139868A
Application number: CN202280056394.5A
Authority: CN
Inventors: 克里斯多佛·J·伯恩斯; 格伦·科伯恩; 楚国华; 斯蒂芬·M·康登; 史蒂文·A·博伊德; 丹尼尔·C·佩维尔
Original assignee: VenatoRx Pharmaceuticals Inc
Current assignee: VenatoRx Pharmaceuticals Inc
Priority date: 2021-06-14
Filing date: 2022-06-13
Publication date: 2024-06-04

Abstract

Described herein are orally bioavailable nucleoside analogs and pharmaceutical compositions comprising the compounds. The subject compounds and compositions are useful for treating coronavirus infections, including SARS-CoV-2 infection.

Description

Orally bioavailable nucleoside analogs

Cross reference

The present application claims the benefit of U.S. provisional application Ser. No. 63/210,385 filed on month 14 of 2021, U.S. provisional application Ser. No. 63/257,820 filed on month 10 of 2021, and U.S. provisional application Ser. No. 63/328,106 filed on month 4 of 2022, which are hereby incorporated by reference in their entireties.

Background

Adefovir (remdesivir) is a parenterally administered prodrug that was previously developed for the treatment of ebola virus disease and recently obtained an urgent use authorization (Eastman, r.t., roth, j.s., brimacombe, k.r., simeonov, a., shen, m., patnaik, s, and Hall,M.D.(2020).Remdesivir:A Review of Its Discovery and Development Leading to Emergency Use Authorization for Treatment of COVID-19.ACS Cent Sci 6,672-683). parent compounds are 1' -cyano-modified adenosine C-nucleoside analogs (GS-441524) for the treatment of severe acute respiratory syndrome-coronavirus type 2 (SARS-CoV-2) infection, it is phosphorylated by intracellular nucleotide kinases into an active triphosphateed form (GS-443902). GS-443902 inhibits viral replication by competing with endogenous nucleotides for incorporation into the nascent RNA strand via viral RNA-dependent RNA polymerase, resulting in the production of a nonfunctional viral genome via lethal mutagenesis (Siegel, d., hui, h.c., doerffler, e., clarke, m.o., chun, k., zhang, l., neville, s, carra, e., lew, w, ross, b., et al (2017).Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1-f][triazin-4-amino]Adenine C-Nucleoside(GS-5734)for the Treatment of Ebola and Emerging Viruses.J Med Chem 60,1648-1661). radevir (GS-5734) is a single phosphoramidate prodrug of GS-441524 and exhibits broad-spectrum antiviral activity against a variety of different RNA virus families including: filoviruses (e.g., ebola virus, marburg virus), paramyxoviruses (e.g., parainfluenza type II virus, nipah virus, hendra virus, measles virus, mumps virus), coronaviruses (e.g., SARS-CoV-2, MERS-CoV) and pneumoviruses (e.g., respiratory syncytial virus) (Cho, a., samenders, o.l., butler, t., zhang, l., xu, j., vela, j.e., feng, j.y., ray, a.s., and Kim,C.U.(2012).Synthesis and antiviral activity of a series of 1'-substituted 4-aza-7,9-dideazaadenosine C-nucleosides.Bioorg Med Chem Lett 22,2705-2707).

Coronaviruses are a large family of viruses that are common in humans and many different species of animals, including humans, camels, cattle, cats and bats. Human coronaviruses infect humans and can cause mild to moderate upper, lower and/or gastrointestinal diseases. An example is the "middle east respiratory syndrome coronavirus" (MERS-CoV or MERS), which was first reported in sauter arabia in 2012 and has been transmitted to several countries. Another example is SARS-CoV, a coronavirus that causes "Severe acute respiratory syndrome" (SARS). Yet another example is "coronavirus disease 2019" (COVID-19), also known as SARS-CoV-2, which can infect humans and then spread between humans. SARS-CoV-2 virus is a beta coronavirus, similar to MERS-CoV and SARS-CoV. Other human coronaviruses include 222E (alpha coronavirus), NL63 (alpha coronavirus), OC43 (beta coronavirus), and HKU1 (beta coronavirus).

Disclosure of Invention

The present disclosure relates to small molecule compounds that block coronavirus replication, which have the potential to be used as monotherapy or in combination with additional antiviral agents and/or other agents for the treatment of coronavirus infections.

Disclosed herein is a compound of formula (II):

Wherein:

X is hydrogen or-CN;

G is

R ¹¹ is hydrogen, -C (=o) R ²¹、-C(＝O)OR²¹ or C ₁-C₆ alkyl optionally substituted by one or more R ^11a;

Each R ^11a is independently halogen, -CN, -OH, -OR ^a、-NR^cR^d, cycloalkyl OR heterocycloalkyl;

or two R ^11a on the same atom together to form oxo;

R ²¹ is C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^21a;

Each R ^21a is independently halogen 、-CN、-NO₂、-OH、-OR^a、-OC(＝O)R^a、-OC(＝O)OR^b、-OC(＝O)NR^cR^d、-S(＝O)R^a、-S(＝O)₂R^a、-S(＝O)₂NR^cR^d、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ heteroalkyl, C ₂-C₆ alkenyl, C ₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R;

Or two R ^21a on the same atom together to form oxo;

Or two R ^21a taken together to form cycloalkyl or heterocycloalkyl; each of which is optionally and independently substituted with one or more R;

R ¹² is hydrogen, -C (=o) R ²²、-C(＝O)OR²² or C ₁-C₆ alkyl optionally substituted by one or more R ^12a;

Each R ^12a is independently halogen, -CN, -OH, -OR ^a、-NR^cR^d, cycloalkyl OR heterocycloalkyl;

Or two R ^12a on the same atom together to form oxo;

r ²² is C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^22a;

Each R ^22a is independently halogen 、-CN、-NO₂、-OH、-OR^a、-OC(＝O)R^a、-OC(＝O)OR^b、-OC(＝O)NR^cR^d、-S(＝O)R^a、-S(＝O)₂R^a、-S(＝O)₂NR^cR^d、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ heteroalkyl, C ₂-C₆ alkenyl, C ₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R;

or two R ^22a on the same atom together to form oxo;

or two R ^22a taken together to form cycloalkyl or heterocycloalkyl; each of which is optionally and independently substituted with one or more R;

R ¹³ is hydrogen or C ₁-C₆ alkyl;

r ¹⁴ is-OH or fluoro;

R ¹⁵ is hydrogen, -C (=o) R ²⁵、-C(＝O)OR²⁵、-CH₂-O-C(＝O)R²⁵、-CH₂-O-C(＝O)OR²⁵ or C ₁-C₆ alkyl optionally substituted by one or more R ^15a;

Each R ^15a is independently halogen, -CN, -OH, -OR ^a、-NR^cR^d, cycloalkyl OR heterocycloalkyl;

Or two R ^15a on the same atom together to form oxo;

R ²⁵ is C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^25a;

Each R ^25a is independently halogen 、-CN、-NO₂、-OH、-OR^a、-OC(＝O)R^a、-OC(＝O)OR^b、-OC(＝O)NR^cR^d、-S(＝O)R^a、-S(＝O)₂R^a、-S(＝O)₂NR^cR^d、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ heteroalkyl, C ₂-C₆ alkenyl, C ₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R;

Or two R ^25a on the same atom together to form oxo;

Or two R ^25a taken together to form cycloalkyl or heterocycloalkyl; each of which is optionally and independently substituted with one or more R;

r ¹⁶ is-C (=O) R ²⁶、-C(＝O)OR²⁶、-CH₂-O-C(＝O)R²⁶ or-CH ₂-O-C(＝O)OR²⁶,

R ²⁶ is C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl) or C ₁-C₆ alkylene (heteroaryl); wherein alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^26a;

Each R ^26a is independently halogen 、-CN、-NO₂、-OH、-OR^a、-OC(＝O)R^a、-OC(＝O)OR^b、-OC(＝O)NR^cR^d、-SH、-SR^a、-S(＝O)R^a、-S(＝O)₂R^a、-S(＝O)₂NR^cR^d、-NR^cR^d、-NR^bC(＝O)NR^cR^d、-NR^bC(＝O)R^a、-NR^bC(＝O)OR^b、-NR^bS(＝O)₂R^a、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ heteroalkyl, C ₂-C₆ alkenyl, C ₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

or two R ^26a on the same atom together to form oxo;

Or two R ^26a on the same carbon together to form cycloalkyl or heterocycloalkyl; each of which is optionally substituted with one or more R;

Each R ^a is independently C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ heteroalkyl, C ₂-C₆ alkenyl, C ₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkyl (cycloalkyl), C ₁-C₆ alkyl (heterocycloalkyl), C ₁-C₆ alkyl (aryl), or C ₁-C₆ alkyl (heteroaryl), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R;

each R ^b is independently hydrogen, C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ heteroalkyl, C ₂-C₆ alkenyl, C ₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkyl (cycloalkyl), C ₁-C₆ alkyl (heterocycloalkyl), C ₁-C₆ alkyl (aryl), or C ₁-C₆ alkyl (heteroaryl), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R;

R ^c and R ^d are each independently hydrogen, C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ heteroalkyl, C ₂-C₆ alkenyl, C ₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkyl (cycloalkyl), C ₁-C₆ alkyl (heterocycloalkyl), C ₁-C₆ alkyl (aryl), or C ₁-C₆ alkyl (heteroaryl), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R;

Or R ^c and R ^d together with the atoms to which they are attached to form heterocycloalkyl optionally substituted with one or more R; and

Each R is independently halogen 、-CN、-OH、-OCH₃、-S(＝O)CH₃、-S(＝O)₂CH₃、-S(＝O)₂NH₂、-S(＝O)₂NHCH₃、-S(＝O)₂N(CH₃)₂、-NH₂、-NHCH₃、-N(CH₃)₂、-C(＝O)CH₃、-C(＝O)OH、-C(＝O)OCH₃、C₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ aminoalkyl, and C ₁-C₆ heteroalkyl;

Or two R groups on the same atom together to form oxo;

provided that when G is And X is-CN, or G is/>And X is hydrogen; at least one of R ¹¹、R¹² or R ¹⁵ is not hydrogen.

Disclosed herein is a compound of formula (III):

Wherein:

X is hydrogen or-CN;

G is

or two R ^11a on the same atom together to form oxo;

Or two R ^21a on the same atom together to form oxo;

Or two R ^12a on the same atom together to form oxo;

or two R ^22a on the same atom together to form oxo;

R ¹³ is hydrogen or C ₁-C₆ alkyl;

r ¹⁴ is-OH or fluoro;

R ¹⁵ is-C (=o) R ²⁵、-C(＝O)OR²⁵、-CH₂-O-C(＝O)R²⁵ or-CH ₂-O-C(＝O)OR²⁵;

R ²⁵ is C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl) or C ₁-C₆ alkylene (heteroaryl); wherein alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^26a;

Each R ^25a is independently halogen 、-CN、-NO₂、-OH、-OR^a、-OC(＝O)R^a、-OC(＝O)OR^b、-OC(＝O)NR^cR^d、-SH、-SR^a、-S(＝O)R^a、-S(＝O)₂R^a、-S(＝O)₂NR^cR^d、-NR^cR^d、-NR^bC(＝O)NR^cR^d、-NR^bC(＝O)R^a、-NR^bC(＝O)OR^b、-NR^bS(＝O)₂R^a、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ heteroalkyl, C ₂-C₆ alkenyl, C ₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Or two R ^25a on the same atom together to form oxo;

R ¹⁶ is hydrogen, -C (=o) R ²⁶、-C(＝O)OR²⁶、-CH₂-O-C(＝O)R²⁶、-CH₂-O-C(＝O)OR²⁶ or C ₁-C₆ alkyl optionally substituted by one or more R ^16a;

Each R ^16a is independently halogen, -CN, -OH, -OR ^a、-NR^cR^d, cycloalkyl OR heterocycloalkyl;

or two R ^16a on the same atom together to form oxo;

R ²⁶ is C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^26a;

each R ^26a is independently halogen 、-CN、-NO₂、-OH、-OR^a、-OC(＝O)R^a、-OC(＝O)OR^b、-OC(＝O)NR^cR^d、-S(＝O)R^a、-S(＝O)₂R^a、-S(＝O)₂NR^cR^d、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ heteroalkyl, C ₂-C₆ alkenyl, C ₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R;

or two R ^26a on the same atom together to form oxo;

or two R ^26a taken together to form cycloalkyl or heterocycloalkyl; each of which is optionally and independently substituted with one or more R;

Or two R groups on the same atom together to form oxo;

provided that when G is And X is hydrogen; at least one of R ¹¹、R¹² or R ¹⁶ is not hydrogen.

Also disclosed herein is a compound of formula (IV):

Wherein:

X is hydrogen or-CN;

G is

R ¹² is-C (=o) R ²²、-C(＝O)OR²² or C ₁-C₆ alkyl optionally substituted by one or more R ^12a;

Or two R ^12a on the same atom together to form oxo;

or two R ^22a on the same atom together to form oxo;

R ¹³ is hydrogen or C ₁-C₆ alkyl;

r ¹⁴ is-OH or fluoro;

Or two R ^25a on the same atom together to form oxo;

Or two R groups on the same atom together to form oxo.

Also disclosed herein is a compound of formula (V):

Wherein:

X is hydrogen or-CN;

G is

Or two R ^12a on the same atom together to form oxo;

or two R ^22a on the same atom together to form oxo;

R ¹³ is hydrogen or C ₁-C₆ alkyl;

r ¹⁴ is-OH or fluoro;

r ¹⁵ is hydrogen, -C (=o) R ²⁵、-C(＝O)OR²⁵、-CH₂-O-C(＝O)R²⁵ or-CH ₂-O-C(＝O)OR²⁵;

Or two R ^25a on the same atom together to form oxo;

R ¹⁶ is-C (=o) R ²⁶、-C(＝O)OR²⁶、-CH₂-O-C(＝O)R²⁶、-CH₂-O-C(＝O)OR²⁶ or C ₁-C₆ alkyl optionally substituted by one or more R ^16a;

or two R ^16a on the same atom together to form oxo;

or two R ^26a on the same atom together to form oxo;

Or two R groups on the same atom together to form oxo.

Also disclosed herein is a compound of formula (VIa), (VIb), or (VIc), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

/>

Wherein:

X is hydrogen or-CN;

Or two R ^12a on the same atom together to form oxo;

or two R ^22a on the same atom together to form oxo;

R ¹³ is hydrogen or C ₁-C₆ alkyl;

r ¹⁴ is-OH or fluoro;

Or two R ^25a on the same atom together to form oxo;

or two R ^16a on the same atom together to form oxo;

or two R ^26a on the same atom together to form oxo;

Or two R groups on the same atom together to form oxo.

Disclosed herein are pharmaceutical compositions comprising a compound of any one of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II), (III), (IV), (V), (VIa), (VIb) and (VIc), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and at least one pharmaceutically acceptable carrier.

Disclosed herein are methods of treating a viral infection comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition disclosed herein, and at least one pharmaceutically acceptable carrier.

In some embodiments, the method further comprises administering at least one antiviral agent in combination with a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition disclosed herein and at least one pharmaceutically acceptable carrier. In some embodiments, the compound or pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the pharmaceutical composition and the at least one antiviral agent are administered simultaneously, about simultaneously, or sequentially in any order. In some embodiments, the compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the pharmaceutical composition and the at least one antiviral agent are administered simultaneously or about simultaneously. In some embodiments, the compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the pharmaceutical composition and at least one antiviral agent are administered sequentially. In some embodiments, the compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the pharmaceutical composition is administered prior to the at least one antiviral agent. In some embodiments, the compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the pharmaceutical composition is administered after at least one antiviral agent.

In some embodiments, the viral infection is caused by a virus selected from the group consisting of: coronavirus disease 2019 (SARS-CoV-2), yellow fever, eastern equine encephalitis virus, human Immunodeficiency Virus (HIV), "african swine fever virus", arboviridae, adenoviridae, arenaviridae, arterivirus, astroviridae, rhabdoviridae, sinviridae, biglyaviridae, bunyaviridae, calicivviridae, cauliflower viridae, circoviridae, coronaviridae, vesicular phage, ebola virus, delta viridae, filoviridae, flaviviridae, iridoviridae, mononegavirales, myotail phage, papilloma virus, papovaviridae, paramyxoviridae, prions, parvoviridae, algae deoxyriboviridae, poxviridae, potyviridae, reoviridae, sinoviridae, retrovirus, multilayer phage, togaviridae, poxviridae, papilloma, coronavirus, influenza, sendai virus (SeV), sindbis virus, han virus, western poxvirus, common cold of any combination thereof. In some embodiments, the compound or pharmaceutically acceptable salt, solvate or stereoisomer thereof or the pharmaceutical composition is administered systemically by intravenous, subcutaneous, intramuscular, oral or by inhalation.

In some embodiments, the at least one antiviral agent is adefovir, ribavirin, famprivir, T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, ST-193, iodate, edestin, trifluoretoside, vidarabine, brivudine, acyclovir, ganciclovir, valganciclovir, cidofovir, valganciclovir, penciclovir, zidovudine, didanosine, zalcitabine, stavudine, abacavir, lamivudine, emtricitabine, tenofovir disoproxil fumarate, tenofovir alafenamide, adefovir, entecavir, telbivudine, sofosbuvir, or a mixture thereof.

In some embodiments, the at least one antiviral agent is Mo Nuola.

In some embodiments, the at least one antiviral agent is a ribonucleic acid (RNA) -dependent RNA polymerase inhibitor, a checkpoint inhibitor or a PD-1/PD-L1 inhibitor, a therapeutic vaccine, an RNA interference (RNAi) therapeutic, an antisense-based therapeutic, a coronavirus entry inhibitor, a TLR agonist, a RIG-I agonist, or an interferon.

Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

Also disclosed herein is a method of treating an infection in a subject comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

Also disclosed herein is a method of treating an infection in a subject comprising administering to the subject a pharmaceutical composition disclosed herein.

In some embodiments, the infection is a viral infection.

In some embodiments, the infection is caused by SARS-CoV or SARS-CoV-2 virus.

In some embodiments, the infection is COVID or COVID-19.

In some embodiments, the method further comprises administering an additional therapeutic agent for treating a coronavirus infection.

In some embodiments, the additional therapeutic agent for treating a coronavirus infection is an RNA-dependent RNA polymerase inhibitor; checkpoint inhibitors (PD-1/PD-L1 inhibitors); a therapeutic vaccine; RNA interference (RNAi) therapeutics; coronavirus entry inhibitors based on antisense therapeutics; TLR agonists; RIG-I agonists or interferons.

Incorporation by reference

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

Detailed Description

The present disclosure provides compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II), (III), (IV), (V), (VIa), (VIb) and (VIc), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, for use in the treatment of viral infections. The present disclosure provides a method of preventing, treating and controlling various viral infections caused by viruses selected from the group consisting of: coronavirus disease 2019 (COVID-19), zika virus, dengue fever, yellow fever, west nile virus, hendra virus, newcastle disease, venezuelan equine encephalitis, chikungunya Gu Niya fever, semliki forest virus, sindbis virus, avian influenza A, porcine reproductive and respiratory syndrome, human immunodeficiency virus type 1, equine herpes virus type 1, pseudorabies virus, BK polyoma virus, and porcine circovirus type 2. The present disclosure also provides a method of preventing, treating and controlling various viral infections caused by viruses selected from the group consisting of: coronavirus disease 2019 (COVID-19), yellow fever, eastern equine encephalitis virus, human Immunodeficiency Virus (HIV), "african swine fever virus", arboviridae, adenoviridae, arenaviridae, arterivirus, astroviridae, rhabdoviridae, biglyrnaviridae, bunyaviridae, calicivviridae, cauliflower viridae, circoviridae, coronaviridae, vesicular phage, ebola virus, delta viridae, filoviridae, flaviviridae, iridoviridae, mononegavirales, myotail phage, papilloma virus, papovaviridae, paramyxoviridae, prions, parvoviridae, algal deoxyriboviridae, poxviridae, potyviridae, reoviridae, retrovirus, rhabdoviridae, multilayer phage, poxviridae, papova, papilloma, coronavirus, influenza, sendai virus (SeV), sindbis virus, han virus, western poxvirus, common cold of any combination thereof.

Adefovir contains a single phosphoramidate substituent which is extensively metabolized via first pass metabolism and inhibits oral delivery of the active metabolite (Siegel, d., hui, h.c., doerffler, e., clarke, m.o., chun, k., zhang, l., neville, s, carra, e., lew, w, ross, b. et al (2017).Discovery and Synthesis of a Phosphoramidate Prodrug of aPyrrolo[2,1-f][triazin-4-amino]Adenine C-Nucleoside(GS-5734)for the Treatment of Ebola and Emerging Viruses.J Med Chem 60,1648-1661)., after intravenous Injection (IV), rapidly hydrolyzes (T _1/2 for about 1 hour) to alanine-substituted metabolite GS-704277 of adefovir in the active parent GS-441524 prior to release of the parent compound GS-441524 exhibits poor oral bioavailability (F% = 4.8%) in rats, and is expected to exhibit low oral bioavailability in humans (Li, y, cao, l., li, g, cong, F, li, y, sun, j, luo, y, chen, g, li, g, wang, p. et al (2021).Remdesivir Metabolite GS-441524Effectively Inhibits SARS-CoV-2Infection in Mouse Models.J Med Chem,ASAP). prolonged half-life in plasma of GS-441524 (T1/2 about 24.5 hours) after IV administration and its potent antiviral activity against SARS-CoV-2 in vitro and in vivo, indicate that optimizing the oral absorption properties of GS-441524 is an attractive strategy for developing antiviral therapies for SARS-CoV-2 (Jorgensen, s.c. j., kebriaei, r. and Dresser,L.D.(2020).Remdesivir:Review of Pharmacology,Pre-clinical Data,and Emerging Clinical Experience for COVID-19.Pharmacotherapy 40,659-671).

There remains a need for novel antiviral nucleosides with improved oral bioavailability for the treatment of coronavirus infections. An oral nucleoside analog for treating SARS-CoV-2 infection (as well as other coronavirus and new/recurrent virus infections, including Ebola virus infections) can play a key role in promoting post-exposure prophylaxis in unvaccinated and immunosuppressed individuals. Oral SARS-CoV-2 antiviral drugs also play an important role in the treatment of indicated cases during the early stages of pre-hospital infection.

Definition of the definition

In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, it will be understood by those skilled in the art that the present invention may be practiced without these specific details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Throughout the specification and the claims which follow, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising" will be interpreted in an open, inclusive sense, i.e. "including but not limited to. Furthermore, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

Reference throughout this specification to "some embodiments" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrase "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Furthermore, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. It should also be noted that the term "or" is generally employed in its sense including "and/or" unless the content clearly dictates otherwise.

As used herein, the following terms have the following meanings, unless otherwise indicated:

As used herein, the term "about" in the context of a given value or range refers to a value that is within 10% of the given value or range.

As used herein, the term "and/or" should be taken to be a specific disclosure of each of the two specified features or components, including or excluding the other. For example, "a and/or B" is considered a specific disclosure of each of (i) a, (ii) B, and (iii) a and B, as if each were individually set forth herein.

As used herein, the terms "a" or "an" when used in conjunction with the term "comprising" in the claims and/or specification may mean "one or more," at least one "and" one or more than one "but are also consistent with the meaning of" one or more than one, "" at least one, "" one or more than one. Similarly, the word "another/another" may mean at least a second/second or more/more.

"Oxo" refers to = O, an oxygen with a double bond attached to an atom such as carbon.

"Alkyl" refers to straight or branched chain saturated hydrocarbon monoradicals having from one to about ten carbon atoms, more preferably from one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-dimethyl-1-butyl, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, Isopentyl, neopentyl, tertiary pentyl and hexyl, and longer alkyl groups such as heptyl, octyl, and the like. Whenever present herein, a numerical range such as "C ₁-C₆ alkyl" or "C _1-6 alkyl" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the definition of the invention also covers the occurrence of the term "alkyl" where a numerical range is not specified. In some embodiments, the alkyl is a C _1-10 alkyl. In some embodiments, the alkyl is a C _1-6 alkyl. In some embodiments, the alkyl is a C _1-5 alkyl. In some embodiments, the alkyl is a C _1-4 alkyl. In some embodiments, the alkyl is a C _1-3 alkyl. In some embodiments, the alkyl is a C _10-15 alkyl. In some embodiments, the alkyl is a C _16-20 alkyl. Unless specifically stated otherwise in the specification, an alkyl group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, carboxylic acid, ester, alkoxy, arylalkoxy, aryloxy, heteroarylalkoxy, cycloalkoxy, or cycloalkylalkoxy. In some embodiments, the alkyl group is optionally substituted with one or more-O-groups interposed between two adjacent carbon atoms at one or more positions along the alkyl chain. In some embodiments, alkyl is optionally substituted with oxo, halogen, -CN, -OH, -OMe, -NH ₂, or-NO ₂. In some embodiments, alkyl is optionally substituted with halogen, -CN, -OH, or-OMe. In some embodiments, the alkyl group is optionally substituted with halo.

"Alkenyl" refers to a straight or branched hydrocarbon mono-radical having one or more carbon-carbon double bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. The group may be in cis or trans conformation with respect to the double bond and should be understood to include both isomers. Examples include, but are not limited to, vinyl (-ch=ch ₂), 1-propenyl (-CH ₂CH＝CH₂), isopropenyl [ -C (CH ₃)＝CH₂), butenyl, 1, 3-butadienyl, and the like, whenever appearing herein, a numerical range such as "C ₂-C₆ alkenyl" or "C _2-6 alkenyl" means that an alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the definition of the present invention also covers the appearance of the term "alkenyl" without a specified numerical range unless specifically stated otherwise in the specification, an alkenyl group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.

"Alkynyl" refers to a straight or branched hydrocarbon mono-radical having one or more carbon-carbon triple bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl, and the like. Whenever present herein, a numerical range such as "C ₂-C₆ alkynyl" or "C _2-6 alkynyl" means that an alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the definition of the invention also covers the occurrence of the term "alkynyl" without specifying a numerical range. Unless specifically stated otherwise in the specification, alkynyl groups may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkynyl is optionally substituted with oxo, halogen, -CN, -OH, -OMe, -NH ₂, or-NO ₂. In some embodiments, alkynyl is optionally substituted with halogen, -CN, -OH, or-OMe. In some embodiments, alkynyl is optionally substituted with halo.

"Alkylene" means a straight or branched divalent hydrocarbon chain. Unless specifically stated otherwise in the specification, alkylene groups may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with oxo, halogen, -CN, -OH, -OMe, -NH ₂, or-NO ₂. In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or-OMe. In some embodiments, the alkylene is optionally substituted with halo.

"Alkoxy" refers to a radical of formula-OR _a, wherein R _a is an alkyl radical as defined. Unless specifically stated otherwise in the specification, an alkoxy group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy group is optionally substituted with halogen, -CN, -OH, -OMe, -NH ₂, or-NO ₂. In some embodiments, the alkoxy group is optionally substituted with halogen, -CN, -OH, or-OMe. In some embodiments, the alkoxy group is optionally substituted with halogen.

"Aryl" refers to free radicals derived from hydrocarbon ring systems containing from 6 to 30 carbon atoms and at least one aromatic ring. Aryl radicals may be monocyclic, bicyclic, tricyclic or tetracyclic, which may include fused ring systems (when fused to cycloalkyl or heterocycloalkyl rings, aryl groups are bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6 to 10 membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, those derived from anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene,Aryl radicals of hydrocarbon ring systems of fluoranthene, fluorene, asymmetric indacene, symmetric indacene, indane, indene, naphthalene, phenalene, phenanthrene, obsidiene, pyrene and benzophenanthrene. Unless specifically stated otherwise in the specification, aryl groups may be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF ₃、-OH、-OMe、-NH₂, or-NO ₂. In some embodiments, aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF ₃, -OH, or-OMe. In some embodiments, aryl is optionally substituted with halo.

"Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocycle which may include fused ring systems (cycloalkyl being bonded through a non-aromatic ring atom when fused to an aryl or heteroaryl ring) or bridged ring systems. In some embodiments, cycloalkyl groups are fully saturated. Representative cycloalkyl groups include, but are not limited to, cycloalkyl groups having three to fifteen carbon atoms (C ₃-C₁₅ cycloalkyl), three to ten carbon atoms (C ₃-C₁₀ cycloalkyl), three to eight carbon atoms (C ₃-C₈ cycloalkyl), three to six carbon atoms (C ₃-C₆ cycloalkyl), three to five carbon atoms (C ₃-C₅ cycloalkyl), or three to four carbon atoms (C ₃-C₄ cycloalkyl). In some embodiments, cycloalkyl is 3 to 10 membered cycloalkyl. In some embodiments, cycloalkyl is 3 to 6 membered cycloalkyl. In some embodiments, cycloalkyl is 5-to 6-membered cycloalkyl. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl, decalinyl, bicyclo [3.3.0] octane, bicyclo [4.3.0] nonane, cis-decalin, trans-decalin, bicyclo [2.1.1] hexane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane, and bicyclo [3.3.2] decane, and 7, 7-dimethyl-bicyclo [2.2.1] heptyl. Partially saturated cycloalkyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless specifically stated otherwise in the specification, cycloalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF ₃、-OH、-OMe、-NH₂, or-NO ₂. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF ₃, -OH, or-OMe. In some embodiments, cycloalkyl is optionally substituted with halo.

"Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, the halogen is fluoro or chloro. In some embodiments, the halogen is fluoro.

"Haloalkyl" means an alkyl radical as defined above substituted with one or more halo radicals as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2-trifluoroethyl, 1, 2-difluoroethyl, 3-bromo-2-fluoropropyl, 1, 2-dibromoethyl and the like.

"Heteroatom" or "ring heteroatom" refers to oxygen (O), nitrogen (N), sulfur (S), phosphorus (P) and silicon (Si).

"Heterocycloalkyl" means a 3 to 24 membered partially or fully saturated cyclic radical containing 2 to 23 carbon atoms and one to 8 heteroatoms selected from nitrogen, oxygen, phosphorus and sulfur. In some embodiments, the heterocycloalkyl group is fully saturated. In some embodiments, the heterocycloalkyl group comprises one to three heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl group comprises one to three heteroatoms selected from nitrogen and oxygen. In some embodiments, the heterocycloalkyl group comprises one to three nitrogens. In some embodiments, the heterocycloalkyl group comprises one or two nitrogens. In some embodiments, the heterocycloalkyl group comprises one nitrogen. In some embodiments, the heterocycloalkyl group comprises one nitrogen and one oxygen. Unless specifically stated otherwise in the specification, a heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused ring systems (when fused to an aryl or heteroaryl ring, heterocycloalkyl groups are bonded through non-aromatic ring atoms) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical may optionally be oxidized; the nitrogen atom may optionally be quaternized. Representative heterocycloalkyl groups include, but are not limited to, heterocycloalkyl groups having from two to fifteen carbon atoms (C ₂-C₁₅ heterocycloalkyl), from two to ten carbon atoms (C ₂-C₁₀ heterocycloalkyl), from two to eight carbon atoms (C ₂-C₈ heterocycloalkyl), from two to seven carbon atoms (C ₂-C₇ heterocycloalkyl), from two to six carbon atoms (C ₂-C₆ heterocycloalkyl), from two to five carbon atoms (C ₂-C₅ heterocycloalkyl), or from two to four carbon atoms (C ₂-C₄ heterocycloalkyl). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl [1,3] dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinyl, pyrrolidinyl, pyrazolidinyl, quinolyl, thiazolidinyl, tetrahydrofuranyl, trithiophene, tetrahydropyranyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1, 1-dioxo-thiomorpholinyl, 1, 3-dihydroisobenzofuran-1-yl, 3-oxo-1, 3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1, 3-dioxol-4-yl and 2-oxo-1, 3-dioxol-4-yl. The term heterocycloalkyl also includes all cyclic forms of carbohydrates including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Unless otherwise indicated, heterocycloalkyl groups have 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl group, the number of carbon atoms in the heterocycloalkyl group is different from the total number of atoms (including heteroatoms) that make up the heterocycloalkyl group (i.e., the backbone atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3 to 8 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3 to 7 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3 to 6 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4 to 6 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkyl. Unless specifically indicated otherwise in the specification, heterocycloalkyl groups may be optionally substituted as described below, for example by oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF ₃、-OH、-OMe、-NH₂, or-NO ₂. In some embodiments, heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF ₃, -OH, or-OMe. In some embodiments, the heterocycloalkyl group is optionally substituted with halo.

"Heteroaryl" means a 5 to 14 membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from nitrogen, oxygen, phosphorus and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl group comprises one to three heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group comprises one to three heteroatoms selected from nitrogen and oxygen. In some embodiments, heteroaryl groups comprise one to three nitrogens. In some embodiments, heteroaryl groups comprise one or two nitrogens. In some embodiments, the heteroaryl group comprises one nitrogen. Heteroaryl radicals may be monocyclic, bicyclic, tricyclic or tetracyclic, which may include fused ring systems (heteroaryl groups are bonded through an aromatic ring atom when fused to a cycloalkyl or heterocycloalkyl ring) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may optionally be oxidized; the nitrogen atom may optionally be quaternized. In some embodiments, the heteroaryl is a 5-to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5-to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6 membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl. Examples include, but are not limited to, azepinyl (azepinyl), acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [ b ] [1,4] dioxaheptenyl, 1, 4-benzodioxanyl, benzonaphtalenofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothienyl) (benzothienyl (benzothiophenyl)) Benzotriazolyl, benzo [4,6] imidazo [1,2-a ] pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-pyrimidyl oxide, 1-oxopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, Purinyl, pyrrolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thienyl (thiophenyl) (i.e., thienyl (thienyl)). Unless specifically stated otherwise in the specification, heteroaryl groups may be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF ₃、-OH、-OMe、-NH₂, or-NO ₂. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF ₃, -OH, or-OMe. In some embodiments, heteroaryl is optionally substituted with halo.

The term "alkylarylene" refers to an arylene moiety (also referred to herein as an alkylene linker) covalently bonded to an alkylene moiety. In some embodiments, the alkylarylene group has the formula:

The alkylarylene moiety may be substituted (e.g., with a substituent) on the alkylene moiety or arylene linker (e.g., on carbon 2, 3, 4, or 6) with a halogen, oxo 、-N₃、-CF₃、-CCl₃、-CBr₃、-CI₃、-CN、-CHO、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₂CH₃、-SO₃H、-OSO₃H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、 substituted or unsubstituted C ₁-C₅ alkyl, or a substituted or unsubstituted 2-to 5-membered heteroalkyl. In some embodiments, the alkylarylene group is unsubstituted.

Each of the above terms (e.g., "alkyl," "heteroalkyl," "cycloalkyl," "heterocycloalkyl," "aryl," and "heteroaryl") includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

Substituents of alkyl and heteroalkyl radicals (including those commonly referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) may be one or more selected from, but not limited to, the following: -OR ', =o, =nr', =n-OR ', -NR' R ', -SR', -halogen 、-SiR'R"R"'、-OC(O)R'、-C(O)R'、-CO₂R'、-CONR'R"、-OC(O)NR'R"、-NR"C(O)R'、-NR'-C(O)NR"R"'、-NR"C(O)₂R'、-NR-C(NR'R"R"')＝NR""、-NR-C(NR'R")＝NR"'、-S(O)R'、-S(O)₂R'、-S(O)₂NR'R"、-NRSO₂R'、-NR'NR"R"'、-ONR'R"、-NR'C(O)NR"NR"'R""、-CN、-NO₂、-NR'SO₂R"、-NR'C(O)R"、-NR'C(O)-OR"、-NR'OR", numbers range from 0 to (2 m '+1), where m' is the total number of carbon atoms in such radicals. R, R ', R ", R'" and R "" each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy or thioalkoxy, or arylalkyl groups. For example, when a compound described herein comprises more than one R group, each R group is independently selected, as are each of the R ', R ", R'" and R "" groups when more than one of these groups is present. When R 'and R' are attached to the same nitrogen atom, they may be combined with the nitrogen atom to form a 4-membered ring, a 5-membered ring, a 6-membered ring, or a 7-membered ring. For example, -NR' R "includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the discussion of the substituents above, those skilled in the art will understand that the term "alkyl" means a group that includes a carbon atom bound to a group other than a hydrogen group, such as haloalkyl (e.g., -CF ₃ and-CH ₂CF₃) and acyl (e.g., -C (O) CH ₃、-C(O)CF₃、-C(O)CH₂OCH₃, etc.).

Similar to the substituents described for alkyl radicals, the substituents for aryl and heteroaryl groups are different and are selected from, for example: -OR ', -NR ' R ', -SR ', -halogen 、-SiR'R"R"'、-OC(O)R'、-C(O)R'、-CO₂R'、-CONR'R"、-OC(O)NR'R"、-NR"C(O)R'、-NR'-C(O)NR"R"'、-NR"C(O)₂R'、-NR-C(NR'R"R"')＝NR""、-NR-C(NR'R")＝NR"'、-S(O)R'、-S(O)₂R'、-S(O)₂NR'R"、-NRSO₂R'、-NR'NR"R"'、-ONR'R"、-NR'C(O)NR"NR"'R""、-CN、-NO₂、-R'、-N₃、-CH(Ph)₂、 fluoro (C ₁-C₄) alkoxy and fluoro (C ₁-C₄) alkyl, -NR ' SO ₂ R ', -NR ' C (O) -OR ', -NR ' OR ', the number ranges from zero to the total number of open valences on the aromatic ring system, and wherein R ', R ", R '" and R ' "preferably independently refer to hydrogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted heteroalkyl, substituted OR unsubstituted cycloalkyl, substituted OR unsubstituted heterocycloalkyl, substituted OR unsubstituted aryl and substituted OR unsubstituted heteroaryl. For example, when a compound described herein comprises more than one R group, each R group is independently selected, as are each of the R ', R ", R'" and R "" groups when more than one of these groups is present.

Substituents on a ring (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be described as substituents on the ring, rather than substituents on a particular atom of the ring (commonly referred to as float substituents). In such cases, a substituent may be attached to any of the ring atoms (following valence rules), and in the case of a fused ring or spiro ring, the substituent described as being associated with one member of the fused ring or spiro ring (a floating substituent on a single ring) may be a substituent on any of the fused ring or spiro ring (a floating substituent on a polycyclic ring). When a substituent is attached to a ring, but is not a specific atom (a floating substituent), and the subscript of the substituent is an integer greater than one, the plurality of substituents may be on the same atom, the same ring, different atoms, different fused rings, different spiro rings, and each substituent may optionally be different. In the case where the point of attachment of the ring to the remainder of the molecule is not limited to a single atom (floating substituent), the point of attachment may be any atom of the ring, and in the case of a fused ring or a spiro ring, any atom of any one of the fused ring or the spiro ring, while adhering to the rule of chemical valence. Where the ring, fused ring, or spiro ring contains one or more ring heteroatoms and the ring, fused ring, or spiro ring is shown to have one or more floating substituents (including but not limited to points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms. In structures or formulas having a floating substituent, where a ring heteroatom is shown as being bound to one or more hydrogens (e.g., a ring nitrogen having two bonds to the ring atom and a third bond to hydrogen), the substituent will be understood to replace hydrogen while observing valence rules when the heteroatom is bound to the floating substituent.

Two or more substituents may optionally combine to form an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group. Such so-called ring-forming substituents are found to be typically (although not necessarily) attached to the cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure produce a spiro ring structure. In yet another embodiment, the ring-forming substituent is attached to a non-adjacent member of the base structure.

Two substituents on adjacent atoms of an aryl or heteroaryl ring may optionally form a ring of the formula-T-C (O) - (CRR ') _q -U-, wherein T and U are independently-NR-, -O-, -CRR' -, or a single bond, and q is an integer from 0 to 3. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with substituents of formula-A- (CH ₂)_r -B-, wherein A and B are independently-CRR ' -stem-alternatively, two substituents on adjacent atoms of an aryl or heteroaryl ring may be optionally replaced by substituents of the formula- (CRR ') _s-X'-(C"R"R"')_d -, wherein S and d are independently integers from 0 to 3, and X ' is-O-, -NR ' -, -S-, -S (O) -, -S (O) ₂ -or-S (O) ₂ NR ' -, the substituents R, R ', R "and R '" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, and aryl, and are preferably substituted or unsubstituted alkyl, aryl, and are preferably substituted or unsubstituted. Substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

The term "amino acid" refers to a molecule that comprises both amino groups and carboxyl groups. Suitable amino acids include, but are not limited to, the D-and L-isomers of naturally occurring amino acids, as well as non-naturally occurring amino acids prepared by organic synthesis or other metabolic pathways. The term amino acid as used herein includes, but is not limited to, alpha-amino acids, natural amino acids, unnatural amino acids, and amino acid analogs.

The term "alpha-amino acid" refers to a molecule comprising both an amino group and a carboxyl group bound to a carbon, which carbon is referred to as an alpha-carbon.

The term "β -amino acid" refers to a molecule that comprises both an amino group and a carboxyl group in the β configuration.

The term "naturally occurring amino acid" refers to any of the twenty amino acids commonly found in naturally synthesized peptides and known by the single letter abbreviations A, R, N, C, D, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y and V.

The following table shows a summary of the nature of the natural amino acids:

/>

"hydrophobic amino acids" include small hydrophobic amino acids and large hydrophobic amino acids. "small hydrophobic amino acids" are glycine, alanine, proline and analogs thereof. "Large hydrophobic amino acids" are valine, leucine, isoleucine, phenylalanine, methionine, tryptophan and the like. "polar amino acids" are serine, threonine, asparagine, glutamine, cysteine, tyrosine and the like. "charged amino acids" are lysine, arginine, histidine, aspartic acid, glutamic acid, and analogs thereof.

The term "amino acid analog" refers to a molecule that is similar in structure to an amino acid and that can substitute for an amino acid in the formation of a peptidomimetic macrocycle. Amino acid analogs include, but are not limited to, β -amino acids and amino acids in which the amino or carboxyl group is substituted with a similarly reactive group (e.g., primary amine is substituted with a secondary or tertiary amine, or the carboxyl group is substituted with an ester).

The term "unnatural amino acid" refers to an amino acid that is not one of the twenty amino acids commonly found in naturally occurring peptides and known by the single letter abbreviations A, R, N, C, D, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y and V. Unnatural amino acids or amino acid analogs include, but are not limited to, structures according to:

/>

Amino acid analogs include β -amino acid analogs. Examples of β -amino acid analogs include, but are not limited to, the following: cyclic beta-amino acid analogs; beta-alanine; (R) - β -phenylalanine; (R) -1,2,3, 4-tetrahydro-isoquinoline-3-acetic acid; (R) -3-amino-4- (1-naphthyl) -butyric acid; (R) -3-amino-4- (2, 4-dichlorophenyl) butanoic acid; (R) -3-amino-4- (2-chlorophenyl) -butyric acid; (R) -3-amino-4- (2-cyanophenyl) -butyric acid; (R) -3-amino-4- (2-fluorophenyl) -butyric acid; (R) -3-amino-4- (2-furyl) -butyric acid; (R) -3-amino-4- (2-methylphenyl) -butyric acid; (R) -3-amino-4- (2-naphthyl) -butyric acid; (R) -3-amino-4- (2-thienyl) -butanoic acid; (R) -3-amino-4- (2-trifluoromethylphenyl) -butyric acid; (R) -3-amino-4- (3, 4-dichlorophenyl) butanoic acid; (R) -3-amino-4- (3, 4-difluorophenyl) butanoic acid; (R) -3-amino-4- (3-benzothienyl) -butyric acid; (R) -3-amino-4- (3-chlorophenyl) -butyric acid; (R) -3-amino-4- (3-cyanophenyl) -butyric acid; (R) -3-amino-4- (3-fluorophenyl) -butyric acid; (R) -3-amino-4- (3-methylphenyl) -butyric acid; (R) -3-amino-4- (3-pyridinyl) -butyric acid; (R) -3-amino-4- (3-thienyl) -butanoic acid; (R) -3-amino-4- (3-trifluoromethylphenyl) -butyric acid; (R) -3-amino-4- (4-bromophenyl) -butyric acid; (R) -3-amino-4- (4-chlorophenyl) -butyric acid; (R) -3-amino-4- (4-cyanophenyl) -butyric acid; (R) -3-amino-4- (4-fluorophenyl) -butyric acid; (R) -3-amino-4- (4-iodophenyl) -butyric acid; (R) -3-amino-4- (4-methylphenyl) -butyric acid; (R) -3-amino-4- (4-nitrophenyl) -butyric acid; (R) -3-amino-4- (4-pyridinyl) -butyric acid; (R) -3-amino-4- (4-trifluoromethylphenyl) -butyric acid; (R) -3-amino-4-pentafluoro-phenylbutyric acid; (R) -3-amino-5-hexenoic acid; (R) -3-amino-5-hexynoic acid; (R) -3-amino-5-phenylpentanoic acid; (R) -3-amino-6-phenyl-5-hexenoic acid; (S) -1,2,3, 4-tetrahydro-isoquinoline-3-acetic acid; (S) -3-amino-4- (1-naphthyl) -butyric acid; (S) -3-amino-4- (2, 4-dichlorophenyl) butanoic acid; (S) -3-amino-4- (2-chlorophenyl) -butyric acid; (S) -3-amino-4- (2-cyanophenyl) -butyric acid; (S) -3-amino-4- (2-fluorophenyl) -butyric acid; (S) -3-amino-4- (2-furyl) -butyric acid; (S) -3-amino-4- (2-methylphenyl) -butyric acid; (S) -3-amino-4- (2-naphthyl) -butyric acid; (S) -3-amino-4- (2-thienyl) -butanoic acid; (S) -3-amino-4- (2-trifluoromethylphenyl) -butyric acid; (S) -3-amino-4- (3, 4-dichlorophenyl) butanoic acid; (S) -3-amino-4- (3, 4-difluorophenyl) butanoic acid; (S) -3-amino-4- (3-benzothienyl) -butyric acid; (S) -3-amino-4- (3-chlorophenyl) -butyric acid; (S) -3-amino-4- (3-cyanophenyl) -butyric acid; (S) -3-amino-4- (3-fluorophenyl) -butyric acid; (S) -3-amino-4- (3-methylphenyl) -butyric acid; (S) -3-amino-4- (3-pyridinyl) -butyric acid; (S) -3-amino-4- (3-thienyl) -butanoic acid; (S) -3-amino-4- (3-trifluoromethylphenyl) -butyric acid; (S) -3-amino-4- (4-bromophenyl) -butyric acid; (S) -3-amino-4- (4-chlorophenyl) -butyric acid; (S) -3-amino-4- (4-cyanophenyl) -butyric acid; (S) -3-amino-4- (4-fluorophenyl) -butyric acid; (S) -3-amino-4- (4-iodophenyl) -butyric acid; (S) -3-amino-4- (4-methylphenyl) -butyric acid; (S) -3-amino-4- (4-nitrophenyl) -butyric acid; (S) -3-amino-4- (4-pyridinyl) -butyric acid; (S) -3-amino-4- (4-trifluoromethylphenyl) -butyric acid; (S) -3-amino-4-pentafluoro-phenylbutyric acid; (S) -3-amino-5-hexenoic acid; (S) -3-amino-5-hexynoic acid; (S) -3-amino-5-phenylpentanoic acid; (S) -3-amino-6-phenyl-5-hexenoic acid; 1,2,5, 6-tetrahydropyridine-3-carboxylic acid; 1,2,5, 6-tetrahydropyridine-4-carboxylic acid; 3-amino-3- (2-chlorophenyl) -propionic acid; 3-amino-3- (2-thienyl) -propionic acid; 3-amino-3- (3-bromophenyl) -propionic acid; 3-amino-3- (4-chlorophenyl) -propionic acid; 3-amino-3- (4-methoxyphenyl) -propionic acid; 3-amino-4, 4-trifluoro-butyric acid; 3-aminoadipic acid; d-beta-phenylalanine; beta-leucine; l-beta-homoalanine; l-beta-homoaspartic acid gamma-benzyl ester; l-beta-homoglutamic acid delta-benzyl ester; l-beta-homoisoleucine; l-beta-homoleucine; l-beta-homomethionine; l-beta-homophenylalanine; l-beta-homoproline; l-beta-homotryptophan; l-beta-homovaline; L-Nω -benzyloxycarbonyl- β -homolysine; n omega-L-beta-homoarginine; O-benzyl-L-beta-homohydroxyproline; O-benzyl-L-beta-homoserine; O-benzyl-L-beta-homothreonine; O-benzyl-L-beta-homotyrosine; gamma-trityl-L-beta-homoasparagine; (R) - β -phenylalanine; l-beta-homoaspartic acid gamma-tert-butyl ester; l-beta-homoglutamic acid delta-tert-butyl ester; L-Nω - β -homolysine; nδ -trityl-L- β -homoglutamine; n omega-2, 4,6, 7-pentamethyl-dihydrobenzofuran-5-sulfonyl-L-beta-homoarginine; O-tert-butyl-L-beta-homohydroxy-proline; O-tert-butyl-L-beta-homoserine; O-tert-butyl-L-beta-homothreonine; O-tert-butyl-L-beta-homotyrosine; 2-aminocyclopentane carboxylic acid; 2-aminocyclohexane carboxylic acid.

Amino acid analogs include analogs of alanine, valine, glycine, or leucine. Examples of amino acid analogs of alanine, valine, glycine, and leucine include, but are not limited to, the following: alpha-methoxy glycine; alpha-allyl-L-alanine; alpha-aminoisobutyric acid; alpha-methyl-leucine; beta- (1-naphthyl) -D-alanine; beta- (1-naphthyl) -L-alanine; beta- (2-naphthyl) -D-alanine; beta- (2-naphthyl) -L-alanine; beta- (2-pyridyl) -D-alanine; beta- (2-pyridyl) -L-alanine; beta- (2-thienyl) -D-alanine; beta- (2-thienyl) -L-alanine; beta- (3-benzothienyl) -D-alanine; beta- (3-benzothienyl) -L-alanine; beta- (3-pyridyl) -D-alanine; beta- (3-pyridyl) -L-alanine; beta- (4-pyridyl) -D-alanine; beta- (4-pyridyl) -L-alanine; beta-chloro-L-alanine; beta-cyano-L-alanine; beta-cyclohexyl-D-alanine; beta-cyclohexyl-L-alanine; beta-cyclopenten-1-yl-alanine; beta-cyclopentyl-alanine; beta-cyclopropyl-L-Ala-OH dicyclohexylammonium salt; beta-tert-butyl-D-alanine; beta-tert-butyl-L-alanine; gamma-aminobutyric acid; l- α, β -diaminopropionic acid; 2, 4-dinitro-phenylglycine; 2, 5-dihydro-D-phenylglycine; 2-amino-4, 4-trifluoro-butyric acid; 2-fluoro-phenylglycine; 3-amino-4, 4-trifluoro-butyric acid; 3-fluoro-valine; 4, 4-trifluoro-valine; 4, 5-dehydro-L-leu-OH dicyclohexylammonium salt; 4-fluoro-D-phenylglycine; 4-fluoro-L-phenylglycine; 4-hydroxy-D-phenylglycine; 5, 5-trifluoro-leucine; 6-aminocaproic acid; cyclopentyl-D-Gly-OH dicyclohexylammonium salt; cyclopentyl-Gly-OH dicyclohexylammonium salt; d- α, β -diaminopropionic acid; d-alpha-aminobutyric acid; d-alpha-tert-butylglycine; d- (2-thienyl) glycine; d- (3-thienyl) glycine; d-2-aminocaproic acid; d-2-indanyl glycine; d-allyl glycine dicyclohexylammonium salt; d-cyclohexylglycine; d-norvaline; d-phenylglycine; beta-aminobutyric acid; beta-aminoisobutyric acid; (2-bromophenyl) glycine; (2-methoxyphenyl) glycine; (2-methylphenyl) glycine; (2-thiazolyl) glycine; (2-thienyl) glycine; 2-amino-3- (dimethylamino) -propionic acid; l- α, β -diaminopropionic acid; l-alpha-aminobutyric acid; l-alpha-tert-butylglycine; l- (3-thienyl) glycine; l-2-amino-3- (dimethylamino) -propionic acid; -dicyclohexyl-ammonium L-2-aminocaproate salt; l-2-indanyl glycine; l-allyl glycine dicyclohexylammonium salt; l-cyclohexylglycine; l-phenylglycine; l-propargylglycine; l-norvaline; n- α -aminomethyl-L-alanine; d- α, γ -diaminobutyric acid; l-alpha, gamma-diaminobutyric acid; beta-cyclopropyl-L-alanine; (N- β - (2, 4-dinitrophenyl)) -L- α, β -diaminopropionic acid; (N- β -1- (4, 4-dimethyl-2, 6-dioxocyclohex-1-ylidene) ethyl) -D- α, β -diaminopropionic acid; (N- β -1- (4, 4-dimethyl-2, 6-dioxocyclohex-1-ylidene) ethyl) -L- α, β -diaminopropionic acid; (N-beta-4-methyltrityl) -L-alpha, beta-diaminopropionic acid; (N- β -allyloxycarbonyl) -L- α, β -diaminopropionic acid; (N- γ -1- (4, 4-dimethyl-2, 6-dioxocyclohex-1-ylidene) ethyl) -D- α, γ -diaminobutyric acid; (N- γ -1- (4, 4-dimethyl-2, 6-dioxocyclohex-1-ylidene) ethyl) -L- α, γ -diaminobutyric acid; (N- γ -4-methyltrityl) -D- α, γ -diaminobutyric acid; (N- γ -4-methyltrityl) -L- α, γ -diaminobutyric acid; (N- γ -allyloxycarbonyl) -L- α, γ -diaminobutyric acid; d- α, γ -diaminobutyric acid; 4, 5-dehydro-L-leucine; cyclopentyl-D-Gly-OH; cyclopentyl-Gly-OH; d-allyl glycine; d-homocyclohexylalanine; l-1-pyrenylalanine; l-2-aminocaproic acid; l-allylglycine; l-homocyclohexylalanine; n- (2-hydroxy-4-methoxy-Bzl) -Gly-OH.

Amino acid analogs include analogs of arginine or lysine. Examples of amino acid analogs of arginine and lysine include, but are not limited to, the following: citrulline; l-2-amino-3-guanidinopropionic acid; l-2-amino-3-ureido propionic acid; l-citrulline; lys (Me) ₂-OH;Lys(N₃) -OH; n delta-benzyloxycarbonyl-L-ornithine; n omega-nitro-D-arginine; n omega-nitro-L-arginine; alpha-methyl-ornithine; 2, 6-diaminopimelic acid; l-ornithine; (nδ -1- (4, 4-dimethyl-2, 6-dioxo-cyclohex-1-ylidene) ethyl) -D-ornithine; (nδ -1- (4, 4-dimethyl-2, 6-dioxo-cyclohex-1-ylidene) ethyl) -L-ornithine; (N delta-4-methyltrityl) -D-ornithine; (N delta-4-methyltrityl) -L-ornithine; d-ornithine; l-ornithine; arg (Me) (Pbf) -OH; arg (Me) ₂ -OH (asymmetric); arg (Me) ₂ -OH (symmetrical); lys (ivDde) -OH; lys (Me) ₂-OH·HCl;Lys(Me₃) -OH chloride; n omega-nitro-D-arginine; n omega-nitro-L-arginine.

Amino acid analogs include analogs of aspartic acid or glutamic acid. Examples of amino acid analogs of aspartic acid and glutamic acid include, but are not limited to, the following: alpha-methyl-D-aspartic acid; alpha-methyl-glutamic acid; alpha-methyl-L-aspartic acid; gamma-methylene-glutamic acid; (N- γ -ethyl) -L-glutamine; [ N- α - (4-aminobenzoyl) ] -L-glutamic acid; 2, 6-diaminopimelic acid; l-alpha-amino suberic acid; d-2-aminoadipic acid; d- α -amino suberic acid; alpha-aminopimelic acid; iminodiacetic acid; l-2-aminoadipic acid; threo) - β -methyl-aspartic acid; gamma-carboxy-D-glutamic acid gamma, gamma-di-tert-butyl ester; gamma-carboxy-L-glutamic acid gamma, gamma-di-tert-butyl ester; glu (OAll) -OH; L-Asu (OtBu) -OH; pyroglutamic acid.

Amino acid analogs include analogs of cysteine and methionine. Examples of amino acid analogs of cysteine and methionine include, but are not limited to, cys (farnesyl) -OH, cys (farnesyl) -OMe, alpha-methyl-methionine, cys (2-hydroxyethyl) -OH, cys (3-aminopropyl) -OH, 2-amino-4- (ethylsulfanyl) butyric acid, butylsulfanilide, methionine methyl sulfonium chloride, selenomethionine, cysteine, [2- (4-pyridyl) ethyl ] -DL-penicillamine, [2- (4-pyridyl) ethyl ] -L-cysteine, 4-methoxybenzyl-D-penicillamine, 4-methoxybenzyl-L-penicillamine 4-methylbenzyl-D-penicillamine, 4-methylbenzyl-L-penicillamine, benzyl-D-cysteine, benzyl-L-cysteine, benzyl-DL-homocysteine, carbamoyl-L-cysteine, carboxyethyl-L-cysteine, carboxymethyl-L-cysteine, diphenylmethyl-L-cysteine, ethyl-L-cysteine, methyl-L-cysteine, tert-butyl-D-cysteine, trityl-L-homocysteine, trityl-D-penicillamine, cystathionine, homocysteine, L-homocysteine, (2-aminoethyl) -L-cysteine, seleno-L-cystine, cystathionine, cys (StBu) -OH and acetamidomethyl-D-penicillamine.

Amino acid analogs include analogs of phenylalanine and tyrosine. Examples of amino acid analogs of phenylalanine and tyrosine include beta-methyl-phenylalanine, beta-hydroxyphenylalanine, alpha-methyl-3-methoxy-DL-phenylalanine, alpha-methyl-D-phenylalanine, alpha-methyl-L-phenylalanine, 1,2,3, 4-tetrahydroisoquinoline-3-carboxylic acid, 2, 4-dichloro-phenylalanine, 2- (trifluoromethyl) -D-phenylalanine, 2- (trifluoromethyl) -L-phenylalanine, 2-bromo-D-phenylalanine, 2-bromo-L-phenylalanine, 2-chloro-D-phenylalanine, 2-chloro-L-phenylalanine, 2-cyano-D-phenylalanine, 2-cyano-L-phenylalanine, 2-fluoro-D-phenylalanine, 2-fluoro-L-phenylalanine, 2-methyl-D-phenylalanine, 2-methyl-L-phenylalanine, 2-nitro-D-phenylalanine, 2-nitro-L-phenylalanine, 2,4, 5-trihydroxy-phenylalanine, 3,4, 5-trifluoro-D-phenylalanine, 3,4, 5-trifluoro-L-phenylalanine, 3, 4-dichloro-D-phenylalanine, 3, 4-dichloro-L-phenylalanine, 3, 4-difluoro-D-phenylalanine, 3, 4-difluoro-L-phenylalanine, 3, 4-dihydroxy-L-phenylalanine, 3, 4-dimethoxy-L-phenylalanine, 3,5,3' -triiodo-L-thyronine, 3, 5-diiiodo-D-tyrosine, 3, 5-diiiodo-L-thyronine, 3- (trifluoromethyl) -D-phenylalanine, 3- (trifluoromethyl) -L-phenylalanine, 3-amino-L-tyrosine, 3-bromo-D-phenylalanine, 3-bromo-L-phenylalanine, 3-chloro-D-phenylalanine, 3-chloro-L-tyrosine, 3-cyano-D-phenylalanine, 3-cyano-L-phenylalanine, 3-fluoro-D-phenylalanine, 3-fluoro-L-phenylalanine, 3-fluoro-tyrosine, 3-iodo-D-phenylalanine, 3-iodo-L-tyrosine, 3-methoxy-L-tyrosine, 3-methyl-D-phenylalanine, 3-methyl-L-phenylalanine, 3-nitro-D-phenylalanine, 3-nitro-L-tyrosine, 4- (trifluoromethyl) -D-phenylalanine, 4- (trifluoromethyl) -L-phenylalanine, 4-amino-D-phenylalanine, 4-amino-L-phenylalanine, 4-benzoyl-D-phenylalanine, 4-benzoyl-L-phenylalanine, 4-bis (2-chloroethyl) amino-L-phenylalanine, 4-bromo-D-phenylalanine, 4-bromo-L-phenylalanine, 4-chloro-D-phenylalanine, 4-chloro-L-phenylalanine, 4-cyano-D-phenylalanine, 4-cyano-L-phenylalanine, 4-fluoro-D-phenylalanine, 4-fluoro-L-phenylalanine, 4-iodo-D-phenylalanine, 4-iodo-L-phenylalanine, homophenylalanine, thyronine, 3-diphenylalanine, thyronine, ethyl-tyrosine and methyl-tyrosine.

Amino acid analogs include analogs of proline. Examples of amino acid analogs of proline include, but are not limited to, 3, 4-dehydro-proline, 4-fluoro-proline, cis-4-hydroxy-proline, thiazolidine-2-carboxylic acid and trans-4-fluoro-proline.

Amino acid analogs include analogs of serine and threonine. Examples of amino acid analogs of serine and threonine include, but are not limited to, 3-amino-2-hydroxy-5-methylhexanoic acid, 2-amino-3-hydroxy-4-methylpentanoic acid, 2-amino-3-ethoxybutanoic acid, 2-amino-3-methoxybutanoic acid, 4-amino-3-hydroxy-6-methylheptanoic acid, 2-amino-3-benzyloxypropionic acid, 2-amino-3-ethoxypropionic acid, 4-amino-3-hydroxybutyric acid, and α -methylserine.

Amino acid analogs include analogs of tryptophan. Examples of amino acid analogs of tryptophan include, but are not limited to, the following: alpha-methyl-tryptophan; beta- (3-benzothienyl) -D-alanine; beta- (3-benzothienyl) -L-alanine; 1-methyl-tryptophan; 4-methyl-tryptophan; 5-benzyloxy-tryptophan; 5-bromo-tryptophan; 5-chloro-tryptophan; 5-fluoro-tryptophan; 5-hydroxy-tryptophan; 5-hydroxy-L-tryptophan; 5-methoxy-tryptophan; 5-methoxy-L-tryptophan; 5-methyl-tryptophan; 6-bromo-tryptophan; 6-chloro-D-tryptophan; 6-chloro-tryptophan; 6-fluoro-tryptophan; 6-methyl-tryptophan; 7-benzyloxy-tryptophan; 7-bromo-tryptophan; 7-methyl-tryptophan; d-1,2,3, 4-tetrahydro-desmethyl Ha Erming base-3-carboxylic acid; 6-methoxy-1, 2,3, 4-tetrahydrodemethyl Ha Erming base-1-carboxylic acid; 7-azatryptophan; l-1,2,3, 4-tetrahydro-desmethyl Ha Erming base-3-carboxylic acid; 5-methoxy-2-methyl-tryptophan; 6-chloro-L-tryptophan.

In some embodiments, the amino acid analog is racemic. In some embodiments, the D isomer of the amino acid analog is used. In some embodiments, the L isomer of the amino acid analog is used. In other embodiments, the amino acid analog comprises a chiral center in the R or S configuration. In other embodiments, the amino group of the β -amino acid analog is substituted with a protecting group, such as t-butoxycarbonyl (BOC group), 9-Fluorenylmethoxycarbonyl (FMOC), tosyl, and the like. In still other embodiments, the carboxylic acid functionality of the β -amino acid analog is protected, for example, as an ester derivative thereof. In some embodiments, salts of amino acid analogs are used.

The term "amino acid side chain" refers to a moiety attached to the alpha-carbon (or another backbone atom) in an amino acid. For example, the amino acid side chain of alanine is methyl, the amino acid side chain of phenylalanine is benzyl, the amino acid side chain of cysteine is thiomethyl, the amino acid side chain of aspartic acid is carboxymethyl, the amino acid side chain of tyrosine is 4-hydroxyphenylmethyl, and so forth. Other non-naturally occurring amino acid side chains are also included, for example, those that occur naturally (e.g., amino acid metabolites) or those that are synthetically prepared (e.g., alpha disubstituted amino acids).

Certain compounds of the present disclosure have asymmetric carbon atoms (optical or chiral centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms and individual isomers, which may be defined in terms of absolute stereochemistry as (R) -or (S) -or as (D) -or (L) -of the amino acids, are included within the scope of the present invention. The compounds of the present invention do not include those known in the art that are too unstable to be synthesized and/or isolated. The present invention is meant to include both racemic and optically pure forms of the compounds. Optically active (R) -and (S) -or (D) -and (L) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When a compound described herein contains an olefinic bond or other geometric asymmetric center, and unless specified otherwise, the compound is intended to include both E and Z geometric isomers.

As used herein, the term "isomer" refers to a compound that has the same number and kind of atoms, and therefore the same molecular weight, but differs in the structural arrangement or configuration of the atoms.

As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

It will be apparent to those skilled in the art that certain compounds of the present invention may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the invention.

Unless otherwise indicated, structures described herein that do not explicitly indicate stereochemistry are also meant to include all stereochemical forms of the structure; i.e., the R and S configuration of each asymmetric center. Thus, single stereochemical isomers, as well as mixtures of enantiomers and diastereomers of the compounds of the invention are within the scope of the invention.

Unless otherwise indicated, structures described herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the present invention are within the scope of the present invention, except for replacing hydrogen with deuterium or tritium, or replacing carbon with ¹³ C or ¹⁴ C-enriched carbon.

It should be noted that throughout the application, alternatives are written in markush groups, e.g. comprising more than one possible amino acid per amino acid position. It is specifically contemplated that each member of the markush group should be considered separately to include another embodiment, and that the markush group should not be construed as a single unit.

The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optionally substituted alkyl" refers to "alkyl" or "substituted alkyl" as defined above. Furthermore, the optionally substituted groups may be unsubstituted (e.g., -CH ₂CH₃), fully substituted (e.g., -CF ₂CF₃), monosubstituted (e.g., -CH ₂CH₂ F), or substituted at any level between fully substituted and monosubstituted (e.g., -CH ₂CHF₂、-CH₂CF₃、-CF₂CH₃、-CFHCHF₂, etc.). Those of skill in the art will understand that with respect to any group containing one or more substituents, such groups are not intended to introduce any substitution or pattern of substitution that is sterically impractical and/or synthetically infeasible (e.g., substituted alkyl groups include optionally substituted cycloalkyl groups, which in turn are defined to include optionally substituted alkyl groups, potentially infinite). Thus, any substituent described should generally be understood to have a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.

By "derivative" is meant a compound that retains the biological activity of the parent compound from which it is derived, or a prodrug of the parent compound. Derivatives may include esters, amides, ethers of the parent compound obtained by chemically modifying a portion of the parent compound. For example, a derivative may be a compound in which a hydrogen atom or a certain group of atoms is replaced with another atom or group of atoms.

As used herein, recitation of a numerical range of a variable is intended to convey that the variable is equal to any value within that range. Thus, for an inherently discrete variable, the variable is equal to any integer value within the range of values, including the endpoints of the range. Similarly, for an inherently continuous variable, the variable is equal to any real value within the numerical range, including the endpoints of the range. By way of example and not limitation, a variable is described as having a value between 0 and2, the value 0, 1, or 2 if the variable is inherently discrete, and the value 0.0, 0.1, 0.01, 0.001, or any other real value +.0 and +.2 if the variable is inherently continuous.

As used herein, unless specifically stated otherwise, the word "or" is used in an inclusive sense of "and/or" rather than an exclusive sense of "either/or".

An "effective amount" or "therapeutically effective amount" refers to an amount sufficient for the compound to achieve the stated purpose (e.g., effect its administration, treat a disease, decrease enzymatic activity, increase enzymatic activity, decrease signaling pathways, or decrease one or more symptoms of a disease or disorder) relative to the absence of the compound. An example of an "effective amount" is an amount sufficient to achieve the stated purpose (e.g., achieve the effect of its administration, treat a disease, reduce enzyme activity, increase enzyme activity, decrease signaling pathways, or reduce one or more symptoms of a disease or disorder) relative to the absence of the compound. Another example of an "effective amount" is an amount sufficient to help treat, prevent, or alleviate one or more symptoms of a disease, which may also be referred to as a "therapeutically effective amount". "alleviating" (and grammatical equivalents of the phrase) of one or more symptoms means a reduction in the severity or frequency of the symptoms, or elimination of the symptoms. A "prophylactically effective amount" of a drug is an amount of the drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or recurrence) of a lesion, disease, pathology, or condition, or reducing the likelihood of the onset (or recurrence) of a lesion, disease, pathology, or condition, or symptom thereof. Complete prophylactic action does not necessarily occur by administration of one dose, and may only occur after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. As used herein, "activity-reducing amount" refers to the amount of antagonist required to reduce the activity of an enzyme relative to the absence of the antagonist. As used herein, "a functionally disrupted amount" refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. The exact amount will depend on the purpose of the treatment and will be determined by one of skill in the art using known techniques (see, e.g., lieberman, pharmaceutical Dosage Forms (volumes 1-3 ,1992);Lloyd,The Art,Science and Technology of Pharmaceutical Compounding(1999);Pickar,Dosage Calculations(1999); and Remington: THE SCIENCE AND PRACTICE of Pharmacy, 20 th edition, 2003, gennaro editions, lippincott, williams & Wilkins.) the therapeutically effective amount may be determined by measuring the relevant physiological effects and may be adjusted in conjunction with dosing regimens and diagnostic analysis of the subject's condition, etc. for example, measurement of serum levels of a CCR4 inhibitor (or, e.g., a metabolite thereof) at a particular time after administration may indicate whether a therapeutically effective amount has been administered.

For any of the compounds described herein, a therapeutically effective amount can be initially determined by a cell culture assay. The target concentrations will be those of the active compounds that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art.

As used herein, the term "therapeutically effective amount" refers to an amount of a therapeutic agent sufficient to ameliorate a condition such as described above. For example, a therapeutically effective amount will exhibit an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100% for a given parameter. Treatment efficacy may also be expressed as a "fold" increase or decrease. For example, a therapeutically effective amount may have at least 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect than a control. A therapeutically effective amount for use in humans may also be determined from animal models. For example, dosages for humans may be formulated to achieve concentrations that have been found to be effective in animals. As described above, the dose in humans can be adjusted by monitoring the effectiveness of the compound and adjusting the dose up or down. It is well within the ability of the ordinarily skilled artisan to adjust dosages based on the above methods and other methods to achieve maximum efficacy in humans. Adjusting the dose to achieve maximum therapeutic window efficacy or toxicity in humans based on the above methods and other methods is well within the ability of the ordinarily skilled artisan.

By "pharmaceutically acceptable salts" is meant those salts which are suitable for pharmaceutical use, such as, for example, for use in humans and lower animals without undue irritation, allergic response, and the like. Pharmaceutically acceptable salts of amines, carboxylic acids and other types of compounds are well known in the art. For example, pharmaceutically acceptable salts are described in detail in S.M. Berge et al, J Pharmaceutical Sciences,66:1-19 (1977), which is incorporated herein by reference. These salts may be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting the free base or free acid functionality with a suitable reagent, as generally described below. For example, the free base functionality may be reacted with a suitable acid. Suitable pharmaceutically acceptable salts may include metal salts such as alkali metal salts, e.g., sodium, potassium and lithium salts; and alkaline earth metal salts, such as calcium or magnesium salts. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipic acid salts, alginates, ascorbates, aspartic acid salts, benzoic acid salts, bisulfate salts, boric acid salts, camphor acid salts, camphorsulfonic acid salts, citric acid salts, cyclopentane propionic acid salts, digluconate, dodecyl sulfate, formate, fumaric acid salts, glucoheptonate salts, glycerophosphate, gluconate, hemisulfate (hernisulfate), heptanoate, caproate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionic aldehyde salts, lactylate salts, laurate salts, dodecyl sulfate, malate salts, maleate salts, malonic acid salts, methanesulfonic acid salts, nicotinate salts, nitrate salts, oleate salts, oxalate salts, palmitate salts, pectate salts, persulfate salts, 3-phenylpropionate salts, phosphate salts, picrate salts, pivalate salts, propionate salts, stearate salts, succinate salts, sulfate salts, tartrate salts, thiocyanate salts, p-toluenesulfonate salts, undecanoate salts, valerate salts, and the like.

"Treatment" of an individual (e.g., a mammal, such as a human) or cell is any type of intervention used to attempt to alter the natural course of the individual or cell. In some embodiments, the treatment comprises administering the pharmaceutical composition after initiating a pathological event or contacting with a pathogen, and comprises stabilizing the condition (e.g., the condition does not worsen) or alleviating the condition. In some embodiments, treatment further includes prophylactic treatment (e.g., administration of a composition described herein when an individual is suspected of having a viral infection, such as a coronavirus). The terms "treatment", "treatment" and "treatment" also refer to reducing, alleviating, ameliorating or alleviating at least one symptom of a disease or disorder. The terms "treat," "treatment," and "treatment" encompass a disease or disorder described herein in a subject (such as a human) and include: (i) inhibiting the disease or disorder, i.e., arresting its development; (ii) alleviating the disease or condition, i.e. causing regression of the condition; (iii) slowing the progression of the condition; and/or (iv) inhibit, alleviate or slow the progression of one or more symptoms of the disease or disorder. Treatment and therapy refers to intentional physiological intervention that aims to cure, delay or ameliorate one or more symptoms associated with a disease.

"Coronavirus infection" refers to any and all conditions caused by coronavirus infection, including but not limited to SARS-CoV, SARS-CoV-2 and MERS, preferably SARS-CoV-2.

Compounds of formula (I)

Described herein are compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II), (III), (IV), (V), (VIa), (VIb) and (VIc), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, for use in the treatment of viral infections. In some embodiments, the viral infection is a coronavirus infection.

Described herein are compounds of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

Wherein:

X is H or CN;

G is

R ¹ is hydrogen, substituted OR unsubstituted alkyl, -C (O) R ^1A, OR-C (O) OR ^1B;

R ² is hydrogen, substituted or unsubstituted alkyl, -C (O) R ^2A OR-C (O) OR ^2B;

R ³ is hydrogen or methyl;

r ⁴ is OH or F;

R ⁵ is hydrogen, -C (O) R ^5A、-C(O)OR^5B or-CH ₂-O-C(O)R^5C;

r ⁶ is hydrogen, -C (O) R ^6A、-C(O)OR^6B、-CH₂-O-C(O)R^6C, OR-P (O) (OR ^6D)(OR^6E), provided that (1) when G is And when X is CN, R ⁶ is not-P (O) (OR ^6D)(OR^6E), and (2) at least one of R ⁵ and R ⁶ is not hydrogen;

R^1A、R^1B、R^2A、R^2B、R^5A、R^5B、R^5C、R^6A、R^6B、R^6C、R^6D And R ^6E is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or (HO) C (O) R ^5A is a natural or unnatural amino acid; or (HO) C (O) R ^6A is a natural or unnatural amino acid; or R ^6D and R ^6E together with the oxygen atom to which they are attached form a substituted or unsubstituted heterocycle, respectively, or R ^6E includes alkylene, alkenylene, cycloalkylene having a 3-7 membered ring, alkynylene, arylene, heteroarylene, heterocyclylene having a 5-12 membered ring including 1-3 atoms in N, O or S, -O-, -NH-, -S-, -N (C _1-6 alkyl) -, -C (=o) NH-, or a combination thereof, and R ^6E has a length of 10-40 atoms.

In some embodiments, the compound is of formula (Ia):

in some embodiments, the compound is of formula (Ib):

In some embodiments, the compound is of formula (Ic):

in some embodiments, the compound is of formula (Id):

in some embodiments, the compound is of formula (Ie):

in some embodiments, the compound is of formula (If):

in some embodiments, the compound is of formula (Ig):

In some embodiments, R ³ is hydrogen and R ⁴ is OH. In some embodiments, R ³ is methyl and R ⁴ is F. In some embodiments, R ^6D is hydrogen. In some embodiments, R ^6E is substituted or unsubstituted alkyl, or R ^6E comprises alkylene, alkenylene, cycloalkylene having a 3-7 membered ring, alkynylene, arylene, heteroarylene, heterocyclylene having a 5-12 membered ring comprising 1-3 atoms in N, O or S, -O-, -NH-, -S-, -N (C _1-6 alkyl) -, -C (=o) NH-, or a combination thereof, and R ^6E is 10-40 atoms in length. In some embodiments, R ^1A、R^2A、R^5A and R ^6A are independently substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl. In some embodiments, R ^1B、R^2B、R^5B and R ^6B are independently substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl. In some embodiments, R ^5C and R ^6C are independently substituted or unsubstituted alkyl.

In some embodiments, for compounds of formulas (Ia) and (Id):

(1) R ² is hydrogen, R ⁵ is hydrogen, and R ⁶ is-C (O) R ^6A、-C(O)OR^6B、-CH₂-O-C(O)R^6C OR-P (O) (OR ^6D)(OR^6E), OR

(2) R ² is hydrogen, R ⁵ is-C (O) R ^5A、-C(O)OR^5B or-CH ₂-O-C(O)R^5C, and R ⁶ is hydrogen, or

(3) R ² is substituted or unsubstituted alkyl,-C (O) R ^2A OR-C (O) OR ^2B,R⁵ is hydrogen and R ⁶ is hydrogen, OR

(4) R ² is hydrogen, R ⁵ is-C (O) R ^5A、-C(O)OR^5B OR-CH ₂-O-C(O)R^5C, and R ⁶ is-C (O) R ^6A、-C(O)OR^6B、-CH₂-O-C(O)R^6C OR-P (O) (OR ^6D)(OR^6E), OR

(5) R ² is substituted or unsubstituted alkyl,-C (O) R ^2A OR-C (O) OR ^2B,R⁵ is hydrogen and R ⁶ is-C (O) R ^6A、-C(O)OR^6B、-CH₂-O-C(O)R^6C OR-P (O) (OR ^6D)(OR^6E), OR/>

(6) R ² is substituted or unsubstituted alkyl,-C (O) R ^2A OR-C (O) OR ^2B,R⁵ is-C (O) R ^5A、-C(O)OR^5B OR-CH ₂-O-C(O)R^5C, and R ⁶ is-C (O) R ^6A、-C(O)OR^6B、-CH₂-O-C(O)R^6C OR-P (O) (OR ^6D)(OR^6E).

In some embodiments, for a compound of formula (Ie):

(1) R ¹ is hydrogen, R ² is hydrogen, R ⁵ is hydrogen, and R ⁶ is-C (O) R ^6A、-C(O)OR^6B、-CH₂-O-C(O)R^6C OR-P (O) (OR ^6D)(OR^6E), OR

(2) R ¹ is hydrogen, R ² is hydrogen, R ⁵ is-C (O) R ^5A、-C(O)OR^5B or-CH ₂-O-C(O)R^5C, and R ⁶ is hydrogen, or

(3) R ¹ is hydrogen, R ² is substituted or unsubstituted alkyl,-C (O) R ^2A OR-C (O) OR ^2B,R⁵ is hydrogen and R ⁶ is hydrogen, OR

(4) R ¹ is substituted OR unsubstituted alkyl, -C (O) R ^1A OR-C (O) OR ^1B,R² is hydrogen, R ⁵ is hydrogen and R ⁶ is hydrogen,

(5) R ¹ is hydrogen, R ² is hydrogen, R ⁵ is-C (O) R ^5A、-C(O)OR^5B OR-CH ₂-O-C(O)R^5C, and R ⁶ is-C (O) R ^6A、-C(O)OR^6B、-CH₂-O-C(O)R^6C OR-P (O) (OR ^6D)(OR^6E), OR

(6) R ¹ is hydrogen, R ² is substituted or unsubstituted alkyl,-C (O) R ^2A OR-C (O) OR ^2B,R⁵ is hydrogen and R ⁶ is hydrogen, OR

(7) R ¹ is substituted OR unsubstituted alkyl, -C (O) R ^1A OR-C (O) OR ^1B,R² is hydrogen, R ⁵ is hydrogen, and R ⁶ is hydrogen, OR

(8) R ¹ is hydrogen, R ² is substituted or unsubstituted alkyl,-C (O) R ^2A OR-C (O) OR ^2B,R⁵ is-C (O) R ^5A、-C(O)OR^5B OR-CH ₂-O-C(O)R^5C, and R ⁶ is hydrogen, OR

(9) R ¹ is substituted OR unsubstituted alkyl, -C (O) R ^1A OR-C (O) OR ^1B,R² is hydrogen, R ⁵ is-C (O) R ^5A、-C(O)OR^5B OR-CH ₂-O-C(O)R^5C, and R ⁶ is hydrogen, OR

(10) R ¹ is substituted OR unsubstituted alkyl, -C (O) R ^1A OR-C (O) OR ^1B,R² is substituted OR unsubstituted alkyl,-C (O) R ^2A OR-C (O) OR ^2B,R⁵ is hydrogen and R ⁶ is hydrogen, OR/>

(11) R ¹ is hydrogen, R ² is substituted or unsubstituted alkyl,-C (O) R ^2A OR-C (O) OR ^2B,R⁵ is-C (O) R ^5A、-C(O)OR^5B OR-CH ₂-O-C(O)R^5C, and R ⁶ is-C (O) R ^6A、-C(O)OR^6B、-CH₂-O-C(O)R^6C OR-P (O) (OR ^6D)(OR^6E), OR

(12) R ¹ is substituted OR unsubstituted alkyl, -C (O) R ^1A OR-C (O) OR ^1B,R² is hydrogen, R ⁵ is-C (O) R ^5A、-C(O)OR^5B OR-CH ₂-O-C(O)R^5C, and R ⁶ is-C (O) R ^6A、-C(O)OR^6B、-CH₂-O-C(O)R^6C OR-P (O) (OR ^6D)(OR^6E), OR

(13) R ¹ is substituted OR unsubstituted alkyl, -C (O) R ^1A OR-C (O) OR ^1B,R² is substituted OR unsubstituted alkyl,-C (O) R ^2A OR-C (O) OR ^2B,R⁵ is hydrogen and R ⁶ is-C (O) R ^6A、-C(O)OR^6B、-CH₂-O-C(O)R^6C OR-P (O) (OR ^6D)(OR^6E), OR

(14) R ¹ is substituted OR unsubstituted alkyl, -C (O) R ^1A OR-C (O) OR ^1B,R² is substituted OR unsubstituted alkyl,-C (O) R ^2A OR-C (O) OR ^2B,R⁵ is-C (O) R ^5A、-C(O)OR^5B OR-CH ₂-O-C(O)R^5C, and R ⁶ is hydrogen, OR

(15) R ¹ is substituted OR unsubstituted alkyl, -C (O) R ^1A OR-C (O) OR ^1B,R² is substituted OR unsubstituted alkyl,-C (O) R ^2A OR-C (O) OR ^2B,R⁵ is-C (O) R ^5A、-C(O)OR^5B OR-CH ₂-O-C(O)R^5C and R ⁶ is-C (O) R ^6A、-C(O)OR^6B、-CH₂-O-C(O)R^6C OR-P (O) (OR ^6D)(OR^6E).

In some embodiments, for compounds of formulas (Ib) and (If):

(5) R ² is substituted or unsubstituted alkyl,-C (O) R ^2A OR-C (O) OR ^2B,R⁵ is hydrogen and R ⁶ is-C (O) R ^6A、-C(O)OR^6B、-CH₂-O-C(O)R^6C OR-P (O) (OR ^6D)(OR^6E), OR

In some embodiments, for compounds of formulas (Ic) and (Ig):

(1) R ⁵ is hydrogen and R ⁶ is-C (O) R ^6A、-C(O)OR^6B、-CH₂-O-C(O)R^6C OR-P (O) (OR ^6D)(OR^6E), OR

(2) R ⁵ is-C (O) R ^5A、-C(O)OR^5B or-CH ₂-O-C(O)R^5C, and R ⁶ is hydrogen, or

(3) R ⁵ is-C (O) R ^5A、-C(O)OR^5B OR-CH ₂-O-C(O)R^5C, and R ⁶ is-C (O) R ^6A、-C(O)OR^6B、-CH₂-O-C(O)R^6C OR-P (O) (OR ^6D)(OR^6E).

In some embodiments, R ³ is hydrogen and R ⁴ is OH. In some embodiments, R ³ is methyl and R ⁴ is F. In some embodiments, R ⁶ is hydrogen. In some embodiments, R ⁶ is-C (O) R ^6A, and wherein (HO) C (O) R ^6A is a natural amino acid. In some embodiments, R ⁶ is-C (O) R ^6A, and wherein R ^6A is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R ⁶ is-C (O) OR ^6B, and wherein R ^6B is substituted OR unsubstituted alkyl, substituted OR unsubstituted heteroalkyl, substituted OR unsubstituted arylalkyl, substituted OR unsubstituted heteroarylalkyl, substituted OR unsubstituted cycloalkyl, substituted OR unsubstituted heterocycloalkyl, substituted OR unsubstituted aryl, OR substituted OR unsubstituted heteroaryl. In some embodiments, R ⁶ is-CH ₂-O-C(O)R^6C, and wherein R ^6C is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R ⁶ is-P (O) (OR ^6D)(OR^6E). In some embodiments, R ^6D is hydrogen and R ^6E is substituted or unsubstituted alkyl, or R ^6E includes alkylene, alkenylene, cycloalkylene with 3-7 membered ring, alkynylene, arylene, heteroarylene, heterocyclylene with 5-12 membered ring including 1-3 atoms in N, O or S, -O-, -NH-, -S-, -N (C _1-6 alkyl) -, -C (=o) NH-, or a combination thereof, and R ^6E is 10-40, 15-40, or 20-40 atoms in length. In some embodiments, R ⁵ is hydrogen. In some embodiments, R ⁵ is-C (O) R ^5A, and wherein (HO) C (O) R ^5A is a natural amino acid.

In some embodiments, R ⁵ is-C (O) R ^5A, and R ^5A is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R ⁵ is-C (O) OR ^5B, and R ^5B is substituted OR unsubstituted alkyl, substituted OR unsubstituted heteroalkyl, substituted OR unsubstituted arylalkyl, substituted OR unsubstituted heteroarylalkyl, substituted OR unsubstituted cycloalkyl, substituted OR unsubstituted heterocycloalkyl, substituted OR unsubstituted aryl, OR substituted OR unsubstituted heteroaryl. In some embodiments, R ⁵ is-CH ₂-O-C(O)R^5C, and wherein R ^5C is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments, R ² is hydrogen. In some embodiments, R ² is substituted or unsubstituted alkyl. In some embodiments, R ² isIn some embodiments, R ² is-C (O) R ^2A, and wherein R ^2A is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R ² is-C (O) OR ^2B, and wherein R ^2B is substituted OR unsubstituted alkyl, substituted OR unsubstituted heteroalkyl, substituted OR unsubstituted arylalkyl, substituted OR unsubstituted heteroarylalkyl, substituted OR unsubstituted cycloalkyl, substituted OR unsubstituted heterocycloalkyl, substituted OR unsubstituted aryl, OR substituted OR unsubstituted heteroaryl.

In some embodiments, R ¹ is hydrogen. In some embodiments, R ¹ is substituted or unsubstituted alkyl. In some embodiments, R ¹ is-C (O) R ^1A, and wherein R ^1A is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R ¹ is-C (O) OR ^1B, and wherein R ^1B is substituted OR unsubstituted alkyl, substituted OR unsubstituted heteroalkyl, substituted OR unsubstituted arylalkyl, substituted OR unsubstituted heteroarylalkyl, substituted OR unsubstituted cycloalkyl, substituted OR unsubstituted heterocycloalkyl, substituted OR unsubstituted aryl, OR substituted OR unsubstituted heteroaryl.

Also disclosed herein is a compound of formula (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

Wherein:

X is hydrogen or-CN;

G is

Each R ^11a is independently halogen, -CN, -OH, -OR ^a、-NR^cR^d, cycloalkyl OR heterocycloalkyl; or two R ^11a on the same atom together to form oxo;

Or two R ^21a on the same atom together to form oxo;

Each R ^12a is independently halogen, -CN, -OH, -OR ^a、-NR^cR^d, cycloalkyl OR heterocycloalkyl; or two R ^12a on the same atom together to form oxo;

or two R ^22a on the same atom together to form oxo;

R ¹³ is hydrogen or C ₁-C₆ alkyl;

r ¹⁴ is-OH or fluoro;

Each R ^15a is independently halogen, -CN, -OH, -OR ^a、-NR^cR^d, cycloalkyl OR heterocycloalkyl; or two R ^15a on the same atom together to form oxo;

Or two R ^25a on the same atom together to form oxo;

R ¹⁶ is-C (=o) R ²⁶、-C(＝O)OR²⁶、-CH₂-O-C(＝O)R²⁶ or-CH ₂-O-C(＝O)OR²⁶;R²⁶ is C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl) or C ₁-C₆ alkylene (heteroaryl); wherein alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^26a;

or two R ^26a on the same atom together to form oxo;

Or two R groups on the same atom together to form oxo;

provided that when G is And X is-CN, or G is/>And X is hydrogen; at least one of R ¹¹、R¹² or R ¹⁵ is not hydrogen. /(I)

In some embodiments of the compounds of formula (II), X is hydrogen. In some embodiments of the compounds of formula (II), X is-CN.

In some embodiments of the compounds of formula (II), R ¹³ is hydrogen. In some embodiments of the compounds of formula (II), R ¹³ is C ₁-C₆ alkyl.

In some embodiments of the compounds of formula (II), R ¹⁴ is —oh. In some embodiments of the compound of formula (II), R ¹⁴ is fluoro.

In some embodiments of the compounds of formula (II), G isIn some embodiments of the compounds of formula (II), G is/>In some embodiments of the compounds of formula (II), G isIn some embodiments of the compounds of formula (II), G is/>

In some embodiments of the compounds of formula (II),

R ¹⁵ is-C (=o) R ²⁵、-C(＝O)OR²⁵、-CH₂-O-C(＝O)R²⁵、-CH₂-O-C(＝O)OR²⁵ or C ₁-C₆ alkyl optionally substituted by one or more R ^15a; and

R ¹⁶ is-C (=O) R ²⁶、-C(＝O)OR²⁶、-CH₂-O-C(＝O)R²⁶ or-CH ₂-O-C(＝O)OR²⁶. In some embodiments of the compounds of formula (II),

R ¹⁵ is hydrogen, -C (=o) R ²⁵、-C(＝O)OR²⁵、-CH₂-O-C(＝O)R²⁵、-CH₂-O-C(＝O)OR²⁵ or C ₁-C₆ alkyl optionally substituted by one or more R ^15a; and

R ¹¹ is-C (=o) R ²¹、-C(＝O)OR²¹ or C ₁-C₆ alkyl optionally substituted by one or more R ^11a;

R ¹⁶ is-C (=O) R ²⁶、-C(＝O)OR²⁶、-CH₂-O-C(＝O)R²⁶ or-CH ₂-O-C(＝O)OR²⁶.

In some embodiments of the compounds of formula (II), R ¹¹ is hydrogen, -C (=o) R ²¹ or C ₁-C₆ alkyl optionally substituted with one or more R ^11a. In some embodiments of the compound of formula (II), R ¹¹ is hydrogen or-C (=o) R ²¹. In some embodiments of the compounds of formula (II), R ¹¹ is hydrogen. In some embodiments of the compound of formula (II), R ¹¹ is-C (=o) R ²¹.

In some embodiments of the compounds of formula (II), each R ^11a is independently halogen, -CN, -OH, -OR ^a, OR-NR ^cR^d. In some embodiments of the compound of formula (II), each R ^11a is independently halogen.

In some embodiments of the compounds of formula (II), R ²¹ is C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^21a. In some embodiments of compounds of formula (II), R ²¹ is C ₁-C₆ alkyl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl). In some embodiments of the compounds of formula (II), R ²¹ is C ₁-C₆ alkyl, C ₁-C₆ alkylene (cycloalkyl) or C ₁-C₆ alkylene (aryl).

In some embodiments of the compound of formula (II), each R ^21a is independently halogen 、-CN、-OH、-OR^a、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl. In some embodiments of the compound of formula (II), each R ^21a is independently halogen, -OH, -OR ^a、-NR^cR^d、C₁-C₆ alkyl OR C ₁-C₆ haloalkyl.

In some embodiments of the compounds of formula (II), R ¹² is hydrogen, -C (=o) R ²²、-C(＝O)OR²², or C ₁-C₆ alkyl. In some embodiments of the compound of formula (II), R ¹² is-C (=o) R ²²、-C(＝O)OR²² or C ₁-C₆ alkyl. In some embodiments of the compound of formula (II), R ¹² is hydrogen or-C (=o) R ²². In some embodiments of the compound of formula (II), R ¹² is hydrogen OR-C (=o) OR ²². In some embodiments of the compounds of formula (II), R ¹² is hydrogen or C ₁-C₆ alkyl.

In some embodiments of the compounds of formula (II), each R ^12a is independently halogen, -CN, -OH, -OR ^a, OR-NR ^cR^d. In some embodiments of the compound of formula (II), each R ^12a is independently halogen.

In some embodiments of the compounds of formula (II), R ²² is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^22a. In some embodiments of the compounds of formula (II), R ²² is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl). In some embodiments of the compounds of formula (II), R ²² is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, aryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl). In some embodiments of the compounds of formula (II), R ²² is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, aryl, C ₁-C₆ alkylene (cycloalkyl) or C ₁-C₆ alkylene (aryl).

In some embodiments of the compounds of formula (II), R ²² is C ₁-C₆ alkyl or C ₁-C₆ alkylene (aryl); wherein alkyl, alkylene, and aryl are optionally and independently substituted with one or more R ^22a. In some embodiments of the compounds of formula (II), R ²² is C ₁-C₆ alkyl optionally and independently substituted with one or more R ^22a.

In some embodiments of the compound of formula (II), each R ^22a is independently halogen 、-CN、-OH、-OR^a、-OC(＝O)R^a、-OC(＝O)OR^b、-OC(＝O)NR^cR^d、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl.

In some embodiments of the compound of formula (II), each R ^22a is independently halogen 、-CN、-OH、-OR^a、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl. In some embodiments of the compound of formula (II), each R ^22a is independently halogen, -OH, -OR ^a、-NR^cR^d、C₁-C₆ alkyl OR C ₁-C₆ haloalkyl. In some embodiments of the compound of formula (II), each R ^22a is independently halogen, -OC (=o) R ^a or-NR ^cR^d. In some embodiments of the compound of formula (II), each R ^22a is independently-OC (=o) R ^a or-NR ^cR^d. In some embodiments of the compound of formula (II), each R ^22a is independently-OC (=o) R ^a.

In some embodiments of the compound of formula (II), R ¹⁵ is hydrogen, -C (=o) R ²⁵, or-CH ₂-O-C(＝O)R²⁵. In some embodiments of the compound of formula (II), R ¹⁵ is hydrogen or-C (=o) R ²⁵. In some embodiments of the compound of formula (II), R ¹⁵ is-C (=o) R ²⁵. In some embodiments of the compounds of formula (II), R ¹⁵ is hydrogen.

In some embodiments of the compounds of formula (II), each R ^15a is independently halogen, -CN, -OH, -OR ^a, OR-NR ^cR^d. In some embodiments of the compound of formula (II), each R ^15a is independently halogen.

In some embodiments of the compounds of formula (II), R ²⁵ is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^25a. In some embodiments of the compounds of formula (II), R ²⁵ is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ alkylene (cycloalkyl) or C ₁-C₆ alkylene (aryl); wherein alkyl, alkylene, cycloalkyl, and aryl are optionally and independently substituted with one or more R ^25a. In some embodiments of the compounds of formula (II), R ²⁵ is C ₁-C₆ alkylene (cycloalkyl) or C ₁-C₆ alkylene (aryl); wherein alkylene, cycloalkyl and aryl are optionally and independently substituted with one or more R ^25a.

In some embodiments of the compound of formula (II), each R ^25a is independently halogen 、-CN、-OH、-OR^a、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl. In some embodiments of the compound of formula (II), each R ^25a is independently halogen, -OH, -OR ^a、-NR^cR^d、C₁-C₆ alkyl OR C ₁-C₆ haloalkyl.

In some embodiments of the compound of formula (II), R ¹⁶ is-C (=o) R ²⁶. In some embodiments of the compound of formula (II), R ¹⁶ is-C (=o) OR ²⁶. In some embodiments of the compound of formula (II), R ¹⁶ is-CH ₂-O-C(＝O)R²⁶.

In some embodiments of the compounds of formula (II), R ²⁶ is C ₁-C₆ alkylene (cycloalkyl) or C ₁-C₆ alkylene (aryl); wherein alkylene, cycloalkyl and aryl are optionally and independently substituted with one or more R ^26a. In some embodiments of the compounds of formula (II), R ²⁶ is C ₁-C₆ alkylene (cycloalkyl); wherein alkylene and cycloalkyl are optionally and independently substituted with one or more R ^26a. In some embodiments of the compounds of formula (II), R ²⁶ is C ₁-C₆ alkylene (aryl); wherein alkylene and aryl are optionally and independently substituted with one or more R ^26a.

In some embodiments of the compound of formula (II), each R ^26a is independently halogen 、-CN、-OH、-OR^a、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl. In some embodiments of the compound of formula (II), each R ^26a is independently halogen, -OH, -OR ^a、-NR^cR^d、C₁-C₆ alkyl OR C ₁-C₆ haloalkyl.

Also disclosed herein is a compound of formula (III):

Wherein:

X is hydrogen or-CN;

G is

Or two R ^21a on the same atom together to form oxo;

or two R ^22a on the same atom together to form oxo;

R ¹³ is hydrogen or C ₁-C₆ alkyl;

r ¹⁴ is-OH or fluoro;

R ¹⁵ is-C (=o) R ²⁵、-C(＝O)OR²⁵、-CH₂-O-C(＝O)R²⁵ or-CH ₂-O-C(＝O)OR²⁵;R²⁵ is C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl) or C ₁-C₆ alkylene (heteroaryl); wherein alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^26a;

Or two R ^25a on the same atom together to form oxo;

Each R ^16a is independently halogen, -CN, -OH, -OR ^a、-NR^cR^d, cycloalkyl OR heterocycloalkyl; or two R ^16a on the same atom together to form oxo;

or two R ^26a on the same atom together to form oxo;

Or two R groups on the same atom together to form oxo;

In some embodiments of the compounds of formula (III), X is hydrogen. In some embodiments of the compounds of formula (III), X is-CN.

In some embodiments of the compounds of formula (III), R ¹³ is hydrogen. In some embodiments of the compounds of formula (III), R ¹³ is C ₁-C₆ alkyl.

In some embodiments of the compounds of formula (III), R ¹⁴ is —oh. In some embodiments of the compound of formula (III), R ¹⁴ is fluoro.

In some embodiments of the compounds of formula (III), G isIn some embodiments of the compounds of formula (III), G is/>In some embodiments of the compounds of formula (III), G isIn some embodiments of the compounds of formula (III), G is/>

In some embodiments of the compounds of formula (III),

R ¹⁵ is-C (=o) R ²⁵、-C(＝O)OR²⁵、-CH₂-O-C(＝O)R²⁵ or-CH ₂-O-C(＝O)OR²⁵; and

R ¹⁶ is-C (=o) R ²⁶、-C(＝O)OR²⁶、-CH₂-O-C(＝O)R²⁶、-CH₂-O-C(＝O)OR²⁶ or C ₁-C₆ alkyl optionally substituted by one or more R ^16a.

In some embodiments of the compounds of formula (III),

R ¹⁶ is hydrogen, -C (=o) R ²⁶、-C(＝O)OR²⁶、-CH₂-O-C(＝O)R²⁶、-CH₂-O-C(＝O)OR²⁶ or C ₁-C₆ alkyl optionally substituted by one or more R ^16a.

In some embodiments of the compounds of formula (III),

In some embodiments of the compounds of formula (III), R ¹¹ is hydrogen, -C (=o) R ²¹ or C ₁-C₆ alkyl optionally substituted with one or more R ^11a. In some embodiments of the compound of formula (III), R ¹¹ is hydrogen or-C (=o) R ²¹. In some embodiments of the compounds of formula (III), R ¹¹ is hydrogen. In some embodiments of the compound of formula (III), R ¹¹ is-C (=o) R ²¹.

In some embodiments of the compounds of formula (III), each R ^11a is independently halogen, -CN, -OH, -OR ^a, OR-NR ^cR^d. In some embodiments of the compound of formula (III), each R ^11a is independently halogen.

In some embodiments of the compounds of formula (III), R ²¹ is C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^21a. In some embodiments of the compounds of formula (III), R ²¹ is C ₁-C₆ alkyl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl). In some embodiments of the compounds of formula (III), R ²¹ is C ₁-C₆ alkyl, C ₁-C₆ alkylene (cycloalkyl) or C ₁-C₆ alkylene (aryl).

In some embodiments of the compound of formula (III), each R ^21a is independently halogen 、-CN、-OH、-OR^a、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl. In some embodiments of the compounds of formula (III), each R ^21a is independently halogen, -OH, -OR ^a、-NR^cR^d、C₁-C₆ alkyl OR C ₁-C₆ haloalkyl.

In some embodiments of the compounds of formula (III), R ¹² is hydrogen, -C (=o) R ²²、-C(＝O)OR²², or C ₁-C₆ alkyl. In some embodiments of the compound of formula (III), R ¹² is-C (=o) R ²²、-C(＝O)OR²² or C ₁-C₆ alkyl. In some embodiments of the compound of formula (III), R ¹² is hydrogen or-C (=o) R ²². In some embodiments of the compound of formula (III), R ¹² is hydrogen OR-C (=o) OR ²². In some embodiments of the compounds of formula (III), R ¹² is hydrogen or C ₁-C₆ alkyl. In some embodiments of the compound of formula (III), R ¹² is-C (=o) OR ²².

In some embodiments of the compounds of formula (III), each R ^12a is independently halogen, -CN, -OH, -OR ^a, OR-NR ^cR^d. In some embodiments of the compound of formula (III), each R ^12a is independently halogen.

In some embodiments of the compounds of formula (III), R ²² is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^22a. In some embodiments of the compounds of formula (III), R ²² is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl). In some embodiments of the compounds of formula (III), R ²² is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, aryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl). In some embodiments of the compounds of formula (III), R ²² is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, aryl, C ₁-C₆ alkylene (cycloalkyl) or C ₁-C₆ alkylene (aryl).

In some embodiments of the compounds of formula (III), R ²² is C ₁-C₆ alkyl or C ₁-C₆ alkylene (aryl); wherein alkyl, alkylene, and aryl are optionally and independently substituted with one or more R ^22a. In some embodiments of the compounds of formula (III), R ²² is C ₁-C₆ alkyl optionally and independently substituted with one or more R ^22a.

In some embodiments of the compound of formula (III), each R ^22a is independently halogen 、-CN、-OH、-OR^a、-OC(＝O)R^a、-OC(＝O)OR^b、-OC(＝O)NR^cR^d、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl.

In some embodiments of the compound of formula (III), each R ^22a is independently halogen 、-CN、-OH、-OR^a、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl. In some embodiments of the compounds of formula (III), each R ^22a is independently halogen, -OH, -OR ^a、-NR^cR^d、C₁-C₆ alkyl OR C ₁-C₆ haloalkyl. In some embodiments of the compound of formula (III), each R ^22a is independently halogen, -OC (=o) R ^a or-NR ^cR^d. In some embodiments of the compound of formula (III), each R ^22a is independently-OC (=o) R ^a or-NR ^cR^d. In some embodiments of the compound of formula (IV), each R ^22a is independently-OC (=o) R ^a.

In some embodiments of the compound of formula (III), R ¹⁵ is-C (=o) R ²⁵. In some embodiments of the compound of formula (III), R ¹⁵ is-C (=o) OR ²⁵. In some embodiments of the compound of formula (III), R ¹⁵ is-CH ₂-O-C(＝O)R²⁵.

In some embodiments of the compounds of formula (III), R ²⁵ is C ₁-C₆ alkylene (cycloalkyl) or C ₁-C₆ alkylene (aryl); wherein alkylene, cycloalkyl and aryl are optionally and independently substituted with one or more R ^25a. In some embodiments of the compounds of formula (III), R ²⁵ is C ₁-C₆ alkylene (cycloalkyl); wherein alkylene and cycloalkyl are optionally and independently substituted with one or more R ^25a. In some embodiments of the compounds of formula (III), R ²⁵ is C ₁-C₆ alkylene (aryl); wherein alkylene and aryl are optionally and independently substituted with one or more R ^25a.

In some embodiments of the compound of formula (III), each R ^25a is independently halogen 、-CN、-OH、-OR^a、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl. In some embodiments of the compounds of formula (III), each R ^25a is independently halogen, -OH, -OR ^a、-NR^cR^d、C₁-C₆ alkyl OR C ₁-C₆ haloalkyl.

In some embodiments of the compound of formula (III), R ¹⁶ is hydrogen, -C (=o) R ²⁶, or-CH ₂-O-C(＝O)R²⁶. In some embodiments of the compound of formula (III), R ¹⁶ is hydrogen or-C (=o) R ²⁶. In some embodiments of the compound of formula (III), R ¹⁶ is-C (=o) R ²⁶. In some embodiments of the compounds of formula (III), R ¹⁶ is hydrogen. In some embodiments of the compound of formula (III), R ¹⁶ is-CH ₂-O-C(＝O)R²⁶.

In some embodiments of the compounds of formula (III), each R ^16a is independently halogen, -CN, -OH, -OR ^a, OR-NR ^cR^d. In some embodiments of the compound of formula (III), each R ^16a is independently halogen.

In some embodiments of the compounds of formula (III), R ²⁶ is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^26a. In some embodiments of the compounds of formula (III), R ²⁶ is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ alkylene (cycloalkyl) or C ₁-C₆ alkylene (aryl); wherein alkyl, alkylene, cycloalkyl, and aryl are optionally and independently substituted with one or more R ^26a. In some embodiments of the compounds of formula (III), R ²⁶ is C ₁-C₆ alkylene (cycloalkyl) or C ₁-C₆ alkylene (aryl); wherein alkylene, cycloalkyl and aryl are optionally and independently substituted with one or more R ^26a.

In some embodiments of the compound of formula (III), each R ^26a is independently halogen 、-CN、-OH、-OR^a、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl. In some embodiments of the compounds of formula (III), each R ^26a is independently halogen, -OH, -OR ^a、-NR^cR^d、C₁-C₆ alkyl OR C ₁-C₆ haloalkyl.

Also disclosed herein is a compound of formula (IV):

Wherein:

X is hydrogen or-CN;

G is

or two R ^22a on the same atom together to form oxo;

R ¹³ is hydrogen or C ₁-C₆ alkyl;

r ¹⁴ is-OH or fluoro;

r ¹⁵ is-C (=o) R ²⁵、-C(＝O)OR²⁵、-CH₂-O-C(＝O)R²⁵ or-CH ₂-O-C(＝O)OR²⁵;R²⁵ is C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^25a;

Or two R ^25a on the same atom together to form oxo;

Or two R groups on the same atom together to form oxo.

In some embodiments of the compounds of formula (IV), X is hydrogen. In some embodiments of the compounds of formula (IV), X is-CN. In some embodiments of the compounds of formula (IV), R ¹³ is hydrogen. In some embodiments of the compounds of formula (IV), R ¹³ is C ₁-C₆ alkyl.

In some embodiments of the compounds of formula (IV), R ¹⁴ is —oh. In some embodiments of the compounds of formula (IV), R ¹⁴ is fluoro.

In some embodiments of the compounds of formula (IV), R ¹² is-C (=o) R ²²、-C(＝O)OR²² or C ₁-C₆ alkyl. In some embodiments of the compound of formula (IV), R ¹² is-C (=o) R ²². In some embodiments of the compounds of formula (IV), R ¹² is-C (=o) OR ²². In some embodiments of the compounds of formula (IV), R ¹² is C ₁-C₆ alkyl.

In some embodiments of the compounds of formula (IV), each R ^12a is independently halogen, -CN, -OH, -OR ^a, OR-NR ^cR^d. In some embodiments of the compounds of formula (IV), each R ^12a is independently halogen.

In some embodiments of the compounds of formula (IV), R ²² is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^22a.

In some embodiments of compounds of formula (IV), R ²² is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl). In some embodiments of compounds of formula (IV), R ²² is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, aryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl). In some embodiments of compounds of formula (IV), R ²² is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, aryl, C ₁-C₆ alkylene (cycloalkyl) or C ₁-C₆ alkylene (aryl).

In some embodiments of the compounds of formula (IV), R ²² is C ₁-C₆ alkyl or C ₁-C₆ alkylene (aryl); wherein alkyl, alkylene, and aryl are optionally and independently substituted with one or more R ^22a. In some embodiments of the compounds of formula (IV), R ²² is C ₁-C₆ alkyl optionally and independently substituted with one or more R ^22a.

In some embodiments of the compounds of formula (IV), each R ^22a is independently halogen 、-CN、-OH、-OR^a、-OC(＝O)R^a、-OC(＝O)OR^b、-OC(＝O)NR^cR^d、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl.

In some embodiments of the compounds of formula (IV), each R ^22a is independently halogen 、-CN、-OH、-OR^a、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl. In some embodiments of the compounds of formula (IV), each R ^22a is independently halogen, -OH, -OR ^a、-NR^cR^d、C₁-C₆ alkyl OR C ₁-C₆ haloalkyl. In some embodiments of the compound of formula (IV), each R ^22a is independently halogen, -OC (=o) R ^a or-NR ^cR^d. In some embodiments of the compound of formula (IV), each R ^22a is independently-OC (=o) R ^a or-NR ^cR^d. In some embodiments of the compound of formula (IV), each R ^22a is independently-OC (=o) R ^a.

In some embodiments of the compound of formula (IV), R ¹⁵ is-C (=o) R ²⁵. In some embodiments of the compounds of formula (IV), R ¹⁵ is-C (=o) OR ²⁵. In some embodiments of the compound of formula (IV), R ¹⁵ is-CH ₂-O-C(＝O)R²⁵. In some embodiments of the compounds of formula (IV), R ²⁵ is C ₁-C₆ alkylene (cycloalkyl) or C ₁-C₆ alkylene (aryl); wherein alkylene, cycloalkyl and aryl are optionally and independently substituted with one or more R ^25a. In some embodiments of the compounds of formula (IV), R ²⁵ is C ₁-C₆ alkylene (cycloalkyl); wherein alkylene and cycloalkyl are optionally and independently substituted with one or more R ^25a. In some embodiments of the compounds of formula (IV), R ²⁵ is C ₁-C₆ alkylene (aryl); wherein alkylene and aryl are optionally and independently substituted with one or more R ^25a.

In some embodiments of the compounds of formula (IV), each R ^25a is independently halogen 、-CN、-OH、-OR^a、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl. In some embodiments of the compounds of formula (IV), each R ^25a is independently halogen, -OH, -OR ^a、-NR^cR^d、C₁-C₆ alkyl OR C ₁-C₆ haloalkyl.

Also disclosed herein is a compound of formula (V):

Wherein:

X is hydrogen or-CN;

G is

or two R ^22a on the same atom together to form oxo;

R ¹³ is hydrogen or C ₁-C₆ alkyl;

r ¹⁴ is-OH or fluoro;

R ¹⁵ is hydrogen, -C (=o) R ²⁵、-C(＝O)OR²⁵、-CH₂-O-C(＝O)R²⁵ or-CH ₂-O-C(＝O)OR²⁵;R²⁵ is C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^25a;

Or two R ^25a on the same atom together to form oxo;

or two R ^26a on the same atom together to form oxo;

Or two R groups on the same atom together to form oxo.

In some embodiments of the compounds of formula (V), X is hydrogen. In some embodiments of the compounds of formula (V), X is-CN.

In some embodiments of the compounds of formula (V), R ¹³ is hydrogen. In some embodiments of compounds of formula (V), R ¹³ is C ₁-C₆ alkyl.

In some embodiments of the compounds of formula (V), R ¹⁴ is —oh. In some embodiments of the compounds of formula (V), R ¹⁴ is fluoro.

In some embodiments of the compound of formula (V), R ¹² is-C (=o) R ²²、-C(＝O)OR²² or C ₁-C₆ alkyl. In some embodiments of the compound of formula (V), R ¹² is-C (=o) R ²². In some embodiments of the compounds of formula (V), R ¹² is-C (=o) OR ²². In some embodiments of compounds of formula (V), R ¹² is C ₁-C₆ alkyl.

In some embodiments of the compounds of formula (V), R ²² is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^22a.

In some embodiments of compounds of formula (V), R ²² is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl).

In some embodiments of compounds of formula (V), R ²² is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, aryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl).

In some embodiments of compounds of formula (V), R ²² is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, aryl, C ₁-C₆ alkylene (cycloalkyl) or C ₁-C₆ alkylene (aryl).

In some embodiments of the compounds of formula (V), R ²² is C ₁-C₆ alkyl or C ₁-C₆ alkylene (aryl); wherein alkyl, alkylene, and aryl are optionally and independently substituted with one or more R ^22a.

In some embodiments of the compounds of formula (V), R ²² is C ₁-C₆ alkyl optionally and independently substituted with one or more R ^22a.

In some embodiments of the compounds of formula (V), each R ^22a is independently halogen 、-CN、-OH、-OR^a、-OC(＝O)R^a、-OC(＝O)OR^b、-OC(＝O)NR^cR^d、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl.

In some embodiments of the compounds of formula (V), each R ^22a is independently halogen 、-CN、-OH、-OR^a、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl.

In some embodiments of the compounds of formula (V), each R ^22a is independently halogen, -OH, -OR ^a、-NR^cR^d、C₁-C₆ alkyl OR C ₁-C₆ haloalkyl.

In some embodiments of the compound of formula (V), each R ^22a is independently halogen, -OC (=o) R ^a or-NR ^cR^d. In some embodiments of the compound of formula (V), each R ^22a is independently-OC (=o) R ^a or-NR ^cR^d. In some embodiments of the compound of formula (V), each R ^22a is independently-OC (=o) R ^a.

In some embodiments of the compounds of formula (V), R ¹⁵ is hydrogen.

In some embodiments of the compound of formula (V), R ¹⁵ is-C (=o) R ²⁵.

In some embodiments of the compounds of formula (V), R ¹⁵ is-C (=o) OR ²⁵.

In some embodiments of the compounds of formula (V), R ²⁵ is C ₁-C₆ alkylene (cycloalkyl) or C ₁-C₆ alkylene (aryl); wherein alkylene, cycloalkyl and aryl are optionally and independently substituted with one or more R ^25a.

In some embodiments of the compounds of formula (V), R ²⁵ is C ₁-C₆ alkylene (cycloalkyl); wherein alkylene and cycloalkyl are optionally and independently substituted with one or more R ^25a.

In some embodiments of the compounds of formula (V), R ²⁵ is C ₁-C₆ alkylene (aryl); wherein alkylene and aryl are optionally and independently substituted with one or more R ^25a.

In some embodiments of the compounds of formula (V), each R ^25a is independently halogen 、-CN、-OH、-OR^a、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl.

In some embodiments of the compounds of formula (V), each R ^25a is independently halogen, -OH, -OR ^a、-NR^cR^d、C₁-C₆ alkyl OR C ₁-C₆ haloalkyl.

In some embodiments of the compound of formula (V), R ¹⁶ is-C (=o) R ²⁶.

In some embodiments of the compounds of formula (V), R ¹⁶ is-C (=o) OR ²⁶.

In some embodiments of the compounds of formula (V), R ²⁶ is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^26a.

In some embodiments of compounds of formula (V), R ²⁶ is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl).

In some embodiments of compounds of formula (V), R ²⁶ is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, aryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl).

In some embodiments of compounds of formula (V), R ²⁶ is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, aryl, C ₁-C₆ alkylene (cycloalkyl) or C ₁-C₆ alkylene (aryl).

In some embodiments of the compounds of formula (V), R ²⁶ is C ₁-C₆ alkyl or C ₁-C₆ aminoalkyl.

In some embodiments of the compounds of formula (V), each R ^26a is independently halogen 、-CN、-OH、-OR^a、-OC(＝O)R^a、-OC(＝O)OR^b、-OC(＝O)NR^cR^d、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl.

In some embodiments of the compounds of formula (V), each R ^26a is independently halogen 、-CN、-OH、-OR^a、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl.

In some embodiments of the compounds of formula (V), each R ^26a is independently halogen, -OH, -OR ^a、-NR^cR^d、C₁-C₆ alkyl OR C ₁-C₆ haloalkyl.

In some embodiments of the compound of formula (V), each R ^26a is independently-OC (=o) R ^a or-NR ^cR^d.

Wherein:

X is hydrogen or-CN;

or two R ^22a on the same atom together to form oxo;

R ¹³ is hydrogen or C ₁-C₆ alkyl;

r ¹⁴ is-OH or fluoro;

Or two R ^25a on the same atom together to form oxo;

or two R ^26a on the same atom together to form oxo;

Or two R groups on the same atom together to form oxo.

In some embodiments, the compound is a compound of formula (VIa):

in some embodiments, the compound is a compound of formula (VIb):

In some embodiments, the compound is a compound of formula (VIc):

in some embodiments of the compounds of formula (VIa), (VIb), or (VIc), X is hydrogen. In some embodiments of the compounds of formula (VIa), (VIb), or (VIc), X is-CN.

In some embodiments of the compounds of formula (VIa), (VIb), or (VIc), R ¹³ is hydrogen. In some embodiments of the compounds of formula (VIa), (VIb), or (VIc), R ¹³ is C ₁-C₆ alkyl.

In some embodiments of the compounds of formula (VIa), (VIb), or (VIc), R ¹⁴ is-OH. In some embodiments of the compounds of formula (VIa), (VIb), or (VIc), R ¹⁴ is fluoro.

In some embodiments of the compounds of formula (VIa) or (VIb), R ¹² is hydrogen, -C (=o) R ²²、-C(＝O)OR²², or C ₁-C₆ alkyl. In some embodiments of the compounds of formula (VIa) or (VIb), R ¹² is-C (=o) R ²²、-C(＝O)OR²² or C ₁-C₆ alkyl. In some embodiments of the compounds of formula (VIa) or (VIb), R ¹² is-C (=o) R ²². In some embodiments of the compounds of formula (VIa) OR (VIb), R ¹² is-C (=o) OR ²². In some embodiments of the compounds of formula (VIa) or (VIb), R ¹² is C ₁-C₆ alkyl. In some embodiments of the compounds of formula (VIa) or (VIb), R ¹² is hydrogen.

In some embodiments of the compounds of formula (VIa) or (VIb), R ²² is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^22a.

In some embodiments of compounds of formula (VIa) or (VIb), R ²² is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl).

In some embodiments of compounds of formula (VIa) or (VIb), R ²² is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, aryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl).

In some embodiments of the compounds of formula (VIa) or (VIb), R ²² is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, aryl, C ₁-C₆ alkylene (cycloalkyl) or C ₁-C₆ alkylene (aryl).

In some embodiments of the compounds of formula (VIa) or (VIb), R ²² is C ₁-C₆ alkyl or C ₁-C₆ alkylene (aryl); wherein alkyl, alkylene, and aryl are optionally and independently substituted with one or more R ^22a.

In some embodiments of the compounds of formula (VIa) or (VIb), R ²² is C ₁-C₆ alkyl optionally and independently substituted with one or more R ^22a.

In some embodiments of the compounds of formula (VIa) or (VIb), each R ^22a is independently halogen 、-CN、-OH、-OR^a、-OC(＝O)R^a、-OC(＝O)OR^b、-OC(＝O)NR^cR^d、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl.

In some embodiments of the compounds of formula (VIa) or (VIb), each R ^22a is independently halogen 、-CN、-OH、-OR^a、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl.

In some embodiments of the compounds of formula (VIa) OR (VIb), each R ^22a is independently halogen, -OH, -OR ^a、-NR^cR^d、C₁-C₆ alkyl OR C ₁-C₆ haloalkyl.

In some embodiments of the compounds of formula (VIa) or (VIb), each R ^22a is independently halogen, -OC (=o) R ^a, or-NR ^cR^d. In some embodiments of the compounds of formula (VIa) or (VIb), each R ^22a is independently-OC (=o) R ^a or-NR ^cR^d. In some embodiments of the compounds of formula (VIa) or (VIb), each R ^22a is independently-OC (=o) R ^a.

In some embodiments of the compounds of formula (VIa) OR (VIc), R ¹⁵ is-C (=o) R ²⁵ OR-C (=o) OR ²⁵ OR-CH ₂-O-C(＝O)R²⁵.

In some embodiments of the compounds of formula (VIa) or (VIc), R ¹⁵ is hydrogen.

In some embodiments of the compounds of formula (VIa) or (VIc), R ¹⁵ is-C (=o) R ²⁵.

In some embodiments of the compounds of formula (VIa) OR (VIc), R ¹⁵ is-C (=o) OR ²⁵.

In some embodiments of the compounds of formula (VIa) or (VIc), R ²⁵ is C ₁-C₆ alkylene (cycloalkyl) or C ₁-C₆ alkylene (aryl); wherein alkylene, cycloalkyl and aryl are optionally and independently substituted with one or more R ^25a.

In some embodiments of the compounds of formula (VIa) or (VIc), R ²⁵ is C ₁-C₆ alkylene (cycloalkyl); wherein alkylene and cycloalkyl are optionally and independently substituted with one or more R ^25a.

In some embodiments of the compounds of formula (VIa) or (VIc), R ²⁵ is C ₁-C₆ alkylene (aryl); wherein alkylene and aryl are optionally and independently substituted with one or more R ^25a.

In some embodiments of the compounds of formula (VIa) or (VIc), each R ^25a is independently halogen 、-CN、-OH、-OR^a、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl.

In some embodiments of the compounds of formula (VIa) OR (VIc), each R ^25a is independently halogen, -OH, -OR ^a、-NR^cR^d、C₁-C₆ alkyl OR C ₁-C₆ haloalkyl.

In some embodiments of the compounds of formula (VIb) or (VIc), R ¹⁶ is hydrogen, -C (=o) R ²⁶、-C(＝O)OR²⁶ or C ₁-C₆ alkyl optionally substituted with one or more R ^16a. In some embodiments of the compounds of formula (VIb) OR (VIc), R ¹⁶ is hydrogen, -C (=o) R ²⁶, OR-C (=o) OR ²⁶. In some embodiments of the compounds of formula (VIb) OR (VIc), R ¹⁶ is-C (=o) R ²⁶ OR-C (=o) OR ²⁶. In some embodiments of the compounds of formula (VIb) or (VIc), R ¹⁶ is hydrogen. In some embodiments of the compounds of formula (VIb) or (VIc), R ¹⁶ is-C (=o) R ²⁶. In some embodiments of the compounds of formula (VIb) OR (VIc), R ¹⁶ is-C (=o) OR ²⁶.

In some embodiments of the compounds of formula (VIb) or (VIc), R ²⁶ is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^26a.

In some embodiments of compounds of formula (VIb) or (VIc), R ²⁶ is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl).

In some embodiments of compounds of formula (VIb) or (VIc), R ²⁶ is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, aryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl).

In some embodiments of compounds of formula (VIb) or (VIc), R ²⁶ is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, aryl, C ₁-C₆ alkylene (cycloalkyl) or C ₁-C₆ alkylene (aryl). In some embodiments of the compounds of formula (VIb) or (VIc), R ²⁶ is C ₁-C₆ alkylene (cycloalkyl) or C ₁-C₆ alkylene (aryl).

In some embodiments of the compounds of formula (VIb) or (VIc), R ²⁶ is C ₁-C₆ alkyl or C ₁-C₆ aminoalkyl.

In some embodiments of the compounds of formula (VIb) or (VIc), each R ^26a is independently halogen 、-CN、-OH、-OR^a、-OC(＝O)R^a、-OC(＝O)OR^b、-OC(＝O)NR^cR^d、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl.

In some embodiments of the compounds of formula (VIb) or (VIc), each R ^26a is independently halogen 、-CN、-OH、-OR^a、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl.

In some embodiments of the compounds of formula (VIb) OR (VIc), each R ^26a is independently halogen, -OH, -OR ^a、-NR^cR^d、C₁-C₆ alkyl OR C ₁-C₆ haloalkyl.

In some embodiments of the compounds of formula (VIb) or (VIc), each R ^26a is independently-OC (=o) R ^a or-NR ^cR^d.

In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, each R ^a is independently C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkyl (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkyl (aryl), or C ₁-C₆ alkyl (heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, each R ^a is independently C ₁-C₆ alkyl, C ₁-C₆ haloalkyl or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, each R ^a is independently C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl). In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, each R ^a is independently C ₁-C₆ alkyl, C ₁-C₆ haloalkyl or cycloalkyl, heterocycloalkyl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, each R ^a is independently C ₁-C₆ alkyl or C ₁-C₆ haloalkyl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, each R ^a is independently C ₁-C₆ alkyl.

In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, each R ^b is independently hydrogen, C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, each R ^b is independently hydrogen, C ₁-C₆ alkyl, C ₁-C₆ haloalkyl or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, each R ^b is independently hydrogen, C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl). In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, each R ^b is independently hydrogen, C ₁-C₆ alkyl, C ₁-C₆ haloalkyl or cycloalkyl, heterocycloalkyl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, each R ^b is independently hydrogen, C ₁-C₆ alkyl, or C ₁-C₆ haloalkyl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, each R ^b is independently hydrogen or C ₁-C₆ alkyl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, each R ^b is hydrogen. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, each R ^b is independently C ₁-C₆ alkyl.

In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, each R ^c and R ^d is independently hydrogen, C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, each R ^c and R ^d is independently hydrogen, C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, each R ^c and R ^d is independently hydrogen, C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkyl (heteroaryl). In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, each R ^c and R ^d is independently hydrogen, C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, each R ^c and R ^d is independently hydrogen, C ₁-C₆ alkyl, or C ₁-C₆ haloalkyl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, each R ^c and R ^d is independently hydrogen or C ₁-C₆ alkyl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, each R ^c and R ^d is hydrogen. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, each R ^c and R ^d is independently C ₁-C₆ alkyl.

In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, R ^c and R ^d are taken together with the atoms to which they are attached to form heterocycloalkyl optionally substituted with one or more R.

In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, each R is independently halogen, -CN, -OH, -OC ₁-C₆ alkyl, -NH ₂、-NHC₁-C₆ alkyl, -N (C ₁-C₆ alkyl) ₂、-NHC(＝O)OC₁-C₆ alkyl, -C (=o) C ₁-C₆ alkyl, -C (=o) OH, -C (=o) OC ₁-C₆ alkyl, -C (=o) NH ₂、-C(＝O)N(C₁-C₆ alkyl) ₂、-C(＝O)NHC₁-C₆ alkyl, C ₁-C₆ alkyl, or C ₁-C₆ haloalkyl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, each R is independently halogen, -CN, -OH, -OC ₁-C₆ alkyl, -NH ₂、-C(＝O)C₁-C₆ alkyl, -C (=o) OH, -C (=o) OC ₁-C₆ alkyl, -C (=o) NH ₂、C₁-C₆ alkyl, or C ₁-C₆ haloalkyl. In some embodiments of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, each R is independently halogen, -CN, -OH, -OC ₁-C₆ alkyl, -NH ₂、C₁-C₆ alkyl, or C ₁-C₆ haloalkyl.

In some embodiments of the compounds disclosed herein, each R¹¹、R²¹、R^21a、R¹²、R²²、R^22a、R¹⁵、R²⁵、R^25a、R¹⁶、R²⁶、R^26a、R^a、R^b、R^c、R^d、 cycloalkyl and heterocycloalkyl formed when two R ^25a are together, cycloalkyl and heterocycloalkyl formed when two R ^26a are together, and heterocycloalkyl formed when R ^c and R ^d are together, are optionally and independently substituted with one, two, three, or four substituents as defined herein.

In some embodiments of the compounds disclosed herein, each R¹¹、R²¹、R^21a、R¹²、R²²、R^22a、R¹⁵、R²⁵、R^25a、R¹⁶、R²⁶、R^26a、R^a、R^b、R^c、R^d、 cycloalkyl and heterocycloalkyl formed when two R ^25a are together, cycloalkyl and heterocycloalkyl formed when two R ^26a are together, and heterocycloalkyl formed when R ^c and R ^d are together are optionally and independently substituted with one, two, or three substituents as defined herein.

In some embodiments of the compounds disclosed herein, each R¹¹、R²¹、R^21a、R¹²、R²²、R^22a、R¹⁵、R²⁵、R^25a、R¹⁶、R²⁶、R^26a、R^a、R^b、R^c、R^d、 cycloalkyl and heterocycloalkyl formed when two R ^25a are together, cycloalkyl and heterocycloalkyl formed when two R ^26a are together, and heterocycloalkyl formed when R ^c and R ^d are together, are optionally and independently substituted with one or two substituents as defined herein.

Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, one skilled in the art will choose its groups and substituents to provide stable moieties and compounds.

Described herein are compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II), (III), (IV), (V), (VIa), (VIb) and (VIc) selected from the compounds in table 1, or pharmaceutically acceptable salts, solvates or stereoisomers thereof.

TABLE 1 exemplary Compounds

/>

Additional forms of the compounds disclosed herein

Isomers/stereoisomers

In some embodiments, the compounds described herein exist in geometric isomeric forms. In some embodiments, the compounds described herein have one or more double bonds. The compounds provided herein include all cis (cis), trans (trans), cis (syn), trans (anti), trans (E) and cis (Z) isomers, as well as their corresponding mixtures. In some cases, the compounds described herein have one or more chiral centers, and each center exists in either the R configuration or the S configuration. The compounds described herein include all diastereoisomeric, enantiomeric and epimeric forms and their corresponding mixtures. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereomers resulting from a single preparation step, combination, or interconversion are used in the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by: reacting a racemic mixture of compounds with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereoisomers, and recovering the optically pure enantiomer. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.), and are separated by exploiting these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or, preferably, by separation/resolution techniques based on differences in solubility. In some embodiments, the optically pure enantiomer as well as the resolving agent is then recovered by any practical means that does not result in racemization.

Labeled compounds

In some embodiments, the compounds described herein are present in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically-labeled compounds in the form of pharmaceutical compositions. Thus, in some embodiments, compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as ²H、³H、¹³C、¹⁴C、^l5N、¹⁸O、¹⁷O、³¹P、³²P、³⁵S、¹⁸F and ³⁶ Cl, respectively. The compounds described herein, and pharmaceutically acceptable salts, solvates or stereoisomers thereof, containing the above-mentioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds (e.g., those into which radioisotopes such as ³ H and ¹⁴ C are incorporated) are useful in drug and/or substrate tissue distribution assays. Tritiated (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) isotopes are particularly preferred for their ease of preparation and detectability. Furthermore, substitution with heavy isotopes such as deuterium (i.e., ² H) results in certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.

In some embodiments, the compounds described herein are labeled by other means, including but not limited to using chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Pharmaceutically acceptable salts

In some embodiments, the compounds described herein are present in the form of pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

In some embodiments, the compounds described herein have an acidic group or a basic group and thus react with any of a variety of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein or solvates or stereoisomers thereof, or by separately reacting the purified free form compound with a suitable acid or base and isolating the salt formed thereby.

Examples of pharmaceutically acceptable salts include those prepared by reacting the compounds described herein with an inorganic acid, an organic acid or an inorganic base, such salts include acetates, acrylates, adipates, alginates, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1, 4-dioate, camphorite, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentapropionate, caprate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, hemisulfate, heptanoate, caproate, hexyne-1, 6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propionate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, toluene sulfonate and xylene sulfonate.

Furthermore, the compounds described herein may be prepared as pharmaceutically acceptable salts by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including but not limited to inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, metaphosphoric, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2] oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4' -methylenebis- (3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, t-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. In some embodiments, other acids, such as oxalic acid, while not pharmaceutically acceptable per se, are used in the preparation of salts useful as intermediates in the process of obtaining the compounds disclosed herein, solvates or stereoisomers thereof, and pharmaceutically acceptable acid addition salts thereof.

In some embodiments, those compounds described herein that contain free acid groups are reacted with a suitable base (such as a hydroxide, carbonate, bicarbonate, sulfate of a pharmaceutically acceptable metal cation), with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary or quaternary amine. Representative salts include alkali metal or alkaline earth metal salts such as lithium, sodium, potassium, calcium and magnesium salts, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N ⁺(C_1-4 alkyl) ₄, and the like.

Representative organic amines for use in forming the base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It is to be understood that the compounds described herein also include quaternization of any basic nitrogen-containing groups they contain. In some embodiments, the water-soluble or oil-soluble or dispersible product is obtained by such quaternization.

Solvates of the formula

In some embodiments, the compounds described herein exist as solvates. The present invention provides methods of treating diseases by administering such solvates. The invention further provides methods of treating diseases by administering such solvates as pharmaceutical compositions.

Solvates contain stoichiometric or non-stoichiometric amounts of solvent and, in some embodiments, are formed from pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water or alcoholates are formed when the solvent is an alcohol. Solvates of the compounds described herein may be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein may be conveniently prepared from water/organic solvent mixtures using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol. Furthermore, the compounds provided herein may exist in unsolvated forms as well as solvated forms. In general, for the purposes of the compounds and methods provided herein, solvated forms are considered equivalent to unsolvated forms.

Tautomers

In some cases, the compounds exist as tautomers. The compounds described herein include all possible tautomers in the formulae described herein. Tautomers are compounds that interconvert by migration of a hydrogen atom, accompanied by a transition between a single bond and an adjacent double bond. In the bond arrangement where tautomerism may occur, there will be a chemical equilibrium of the tautomers. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent and pH.

Prodrugs

"Prodrug" means a compound that, in some embodiments, is converted under physiological conditions or by solvolysis to a biologically active compound described herein. Thus, the term "prodrug" refers to a precursor of a pharmaceutically acceptable biologically active compound. Prodrugs are generally inactive when administered to a subject, but are converted to the active compound in vivo, for example, by hydrolysis. Prodrug compounds generally provide solubility, histocompatibility, or delayed release advantages in mammalian organisms (see, e.g., bundgard, h., design of Prodrugs (1985), pages 7-9,21-24 (Elsevier, amsterdam). Prodrugs are delivered by any of the known methods described herein, including but not limited to oral, intravenous, intraperitoneal, or other methods of administration known to those of skill in the art.

Discussion of prodrugs is provided in Higuchi, T.et al, "Pro-drugs as Novel DELIVERY SYSTEMS," A.C.S. symposium Series, volume 14, and Bioreversible CARRIERS IN Drug Design, edwards B.Roche, eds., american Pharmaceutical Association and Pergamon Press, 1987.

The term "prodrug" is also meant to include any covalently bound carrier that releases the active compound in vivo when such prodrug is administered to a mammalian subject. As described herein, prodrugs of an active compound are prepared by modifying functional groups present in the active compound such that the modification is cleaved into the parent active compound in a conventional procedure or in vivo. Prodrugs include compounds wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino, or free sulfhydryl group, respectively. In some embodiments, a prodrug includes any moiety bound to a heteroatom, such as the nitrogen of pyridine, that is cleaved in vivo to form the active compound or metabolite thereof. Examples of prodrugs include, but are not limited to, acetate, formate, phosphate, and benzoate derivatives of alcohol or amine functional groups in the active compounds, and the like.

In some embodiments, the prodrug is a salt. In some embodiments, the prodrug is a phosphate. In some embodiments, the prodrug is an alkyl phosphate. In some embodiments, the prodrug is an alkylated heteroaromatic salt. In some embodiments, the prodrug is a pyridinium salt. In some embodiments, the prodrug is a pyridinium alkyl phosphate. In some embodiments, the prodrug is a pyridinium methylphosphonate. In some embodiments, the prodrug comprises an alkyl phosphate bound to a heteroatom. In some embodiments, the prodrug comprises an alkyl phosphate bound to a heteroatom of a heterocycle.

In some embodiments, a prodrug is any compound that, when administered to a biological system, produces a biologically active compound due to a spontaneous chemical reaction, an enzymatically catalyzed chemical reaction, and/or a metabolic chemical reaction, or a combination thereof. In other embodiments, prodrugs are formed using groups attached to functional groups associated with a drug or active compound that is cleaved in vivo, such as HO-, HS-, HOOC-, NHR-. In some embodiments, prodrugs include, but are not limited to, carboxylic acid esters wherein the group is an alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and esters of hydroxyl, thiol, and amine wherein the attached group is an acyl group, alkoxycarbonyl, aminocarbonyl, phosphate, or sulfate. The groups illustrated above are exemplary, not exhaustive, and other classes of prodrugs are also possible. Such prodrugs of the disclosed compounds fall within this range. In some embodiments, the compounds of the application are prodrugs themselves, and can be converted to other forms when administered to a biological system, including biologically active compound forms.

In some embodiments, the prodrug undergoes some form of chemical conversion to produce a compound that is biologically active or a precursor of a biologically active compound. In some cases, the prodrug has biological activity, higher or lower than the intended active drug itself, and is used to improve the therapeutic efficacy or safety of the drug by improving oral bioavailability and/or pharmacodynamic half-life, etc. The prodrug forms of the compounds are used, for example, to increase bioavailability, improve the acceptability of a subject, such as by masking or reducing undesirable characteristics, such as bitter taste or gastrointestinal irritation, altering solubility, such as for intravenous use, providing prolonged or sustained release or delivery, improving the ease of formulation, or providing site-specific delivery of a compound. Prodrugs are described in Richard B.Silverman at The Organic Chemistry of Drug DESIGN AND Drug Action, ACADEMIC PRESS, san Diego,1992, chapter 8: "Prodrugs and Drug DELIVERY SYSTEMS" at pages 352-401; design of Prodrugs, ELSEVIER SCIENCE, amsterdam,1985, edited by bundgaard; drug DELIVERY SYSTEMS, oxford uni v. Press, oxford,1980, edited by roche Design of Biopharmaceutical Properties through Prodrugs and Analogs,American Pharmaceutical Association,Washington,1977; and edited by r.l.juliano.

In some embodiments, the prodrug comprises a phosphorus moiety, including a phosphate salt or derivative thereof. One such prodrug is the aryl amidate (mcguilgan) type. One report discloses pharmacokinetic evaluation of aryl amidate prodrugs of abacavir in cynomolgus monkeys. (C.McGuigan et al ,"Application of phosphoramidate pronucleotide technology to abacavir leads to a significant enhancement of antiviral potency,"J.Med.Chem.2005,48,3504-3515).

In some embodiments, the compounds of the application comprise a prodrug moiety that is a carbamate, thiocarbamate, or urea to mask an amino group on the active compound. In some embodiments, the prodrug moiety of the carbamate, thiocarbamate, or urea is metabolized in vivo to provide a free amino moiety on the active compound.

Therapeutic method

In one aspect, the present disclosure provides a method of treating, preventing, and/or reducing the severity or extent of a viral infection by administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II), (III), (IV), (V), (VIa), (VIb), and (VIc), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition comprising the compound.

The compounds described herein are useful in a variety of applications for human and animal health. In some embodiments, the compounds described herein are inhibitors of coronaviruses.

In some embodiments, quantification of viral load or other evidence of infection is used to determine efficacy of treatment.

In some embodiments, the compounds described herein reduce viral load in an individual with a coronavirus infection.

As used herein, the term "administration" or "administration" refers to any route of introducing or delivering a composition or formulation to achieve a desired function or treatment. Administration may be by any route suitable for delivering the composition or formulation. Thus, the delivery route may include intravenous, intramuscular, intraperitoneal or subcutaneous delivery. Administration includes self-administration and administration by others.

As used herein, the terms "patient," "subject," "individual," and the like are used interchangeably and refer to any animal or cell thereof, whether in vitro or in situ, suitable for use in the methods described herein. In certain non-limiting embodiments, the patient, subject, or individual is a human.

As used herein, the terms "prevent" and "prevention" refer to taking action to prevent the development of a disease or disorder, or to minimize the extent of a disease or disorder, or to slow the progression thereof, prior to the onset of an apparent disease or disorder.

As used herein, the term "cure" refers to curing, rehabilitating, or restoring to a good state of health or allowing a period of time for which the disease does not recur, such that the risk of recurrence is small.

A subject receiving a therapy described herein (e.g., a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II), (III), (IV), (V), (VIa), (VIb), and (VIc), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition comprising the compound) may experience a reduction in viral count or an improvement in at least one symptom associated with a viral infection (including, e.g., fever, cough, fatigue, pain, etc.) as a result of the therapy.

In one aspect, the present disclosure provides a method for treating, preventing, and/or lessening the severity or extent of a viral infection including, for example, single stranded sense RNA virus, coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV), zika virus, dengue fever, yellow fever, west nile virus, hendra virus, newcastle disease virus, venezuelan equine encephalitis virus, chikungunya virus, semliki forest virus, sindbis virus, avian influenza a, porcine reproductive and respiratory syndrome virus, and human immunodeficiency virus type 1. In another aspect, the present disclosure provides a method for treating, preventing, and/or lessening the severity or extent of a viral infection, including, for example, DNA virus, equine herpes virus type 1, pseudorabies virus, BK polyomavirus, and porcine circovirus 2.COVID-19 pandemic (SARS-CoV-2, a single stranded positive sense RNA virus) is closely related to severe acute respiratory syndrome coronavirus (SARS-CoV).

In some embodiments, the infection is a viral infection. In some embodiments, the infection is caused by SARS-CoV or SARS-CoV-2 virus. In some embodiments, the infection is COVID or COVID-19.

In some embodiments, the viral infection is caused by a virus selected from the group consisting of: coronavirus disease 2019 (SARS-CoV-2), yellow fever, eastern equine encephalitis virus, human Immunodeficiency Virus (HIV), "african swine fever virus", arboviridae, adenoviridae, arenaviridae, arterivirus, astroviridae, rhabdoviridae, sinviridae, biglyaviridae, bunyaviridae, calicivviridae, cauliflower viridae, circoviridae, coronaviridae, vesicular phage, ebola virus, delta viridae, filoviridae, flaviviridae, iridoviridae, mononegavirales, myotail phage, papilloma virus, papovaviridae, paramyxoviridae, prions, parvoviridae, algae deoxyriboviridae, poxviridae, potyviridae, reoviridae, sinoviridae, retrovirus, multilayer phage, togaviridae, poxviridae, papilloma, coronavirus, influenza, sendai virus (SeV), sindbis virus, han virus, western poxvirus, common cold of any combination thereof.

Zaire ebola virus, more commonly referred to as ebola virus, is one of six known species in the genus ebola. Four of the six known ebola viruses, including EBOV, cause severe and often fatal hemorrhagic fever in humans and other mammals, known as Ebola Virus Disease (EVD). In some embodiments, the viral infection is caused by an ebola virus. In some embodiments, the viral infection is caused by ebola virus.

Composition/formulation

The compounds described herein are administered to a subject in need thereof as a pharmaceutical composition alone or in combination with a pharmaceutically acceptable carrier, excipient or diluent according to standard pharmaceutical practice. In one embodiment, the compounds of the invention may be administered to an animal. The compounds may be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.

In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in conventional manner using one or more pharmaceutically acceptable excipients which facilitate processing of the active compound into a pharmaceutically acceptable formulation. Suitable formulations depend on the route of administration selected. The general description of the pharmaceutical compositions described herein may be found, for example, in Remington: THE SCIENCE AND PRACTICE of Pharmacy, nineteenth edition (Easton,Pa.:Mack Publishing Company,1995);Hoover,John E.,Remington's Pharmaceutical Sciences,Mack Publishing Co.,Easton,Pennsylvania 1975;Liberman,H.A. and Lachman, l. Editions, pharmaceutical Dosage Forms, MARCEL DECKER, new York, n.y.,1980; and Pharmaceutical Dosage Forms and Drug DELIVERY SYSTEMS, seventh edition (Lippincott Williams & Wilkins 1999), such disclosures being incorporated by reference.

In some embodiments, the pharmaceutically acceptable excipient is selected from the group consisting of carriers, binders, fillers, suspensions, flavors, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, humectants, plasticizers, stabilizers, permeation enhancers, wetting agents, defoamers, antioxidants, preservatives, and any combination thereof.

The pharmaceutical compositions described herein are administered to a subject by suitable routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes of administration. Pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposome dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, freeze-dried formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.

Pharmaceutical compositions comprising the compounds described herein, or pharmaceutically acceptable salts, solvates or stereoisomers thereof, are manufactured in a conventional manner, such as, by way of example only, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compressing processes.

Pharmaceutical compositions for oral use are obtained by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable adjuvants (if desired) to obtain tablets or dragee cores. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents can be added, such as cross-linked sodium carboxymethyl cellulose, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. In some embodiments, dyes or pigments are added to the tablet or dragee coating for identifying or characterizing different combinations of active compound doses.

Pharmaceutical compositions for oral administration include push-fit capsules made of gelatin, as well as sealed soft capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Push-fit capsules contain the active ingredient mixed with fillers (such as lactose), binders (such as starches) and/or lubricants (such as talc or magnesium stearate) and, optionally, stabilizers. In soft capsules, the active compounds are dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin or liquid polyethylene glycols. In some embodiments, a stabilizer is added.

Pharmaceutical compositions for parenteral use are formulated as infusions or injections. In some embodiments, pharmaceutical compositions suitable for injection or infusion include sterile aqueous solutions, or dispersions, or sterile powders, which contain a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the pharmaceutical composition comprises a liquid carrier. In some embodiments, the liquid carrier is a solvent or liquid dispersion medium that includes, for example, water, saline, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glycerides, and any combination thereof. In some embodiments, the pharmaceutical composition further comprises a preservative to prevent the growth of microorganisms.

As used herein, the term "composition" or "pharmaceutical composition" refers to a composition comprising a therapeutically effective compound and a pharmaceutically acceptable carrier, and optionally other materials, such as one or more inert components (e.g., a detectable agent or label) or one or more active components. The pharmaceutical compositions facilitate administration of a therapeutically effective compound to a subject.

As used herein, the term "carrier" refers to a diluent, adjuvant, excipient, or vehicle in which a pharmaceutical composition is administered. Pharmaceutically acceptable carriers may include one or more physiologically compatible solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like. The composition may include components such as diluents, binders, stabilizers, buffers, salts, lipophilic solvents, preservatives or mixtures thereof. Examples of pharmaceutically acceptable carriers include, but are not limited to, water, saline, phosphate buffered saline, aqueous dextrose, glycerol. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, dextrose, gelatin, mannitol, cellulose malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried milk, glycerol, propylene, glycol, water, ethanol and the like.

The carrier may also encompass buffers or pH adjusting agents, such as salts prepared from organic acids or bases, optionally mixed with non-toxic surfactants. Examples of buffers include, but are not limited to, salts of organic acids such as salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid, tris, tromethamine hydrochloride, and phosphate buffers. Additional carriers may include polymeric excipients or additives such as polyvinylpyrrolidone, polysucrose (a polymeric sugar), dextrates (e.g., cyclodextrins such as 2-hydroxypropyl-orthorhombic (cyclodextrin), polyethylene glycol, flavoring agents such as cherry or wintergreen flavor, antimicrobial agents, sweeteners, antioxidants, antistatic agents. The composition may comprise a pharmaceutical carrier or excipient, a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II), (III), (IV), (V), (VIa), (VIb) and (VIc), and may additionally comprise other pharmaceutical agents (MEDICINAL AGENT), pharmaceutical agents (pharmaceutical agent), carriers, adjuvants, binders, and the like. The pharmaceutical compositions of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene and the like.

The compositions may take the form of solid, semi-solid, lyophilized powder or liquid dosage forms such as, for example, solutions, suspensions, emulsions, aerosols, gels, implants, microneedles, tablets, pills, capsules, soft elastic or hard gelatin capsules, skin patches, pandas (gummy bears), powders, suspensions, extended release formulations, and the like, e.g., in unit dosage forms suitable for simple administration of precise dosages. In one embodiment, the composition takes the form of a tablet, capsule, liquid capsule, sublingual tablet, sublingual spray, nasal spray, fondant and/or skin patch.

In one aspect, the compositions are liquid-based formulations, including but not limited to emulsions, suspensions, solutions, elixirs or syrups in which the disclosed compounds are dissolved and/or suspended, or are in the form of liquid-containing capsules wherein the disclosed compounds are dissolved and/or suspended in the liquid portion of the capsule core. The composition may be a capsule filled with a therapeutically effective amount of a liquid pharmaceutical formulation.

Combination of two or more kinds of materials

Disclosed herein are methods of treating coronavirus infections using the compounds disclosed herein in combination with additional therapeutic agents for treating coronavirus infections.

In some embodiments, the compounds disclosed herein are administered concurrently in combination with an additional therapeutic agent for treating a coronavirus infection. In some embodiments, the compounds disclosed herein are administered sequentially in combination with an additional therapeutic agent for treating a coronavirus infection.

For the treatment of arenaviridae virus infection or coronavirus infection, preferably, the other active therapeutic agent has activity against arenaviridae virus infection (especially lassa virus), coronavirus infection and hooning virus infection. Non-limiting examples of such other active therapeutic agents are ribavirin, fampicvir (also known as T-705 or Avigan), T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, ST-193, and mixtures thereof. The compounds and compositions of the present disclosure are also intended for use with general care provided to patients suffering from arenaviridae virus infections, including parenteral fluids (including dextrose and lactated ringer's fluid) and nutraceuticals, antibiotics (including metronidazole and cephalosporin antibiotics, such as ceftriaxone and cefuroxime) and/or antifungals, fever and pain medications, antiemetics (such as metoclopramide) and/or antidiarrheals, vitamins and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatory agents (such as ibuprofen), analgesics, and drugs for other common diseases in the patient population, such as antimalarial agents (including artemether and artesunate-benzol combination therapy), typhoid vaccines (typhoid) (including quinolone antibiotics, such as ciprofloxacin, macrolide antibiotics, such as azithromycin, cephalosporin antibiotics, such as ceftriaxone or aminopenicillin, such as ampicillin), or shigella.

Any of the compounds of the present disclosure may also be combined with one or more additional active therapeutic agents in a single dosage form for simultaneous or sequential administration to a patient. The combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations.

Co-administration of a compound of the present disclosure with one or more other active therapeutic agents generally refers to simultaneous or sequential administration of the compound of the present disclosure and one or more other active therapeutic agents such that a therapeutically effective amount of both the compound of the present disclosure and the one or more other active therapeutic agents are present in the body of the patient.

Co-administration includes administering a unit dose of a compound of the present disclosure before or after administering a unit dose of one or more other active therapeutic agents, e.g., within seconds, minutes, or hours of administering one or more other active therapeutic agents. For example, a unit dose of a compound of the present disclosure may be administered first, followed by a unit dose of one or more other active therapeutic agents within seconds or minutes. Alternatively, a unit dose of one or more other therapeutic agents may be administered first, followed by administration of a unit dose of a compound of the present disclosure within seconds or minutes. In some cases, it may be desirable to first administer a unit dose of a compound of the present disclosure, and then, after a period of hours (e.g., 1-12 hours), administer a unit dose of one or more other active therapeutic agents. In other cases, it may be desirable to first administer a unit dose of one or more other active therapeutic agents, and then, after a period of hours (e.g., 1-12 hours), administer a unit dose of a compound of the disclosure.

Combination therapies may provide "synergy" and "synergy", i.e., an effect achieved when the active ingredients are used together that is greater than the sum of the effects produced by the compounds alone. When the active ingredients are: (1) When co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or parallel as separate formulations; or (3) by some other scheme, a synergistic effect can be obtained. When delivered in alternating therapy, synergy may be obtained when the compounds are administered or delivered sequentially, e.g., in separate tablets, pills, or capsules, or by different injections in separate syringes. Generally, during alternating therapy, an effective dose of each active ingredient is administered sequentially, i.e., serially, while in combination therapy, an effective dose of two or more active ingredients are administered together. Synergistic antiviral effects mean that the antiviral effect is greater than the expected net additive effect of the individual compounds in the combination.

Other non-limiting examples of additional therapeutic agents for treating coronavirus infections include:

TLR agonists

In some embodiments, the compounds described herein are used in combination with TLR agonists (TLR 7, 8 and/or 9). In some embodiments, the TLR agonist is RG7795, GS-9620, SM360320, or AZD 8848.

RIG-I agonists

In some embodiments, the compounds described herein are used in combination with a RIG-I agonist. In some embodiments, the RIG-I agonist is inarigivir.

Interferon

In some embodiments, the compounds described herein are used in combination with an interferon. In some embodiments, the interferon is interferon alpha (IFN-a), interferon alpha-2 a, recombinant interferon alpha-2 a, polyethylene glycol interferon alpha-2 a, interferon alpha-2 b, recombinant interferon alpha-2 b, interferon alpha-2 bXL, polyethylene glycol interferon alpha-2 b, glycosylated interferon alpha-2 b, interferon alpha-2 c, recombinant interferon alpha-2 c, interferon beta-1 a, polyethylene glycol interferon beta-1 a, interferon delta, interferon lambda (IFN-1), polyethylene glycol interferon lambda-1, interferon omega, interferon tau, interferon gamma (IFN-g), interferon alfacon-1, interferon alpha-n 3, albumin interferon alpha-2 b, BLX-883, DA-3021, PI 101 (also referred to as AOP 2014), PEG-infergen, belerofon, INTEFEN-IFN, albumin/interferon alpha 2a fusion protein, rHSA-IFN alpha 2a, rHSA-2 b, IFN alpha-64, SA-IFN; in particular polyethylene glycol interferon alpha-2 a, polyethylene glycol interferon alpha-2 b, glycosylated interferon alpha-2 b, polyethylene glycol interferon beta-1 a or polyethylene glycol interferon lambda-1.

Preparation of the Compounds

The size and scale of the synthetic process will vary depending on the desired amount of the final product. It should be understood that while specific reactants and amounts are provided in the examples, those skilled in the art will recognize that other alternative and equally viable collections of reactants of the same compounds will also result. Thus, where typical oxidants, reductants, solvents of various nature (aprotic, nonpolar, polar, etc.) are used, equivalents will be known in the art and are contemplated herein for use in the methods of the invention.

For example, in all cases where a desiccant is used, contemplated desiccants include all desiccants reported in the literature and known to the skilled artisan, such as, but not limited to, magnesium sulfate, sodium sulfate, calcium chloride, potassium hydroxide, sulfuric acid, quicklime, phosphorus pentoxide, potassium carbonate, sodium, silica gel, alumina, calcium hydride, lithium Aluminum Hydride (LAH), potassium hydroxide, and the like. (see Burfield et al ,"Dessicant Efficiency in Solvent Drying.A Reappraisal by Application of a Novel Method for Solvent Water Assay,"J.Org.Chem.,42(18):3060-3065,1977).. One skilled in the art may optimize the amount of drying agent added in each post-treatment and is not particularly limited. Furthermore, while general guidance is provided for the post-treatment of the intermediates in each step, one skilled in the art will generally understand that other optional solvents and reagents may be equally replaced during the post-treatment step.

The following many steps represent various post treatments after termination of the reaction. Work-up generally involves quenching the reaction to terminate any remaining catalytic activity and starting reagents. This is typically followed by the addition of an organic solvent and separation of the aqueous layer from the organic layer. The product is typically obtained from the organic layer, and unused reactants and other spurious byproducts and unwanted chemicals are typically trapped in the aqueous layer and discarded. Work-up in standard organic synthesis procedures found throughout the literature is typically followed by drying the product by exposure to a desiccant to remove any excess water or aqueous byproducts partially dissolved in the organic layer and concentrating the remaining organic layer. Concentration of the product dissolved in the solvent may be achieved by any known means, such as evaporation under pressure, evaporation at elevated temperature and pressure, etc. Such concentration may be achieved by using standard laboratory equipment such as rotary evaporator distillation or the like. Optionally, one or more purification steps follow, which may include, but are not limited to, flash column chromatography, filtration through various media, and/or other methods of preparation known in the art (see, e.g., adison Ault, "Techniques and Experiments for Organic Chemistry," 6 th edition, university Science Books, sausalito, calif.,1998,Ann B.McGuire, eds., pages 45-59). Although certain organic co-solvents and quenchers may be indicated in the steps described below, other equivalent organic solvents and quenchers known to those skilled in the art may be equally employed and are fully contemplated herein. Furthermore, most of the post-treatments in most steps can be further varied depending on the preferences and the desired end use or end product. Drying and evaporation (a conventional step on the organic synthesis chemist's bench) need not be used and can be considered optional in all steps. The number of extractions with the organic solvent may be as many as one, two, three, four, five or ten or more depending on the desired results and the scale of the reaction. Unless otherwise indicated, the volume, amount of quencher and volume of organic solvent used in the post-treatment may vary depending on the specific reaction conditions and are optimized to produce the best results.

In addition, in the case where an inert gas or a rare gas is specified, any inert gas commonly used in the art may be substituted for the specified inert gas, such as argon, nitrogen, helium, neon, or the like.

Examples

The following examples are intended to illustrate the general procedure for preparing the compounds of the present invention.

While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Many variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. The following claims are intended to define the scope of the invention and their equivalents and methods and structures within the scope of these claims and their equivalents are thereby covered.

Example 1: synthesis of((2R, 3R,4R, 5S) -5- (4-aminoimidazo [2,1-f ] [1,2,4] triazin-7-yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methylisobutyrate (Compound 1).

Step 1: synthesis of (2R, 3R,4R, 5S) -5- (4-aminoimidazo [2,1-f ] [1,2,4] triazin-7-yl) -2- ((benzoyloxy) methyl) -4-fluoro-5-hydroxy-4-methyltetrahydrof-n-3-ylbenzoate (1.3).

To a suspension of 7-bromoimidazo [2,1-f ] [1,2,4] triazin-4-amine (1.1, 1g,4.7 mmol) in anhydrous THF (25 mL) was added dropwise MeMgCl (3N, 1.6mL,4.7 mmol) at 0deg.C followed by 1, 2-bis (chlorodimethylsilyl) ethane (1.0 g,4.7 mmol) in THF (5 mL) in one portion. A second portion of MeMgCl (3N, 1.6mL,4.7 mmol) was then added. The temperature was controlled below 10℃and ⁱ PrMgCl. LiCl (1.3N, 4mL,5.2 mmol) was added dropwise. The mixture was then stirred at RT for 2h. ((2R, 3R, 4R) -3- (benzoyloxy) -4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl) methylbenzoate (1.2, 3.5g,9.4 mmol) in THF (20 mL) was added dropwise at 0deg.C. The mixture was stirred at RT for an additional 5 hours. The reaction was quenched with NH ₄ Cl (saturated aqueous solution, 20 mL) and extracted with EtOAc (30 mL. Times.3). The combined organics were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (2% to 10% MeOH/DCM) to give 1.3 (1.3 g,51% yield) as a white solid. MS (ESI): the calculated mass for C ₂₅H₂₂FN₅O₆ was 507.16 and the m/z found was 508[ M+H ] ⁺.

Step 2: synthesis of (2R, 3R,4S, 5S) -5- (4-aminoimidazo [2,1-f ] [1,2,4] triazin-7-yl) -2- ((benzoyloxy) methyl) -4-fluoro-4-methyltetrahydrof-n-3-ylbenzoate (1.4).

Triethylsilane (550 mg,4.73mmol,0.76 mL) and BF ₃-OEt₂ (1.4 g,4.73mmol,1.27 mL) were added to a solution of 1.3 (300 mg,0.5912 mmol) in DCE (30 mL) at 0 ℃. The solution was stirred at 55deg.C for 5 hours, then another portion of triethylsilane (550 mg,4.73mmol,0.76 mL) and BF ₃-OEt₂ (1.4 g,4.73mmol,1.27 mL) were added at 0deg.C. The mixture was stirred at 55℃for 16 hours. The reaction was quenched with NaHCO ₃ (saturated aqueous solution, 20 mL) and extracted with DCM (30 mL. Times.3). The combined organics were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (2% to 10% MeOH/DCM) to give 5 (550 mg,44% yield) as a white solid. MS (ESI): the calculated mass for C ₂₅H₂₂FN₅O₅ was 491.16 and the measured m/z was 492[ M+H ] ⁺.

Step 3: synthesis of (2R, 3R,4R, 5S) -5- (4-aminoimidazo [2,1-f ] [1,2,4] triazin-7-yl) -4-fluoro-2- (hydroxymethyl) -4-methyltetrahydrofuran-3-ol (1.5).

(2R, 3R,4S, 5S) -5- (4-aminoimidazo [2,1-f ] [1,2,4] triazin-7-yl) -2- ((benzoyloxy) methyl) -4-fluoro-4-methyltetrahydrof-n-3-ylbenzoate (1.4, 550mg,1.12 mmol) is dissolved in NH ₃ in MeOH (7N, 15 mL). The mixture was stirred at 25 ℃ for 24h and concentrated in vacuo. The residue was washed with DCM (5 ml×2) and dried in vacuo. The crude product was purified by preparative HPLC (acn=5-30% in 0.1% fa/H ₂ O) to give 1.5 (90 mg,28.4% yield) as a white solid. MS (ESI): for a calculated m/z of C ₁₁H₁₄FN₅O₃ of 283.11, the actual measurement was 284.0[M+H]⁺.¹H NMR(400MHz,MeOD)δ8.09(s,1H),7.75(s,1H),5.65(d,J＝24.7Hz,1H),4.18-4.10(m,1H),4.03-3.96(m,2H),3.85-3.82(m,1H),1.20(d,J＝22.0Hz,3H).).¹⁹F NMR(400MHz,MeOD)δ-156.26.

Step 4: synthesis of((2R, 3R,4R, 5S) -5- (4-aminoimidazo [2,1-f ] [1,2,4] triazin-7-yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methylisobutyrate.

To a solution of (2R, 3R,4R, 5S) -5- (4-aminoimidazo [2,1-f ] [1,2,4] triazin-7-yl) -4-fluoro-2- (hydroxymethyl) -4-methyltetrahydrofuran-3-ol (1.5) (80 mg,0.28 mmol) in DMPU (2 mL) was added HCl in dioxane (4M, 0.1 mL). The mixture solution was stirred at 25℃for 15min. Isobutyryl chloride (90 mg,0.84 mmol) was then added at 0deg.C, and the resulting mixture was stirred at 0deg.C for an additional 3h. The reaction was quenched with MeOH (2 mL) and purified by preparative HPLC to give the title compound as a white solid (12.18 mg,12% yield). MS (ESI): for a calculated m/z of C ₁₅H₂₀FN₅O₄ of 353.35, the actual measurement was 354.0.35[M+H]⁺.¹H NMR(400MHz,MeOD)δ8.10(s,1H),7.64(s,1H),5.65(d,J＝8.0Hz,1H),4.51-4.48(m,1H),4.18-4.10(m,2H),4.21-4.09(m,1H),3.91-3.97(m,1H),2.68-2.(m,1H),1.25(d,J＝20.0Hz,3H),1.21(d,J＝8.0Hz,6H).¹⁹F NMR(376MHz,CD₃OD)δ-155.75.

Synthesis of((2R, 3R,4R, 5R) -5- (2-amino-6- (methylamino) -9H-purin-9-yl) -3, 4-dihydroxy-4-methyltetrahydrof-n-2-yl) methylisobutyrate (Compound 2).

Step 1: synthesis of (2R, 3R,4R, 5R) -2- (2-amino-6-chloro-9H-purin-9-yl) -5- ((benzoyloxy) methyl) -3-methyltetrahydrofuran-3, 4-diyl dibenzoate (2.2).

DBU (0.96 g,6.30 mmol) and TMSOTf (1.87 g,8.40 mmol) were added dropwise to a suspension of (2S, 3R,4R, 5R) -5- ((benzoyloxy) methyl) -3-methyltetrahydrofuran-2, 3, 4-triyl tribenzoate (2.1, 1.22g,2.10 mmol) and 6-chloro-9H-purin-2-amine (0.39 g,2.30 mmol) in dry acetonitrile (25 ml) at-40 ℃. The mixture was stirred at-40 ℃ for 20min and then warmed to RT. After 30min, the mixture was heated and stirred at 65 ℃ for an additional 5h. The reaction was quenched with NaHCO ₃ (saturated aqueous solution, 120 mL) and extracted with DCM (40 mL. Times.3). The combined organics were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (0% to 40% EA/PE) to give 2.2 (800 mg,52.4% yield) as a yellow solid. MS (ESI): the calculated mass for C ₃₂H₂₆ClN₅O₇ was 627.15 and the m/z found was 628[ M+H ] ⁺.

Step 2: synthesis of (2R, 3R,4R, 5R) -2- (2-amino-6- (methylamino) -9H-purin-9-yl) -5- ((benzoyloxy) methyl) -3-methyltetrahydrofuran-3, 4-diyl dibenzoate (2.3).

To a solution of 3 (600 mg,0.96 mmol) in n-BuOH (30 mL) was added CH ₃NH₂. HCl (0.60 g,8.89 mmol) and triethylamine (0.42 g,4.16 mmol). The mixture solution was stirred at 90 ℃ for 4h, then the mixture was concentrated in vacuo. The crude product obtained was extracted with DCM (60 mL. Times.3). The combined organics were dried in vacuo to give 2.3 (600 mg, 93.8%) as a white solid. MS (ESI): the calculated m/z for C ₃₃H₃₀N₆O₇ was 622.24, found to be 623[ M+H ] ⁺.

Step 3: synthesis of (2R, 3R,4R, 5R) -2- (2-amino-6- (methylamino) -9H-purin-9-yl) -5- (hydroxymethyl) -3-methyltetrahydrofuran-3, 4-diol (2.4).

(2R, 3R,4R, 5R) -2- (2-amino-6- (methylamino) -9H-purin-9-yl) -5- ((benzoyloxy) methyl) -3-methyltetrahydrofuran-3, 4-diyldibenzoate (2.3, 0.60g,0.96 mmol) was dissolved in NH ₃ in MeOH (7M, 60 mL). The mixture was stirred at 30 ℃ for 72h and concentrated in vacuo. The residue was washed with DCM (40 ml×3) and dried in vacuo to give 2.4 (120 mg, 45.9%) as a white solid. MS (ESI): for a calculated m/z of C ₁₂H₁₈N₆O₄ of 310.31, the actual measurement was 311.2[M+H]⁺.¹H NMR(400MHz,CD₃OD)δ8.07(s,1H),5.91(s,1H),4.24(d,J＝8.7Hz,1H),4.02(d,J＝10.2Hz,2H),3.85(dd,J＝3.2Hz,3.2Hz,1H),3.04(s,3H),0.93(s,3H).

Step 4: synthesis of((2R, 3R,4R, 5R) -5- (2-amino-6- (methylamino) -9H-purin-9-yl) -3, 4-dihydroxy-4-methyltetrahydrofuran-2-yl) methylisobutyrate.

To a solution of 2.4 (100 mg,0.32 mmol) in DMPU (1 mL) was added HCl in dioxane (4M, 0.1 mL). The mixture solution was stirred at 0℃for 15min. Isobutyryl chloride (53 mg,0.50 mmol) was then added to the above solution at 0deg.C, and the resulting mixture was stirred at 0deg.C for an additional 2h. The mixture was purified by preparative HPLC to give the title compound as a white solid (55 mg,43.97% yield). MS (ESI): for a calculated m/z of C ₁₆H₂₄N₆O₅ of 380.18, the actual measurement was 381.1[M+H]⁺.¹H NMR(400MHz,MeOD)δ7.84(s,1H),5.92(s,1H),4.51(dd,J＝2.3Hz,2.3Hz,1H),4.43(dd,J＝4.8Hz,4.8Hz,1H),4.22-4.14(m,2H),3.05(s,3H),2.67(m,1H),1.20(dd,J＝7.0Hz,4.2Hz,7H),0.97(s,3H).

Synthesis of((2R, 3R,4R, 5R) -5- (2-amino-6- (methylamino) -9H-purin-9-yl) -4-fluoro-3-hydroxy-4-methyltetrahydrof-n-2-yl) methylisobutyrate (Compound 3).

Synthesis of (2R, 3R,4R, 5R) -5- (2-amino-6- (methylamino) -9H-purin-9-yl) -2- (((4-chlorobenzoyl) oxy) methyl) -4-fluoro-4-methyltetrahydrofuran-3-yl 4-chlorobenzoate (3.2).

To a solution of (2 r,3r,4r,5 r) -5- (2-amino-6-chloro-9H-purin-9-yl) -2- (((4-chlorobenzoyl) oxy) methyl) -4-fluoro-4-methyltetrahydrofuran-3-yl 4-chlorobenzoate (3.1, 200mg,0.34 mmol) in n-BuOH (20 mL) was added CH ₃NH₂ -HCl (200 mg,2.96 mmol) and triethylamine (141 mg,1.40 mmol). The mixture solution was stirred at 90 ℃ for 4h, then the mixture was concentrated in vacuo to give 3.1 (300 mg, crude) as a white solid. MS (ESI): the calculated m/z for C ₂₆H₂₃Cl₂FN₆O₅ was 588.11, found to be 589.3[ M+H ] ⁺.

Step 2: synthesis of (2R, 3R,4R, 5R) -5- (2-amino-6- (methylamino) -9H-purin-9-yl) -4-fluoro-2- (hydroxymethyl) -4-methyltetrahydrof-n-3-ol (3.3).

(2R, 3R,4R, 5R) -5- (2-amino-6- (methylamino) -9H-purin-9-yl) -2- (((4-chlorobenzoyl) oxy) methyl) -4-fluoro-4-methyltetrahydrofuran-3-yl 4-chlorobenzoate (3.2, 200mg,0.34 mmol) was dissolved in NH ₃ in MeOH (7N, 40 mL). The mixture was stirred at 30 ℃ for 36h and concentrated in vacuo. The mixture was purified by preparative HPLC to give 3.3 (55 mg,50.3% yield) as a white solid. MS (ESI): for a calculated m/z of C ₁₂H₁₇FN₆O₃ of 312.13, the actual measurement was 313.2[M+H]⁺.¹H NMR(400MHz,MeOD)δ7.97(s,1H),6.01(d,J＝18.1Hz,1H),4.30(dd,J＝9.1Hz,9.1Hz,1H),3.96-3.91(m,2H),3.76(dd,J＝3.3Hz,3.3Hz,1H),2.94(s,3H),1.06(d,J＝22.2Hz,3H).

Step 3: synthesis of((2R, 3R,4R, 5R) -5- (2-amino-6- (methylamino) -9H-purin-9-yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methylisobutyrate.

To a solution of (2 r,3r,4r,5 r) -5- (2-amino-6- (methylamino) -9H-purin-9-yl) -4-fluoro-2- (hydroxymethyl) -4-methyltetrahydrof-n-3-ol (3.3, 90mg,0.288 mmol) in DMPU (1 mL) was added HCl in dioxane (4 m,0.1 mL). The solution was stirred at 0deg.C for 15min. Isobutyryl chloride (0.1 mL,0.967 mmol) was then added at 0deg.C and the resulting mixture was stirred at 0deg.C for an additional 2h. The mixture was purified by preparative HPLC to give the title compound as a white solid (50 mg,44.5% yield). MS (ESI): for a calculated m/z of C ₁₆H₂₃FN₆O₄ of 382.18, the actual measurement was 383.3[M+H]⁺.¹H NMR(400MHz,MeOD)δ7.82(s,1H),6.10(d,J＝18.8Hz,1H),4.58(dd,J＝12.4,2.8Hz,1H),4.48-4.39(m,2H),4.21-4.19(m,1H),3.04(s,3H),2.70-2.63(m,1H),1.21(m,9H).¹⁹F NMR(377MHz,MeOD)δ-163.12.

Synthesis of((2R, 3R,4R, 5R) -5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methyl isobutyrate (Compound 4).

To a solution of 4.1 (100 mg,0.38mmol, commercially available) in DMPU (3 mL) was added HCl in dioxane (4M, 0.1 mL). The mixture solution was stirred at 25℃for 15 minutes. Isobutyryl chloride (205 mg,1.92 mmol) was then added at 0deg.C and the resulting mixture was stirred at 0deg.C for an additional 3 hours. The reaction was quenched with MeOH (2 mL) and purified by preparative HPLC to give the title compound as a white solid (60.32 mg,47% yield). MS (ESI): for a calculated m/z of C ₁₄H₁₉FN₂O₆ of 330.31, the actual measurement was 331.0[M+H]⁺.¹H NMR(400MHz,MeOD)δ7.66(d,J＝8.0Hz,1H),6.12(d,J＝20.0Hz,1H),5.75(d,J＝8.0Hz,1H),4.49(dd,J＝2.4Hz,2.4Hz,1H),4.42(d,J＝6.4Hz,1H),4.21-4.09(m,1H),3.91-3.97(m,1H),2.74-2.58(m,1H),1.39(d,J＝22.4Hz,3H),1.21(dd,J＝8.0Hz,1.6Hz,6H).¹⁹F NMR(376MHz,CD₃OD)δ-162.131.

Synthesis of((2R, 3R,4R, 5S) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methyl isobutyrate (Compound 5).

Synthesis of (2R, 3R,4R, 5S) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -2- ((benzoyloxy) methyl) -4-fluoro-5-hydroxy-4-methyltetrahydrof-n-3-ylbenzoate (5.2).

TMSCL (1.3 g,12 mmol) was added dropwise to a solution of 7-iodopyrrolo [2,1-f ] [1,2,4 ] triazin-4-amine (1.5 g,5.8 mmol) in dry THF (21 mL) under nitrogen at 25 ℃. The reaction mixture was clouded and stirred for 15min. The reaction mixture was then cooled to 0deg.C and MeMgCl (3.8 mL,3M,12 mmol) was added dropwise. The reaction mixture became clear. After stirring for 15min, i-PrMgCl-LiCl (4.4 mL,1.3M,5.8 mmol) was added dropwise. The reaction mixture was stirred for an additional 15min. The reaction mixture was cooled to-20℃and a solution of ((2R, 3R, 4R) -3- (benzoyloxy) -4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl) methylbenzoate (2.1 g,5.8 mmol) in dry THF (4 mL) was added dropwise to the flask. The reaction mixture was stirred under nitrogen at-20 ℃ for 1h. The reaction was quenched with saturated aqueous NH ₄ Cl (15 mL) and extracted with ethyl acetate (10 mL. Times.3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na ₂SO₄, then filtered, and the filtrate concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/petroleum ether, 0% to 10%) to give 5.2 (1.4 g,75% purity, 36% yield) as a yellow oil. MS (ESI): the calculated mass for C ₂₆H₂₃FN₄O₆ was 506.16 and the m/z found was 507[ M+H ] ⁺.

Synthesis of (2R, 3R,4S, 5S) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -2- ((benzoyloxy) methyl) -4-fluoro-4-methyltetrahydrof-n-3-ylbenzoate (5.3).

To a solution of 5.2 (0.70 g,1.4 mmol) and triethylsilane (0.48 g,4.1 mmol) in dry DCM (30 mL) was added dropwise boron trifluoride etherate (1.2 g,4.1 mmol) under nitrogen at 0deg.C. The reaction mixture was stirred at 0 ℃ for 2h. The reaction mixture was diluted with DCM (30 mL) and washed with saturated aqueous NaHCO ₃ (15 ml×2), then brine (15 mL), then the organic phase was dried over anhydrous Na ₂SO₄, filtered, and the filtrate concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/petroleum ether, 0% to 10%) to give 5.3 (0.49 g,36% yield) as a white solid. MS (ESI): the calculated mass for C ₂₆H₂₃FN₄O₅ was 490.17 and the m/z found was 491[ M+H ] ⁺.

Synthesis of (2R, 3R,4R, 5S) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -4-fluoro-2- (hydroxymethyl) -4-methyltetrahydrof-n-3-ol (5.4).

A solution of 5.3 (0.49 g,0.99 mmol) in NH ₃/MeOH (10 mL) was stirred at 25℃for 16 h. The reaction mixture was concentrated to dryness. The residue was purified by preparative HPLC [ gradient: purification of 5-30% acn in water (0.1% fa) gave 5.4 (0.20 g,71% yield) as a white solid. MS (ESI): the calculated mass for C ₁₂H₁₅FN₄O₃ was 282.11 and the measured m/z was 283[M+H]⁺.¹H NMR(400MHz,MeOD)δ7.82(s,1H),6.86(dd,J＝29.6,4.5Hz,2H),5.76(d,J＝25.2Hz,1H),4.13-3.95(m,3H),3.83(dd,J＝12.4,4.4Hz,1H),1.11(d,J＝22.0Hz,3H).

Synthesis of((2R, 3R,4R, 5S) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methyl isobutyrate (5).

To a solution of 5.4 (70 mg,0.25 mmol) in DMPU (1.0 mL) was added HCl/1, 4-dioxane (0.1 mL) at 0deg.C. The mixture solution was stirred for 10min, and isobutyryl chloride (0.13 g,1.2 mmol) was added dropwise to the flask. The reaction mixture was stirred under nitrogen at 0 ℃ for 1h and purified by preparative HPLC to give the title compound as a white solid (26 mg,30% yield). MS (ESI): the calculated mass for C ₁₆H₂₁FN₄O₄ was 352.15 and the measured m/z was 353[M+H]⁺.¹H NMR(400MHz,MeOD)δ7.83(s,1H),6.90(d,J＝4.6Hz,1H),6.71(d,J＝4.4Hz,1H),5.76(d,J＝25.6Hz,1H),4.53(d,J＝12.2Hz,1H),4.36(dd,J＝12.3Hz,5.2Hz,1H),4.17-4.11(m,1H),4.10-4.00(m,1H),2.73-2.64(m,1H),1.23(d,J＝6.8Hz,6H),1.14(d,J＝22.0Hz,3H).

EXAMPLE 6 Synthesis of (((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl (2- (octadecyloxy) ethyl) hydrogen phosphate (Compound 6).

Step 1.2 Synthesis of (octadecyloxy) ethyl hydrogen diphosphate (6.2).

To a solution of (R) -alkylene oxide-2-ylmethyl 4-methylbenzenesulfonate (100 mg,0.317 mmol) in THF (3 mL) and triethylamine (64 mg,0.635 mmol) was added phosphorus oxychloride (97 mg,0.635 mmol) in THF (1 mL), the solution was stirred at 0℃for 1h, then water was added, and the resulting mixture was stirred at 25℃for 16h. The reaction mixture was extracted with diethyl ether (5 mL. Times.3). The combined organic phases were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 6.2 (80 mg,57% yield) as a yellow solid. MS (ESI): for a calculated m/z of C ₂₀H₄₃O₅ P of 394.53, the actual measurement was 393.0[M-H]^-.¹H NMR(400MHz,CDCl3)δ7.80(d,J＝8.3Hz,2H),7.35(d,J＝6.4Hz,2H),4.11-3.96(m,3H),3.48-3.37(m,4H),2.45(s,3H),1.51(quint,J＝6.4Hz,2H),1.29-1.24(m,30H),0.88(t,J＝6.8Hz,3H).

Synthesis of (3 aR,4R,6 aR) -4- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6- (hydroxymethyl) -2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxole-4-carbonitrile (6.4).

Sulfuric acid (0.90 g, 98%) was added dropwise to a solution of 6.3 (prepared according to Siegel, d. Et al j. Med. Chem.2017,60,1648-1661, 2g, 0.006mol) and 2, 2-dimethoxypropane (3.45 g,0.033 mol) in acetone (50 mL) at 25 ℃ for 0.5h, then heated to 45 ℃ for 0.5h. The reaction mixture was quenched with NaHCO ₃ (saturated aqueous solution, 10 mL) and extracted with EtOAc (15 mL. Times.3). The combined organic phases were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 5% MeOH/DCM) to give 6.4 (2.3 g,96% yield) as a white solid. MS (ESI): the calculated m/z for C ₁₅H₁₇N₅O₄ was 331.33, found to be 332.0[ M+H ] ⁺.

Synthesis of (((3 aR,4R,6 aR) -6- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) methyl (2- (octadecyloxy) ethyl) hydrogen phosphate (6.5).

To a solution of 6.4 (262 mg,0.663 mmol), 6.2 (200 mg,0.603 mmol) and 4-dimethylaminopyridine (66 mg,0.543 mmol) in pyridine (10 mL) was added DCC (249 mg,1.207 mmol) and the resulting mixture was stirred at 90℃for 16h. The solution was concentrated under reduced pressure to give a crude product which was purified by preparative HPLC to give 6.5 (150 mg,33% yield) as a white solid. MS (ESI): the calculated m/z for C ₃₅H₅₈N₅O₈ P was 707.85, found to be 706.3[ M-H ] ^-.

Synthesis of (((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl (2- (octadecyloxy) ethyl) hydrogen phosphate (6).

To a solution of 6.5 (150 mg,0.211 mmol) in THF (5 mL) at 0deg.C was added dropwise HCl (0.3 mL,12M aqueous solution) and the mixture was stirred at 25deg.C for 16h. The reaction was quenched with NaHCO ₃ (saturated aqueous solution, 5 mL), concentrated under reduced pressure and purified by preparative HPLC to give the title compound as a white solid (120.88 mg,84% yield). MS (ESI): for a calculated m/z of C ₃₂H₅₄N₅O₈ P of 667.78, the actual measurement was 666.4[M-H]^-.¹H NMR(400MHz,MeOD)δ7.91(s,1H),7.03(d,J＝5.2Hz,1H),6.95(d,J＝5.2Hz,1H),4.85(d,J＝5.2Hz,1H),4.36-4.32(m,1H),4.27(t,J＝5.2Hz,1H),4.16-4.04(m,2H),3.90-3.81(m,2H),3.48-3.45(m,2H),3.40-3.35(m,2H),1.55-1.48(m,2H),1.29-2.25(m,30H),0.92(t,J＝6.4Hz,3H).³¹P NMR(162MHz,CD₃OD)δ0.36.

EXAMPLE 7 Synthesis of ((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl ((R) -2- (benzyloxy) -3- (octadecyloxy) propyl) hydrogen phosphate (Compound 7).

Synthesis of (S) -2-hydroxy-3- (octadecyloxy) propyl 4-methylbenzenesulfonate (7.2).

To a solution of (R) -oxiran-2-ylmethyl 4-methylbenzenesulfonate (7.1, 1.0g,4.39 mmol) and octadecan-1-ol (1.7 g,6.1 mmol) in dry DCM (20 mL) was added dropwise boron trifluoride etherate (8 drops) at 25℃under N ₂. The reaction mixture was stirred at 25 ℃ for 16h, then the solution was concentrated to dryness. The residue was purified by flash column chromatography (EtOAc/petroleum ether, 0% to 20%) to give 7.2 (1.4 g,63% yield) as a white solid. MS (ESI): the calculated mass for C ₂₈H₅₀O₅ S was 498.34 and the m/z found was 499[ M+H ] ⁺. Synthesis of (R) -2- (benzyloxy) -3- (octadecyloxy) propyl 4-methylbenzenesulfonate (7.3).

To a solution of 7.2 (1.0 g,2.01 mmol) in 1, 4-dioxane (20 mL) was added benzyl 2, 2-trichloroacetimidate (1.0 g,3.98 mmol) under N ₂ followed by trifluoromethanesulfonic acid (9 drops). The reaction mixture was stirred at 25℃for 1h. TLC showed complete consumption of 7.2. The reaction mixture was diluted with DCM (60 mL) and washed with saturated aqueous NaHCO ₃ (20 ml×2), then with water (20 mL), then the organic phase was dried over anhydrous Na ₂SO₄, filtered and the filtrate was concentrated to dryness. The residue was purified by flash column chromatography (EtOAc/petroleum ether, 0% to 20%) to give 7.3 (0.85 g,80% purity, 60% yield) as a colorless oil and used directly in the next step.

Synthesis of (R) -2- (benzyloxy) -3- (octadecyloxy) propan-1-ol (7.4).

Cesium acetate (0.48 g,2.50 mmol) was added to a solution of 7.3 (0.70 g,1.19 mmol) in dry DMF (2.5 mL) and dry DMSO (10 mL) under N ₂. The reaction mixture was stirred at 60℃for 16h. TLC showed complete consumption of starting material 7.3. The reaction mixture was quenched with water (15 mL) and extracted with diethyl ether (10 mL. Times.3). The organic phase was separated and washed with water (12 ml×3), dried over anhydrous Na ₂SO₄, filtered, and the filtrate concentrated to dryness, re-evaporated with toluene. The residue was dissolved with diethyl ether (10 mL) and LiAlH ₄ (90 mg,2.4 mmol) was added at 0 ℃. The reaction mixture was stirred at 0℃for 30min and at 25℃for 3h. TLC showed complete consumption of intermediate. The reaction mixture was quenched by very slow addition of water (5.0 mL). The mixture was filtered through celite. The mixture was separated and the aqueous phase extracted with DCM (3.0 ml×2). The combined organic phases were dried over anhydrous Na ₂SO₄, filtered, and the filtrate was concentrated to dryness. The residue was purified by flash column chromatography (EtOAc/petroleum ether, 0% to 20%) to give 7.4 (0.34 g,52% yield) as a milky oil ).¹H NMR(400MHz,CDCl₃)δ7.38-7.27(m,5H),4.73-4.61(dd,J＝36.0,11.6Hz,2H),3.78-3.52(m,5H),3.44(td,J＝6.8,1.6Hz,2H),1.57(quint,J＝7.2Hz,2H),1.33-1.24(m,30H),0.88(t,J＝7.2Hz,3H).

Synthesis of (S) -2- (benzyloxy) -3- (octadecyloxy) propyl hydrogen diphosphate (7.5).

To a solution of 7.4 (0.34 g,0.77 mmol) in dry THF (8.0 mL) at 0deg.C under N ₂ was added a solution of triethylamine (78 mg,0.77 mmol) and pyridine (61 mg,0.77 mmol) in dry THF (1.0 mL). The reaction mixture was stirred for 5min, and phosphorus oxychloride (0.24 g,1.5 mmol) was added dropwise to the flask at 0 ℃. The reaction mixture was stirred at 0℃for 4h. Water (5.0 mL) was then added very slowly to the flask. The reaction mixture was stirred at 25℃for 16h. The reaction mixture was extracted with diethyl ether (10 mL. Times.3). The organic phase was dried over anhydrous Na ₂SO₄ and concentrated to dryness to give 7.5 (0.40 g, crude) as a milky oil. MS (ESI): the calculated mass for C ₂₈H₅₁O₆ P was 514.34, the measured m/z was 513[M-H]^-.¹H NMR(400MHz,CDCl₃)δ7.35-7.26(m,5H),6.18(br,5H),4.67(dd,J＝25.7,11.8Hz,2H),4.20-3.99(m,2H),3.79(quint,J＝4.8Hz,1H),3.58-3.51(m,2H),3.42(td,J＝6.8,1.9Hz,2H),1.53(quint,J＝6.4Hz,2H),1.30-1.24(m,30H),0.88(t,J＝7.2Hz,3H).

Synthesis of((3 aR,4R,6 aR) -6- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) methyl ((R) -2- (benzyloxy) -3- (octadecyloxy) propyl) hydrogen phosphate (7.6).

To a solution of 7.5 (0.40 g,0.77 mmol), (3 aR,4R,6 aR) -4- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6- (hydroxymethyl) -2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxole-4-carbonitrile, 6.4 (0.23 g,0.69 mmol) and DMAP (94 mg,0.77 mmol) in pyridine (40 mL) was added DCC (0.24 mg,1.2 mmol). The reaction mixture was stirred at 90℃under N ₂ for 24h. The reaction mixture was concentrated to dryness and the residue was purified by preparative HPLC [ gradient: 50-95% MeOH in water (0.1% NH ₃·H₂ O) ] to give 7.6 (0.28 g,43% yield) as a white solid. MS (ESI): the calculated mass for C ₄₃H₆₆N₅O₉ P was 827.46 and the measured m/z was 826[M-H]^-.¹H NMR(400MHz,MeOD)δ8.02(s,1H),7.40-7.12(m,6H),7.08(d,J＝4.7Hz,1H),5.31(d,J＝6.3Hz,1H),5.07(dd,J＝6.3,2.5Hz,1H),4.68-4.58(m,3H),4.06(t,J＝4.7Hz,2H),3.97-3.86(m,2H),3.74(quint,J＝5.2Hz,1H),3.58-3.48(m,2H),3.43(t,J＝6.8Hz,2H),1.73(s,3H),1.55(quint,J＝6.8Hz,2H),1.42(s,3H),1.38-1.26(m,30H),0.92(t,J＝6.7Hz,3H).

Synthesis of (((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl (2- (octadecyloxy) ethyl) hydrogen phosphate (7).

To a solution of 7.6 (0.10 g,0.12 mmol) in dry THF (5.0 mL) was added concentrated aqueous HCl (0.05 mL) in dry THF (0.5 mL). The reaction mixture was stirred at 25℃for 16h. The reaction mixture was evaporated to dryness with a stream of nitrogen. The residue was purified by preparative HPLC [ gradient: 50% -95% meoh in water (0.1% nh ₃·H₂ O) ] to give the title compound as a white solid (74% yield). MS (ESI): the calculated mass for C ₄₀H₆₂N₅O₉ P was 787.43 and the measured m/z was 786[M-H]^-.¹H NMR(400MHz,MeOD)δ7.96(s,1H),7.36-7.20(m,5H),7.10(d,J＝4.7Hz,2H),4.79(d,J＝5.2Hz,1H),4.63(q,J＝11.9Hz,2H),4.37-4.33(m,1H),4.26(t,J＝5.4Hz,1H),4.19-4.03(m,2H),3.91(tq,J＝10.9,5.4Hz,2H),3.73(quint,J＝4.8Hz,1H),3.57-3.45(m,2H),3.41(t,J＝6.0Hz,2H),1.53(quint,J＝6.8Hz,2H),1.37-1.27(m,30H),0.92(t,J＝6.7Hz,3H).

Example 8.synthesis of 16- (((((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) (hydroxy) phosphoryl) oxy) hexadecanoic acid (compound 8).

Step 1.16 Synthesis of methyl hydroxyhexadecanoate (8.2).

To a solution of 16-hydroxyhexadecanoic acid (8.1, 50mg,0.183 mmol) in MeOH (4 mL) was added p-TSA (13 mg,0.073 mmol), and the mixture was stirred at 25℃for 16h. The reaction was quenched with NaHCO ₃ (50 mg) and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography (EtOAc/petroleum ether, 0% to 30%) to give 8.2 (40 mg,76% yield) as a white solid. MS (ESI): the calculated m/z for C ₁₇H₃₄O₃ was 286.25, found to be 285.0[ M-H ] ^-.

Step 2.16 synthesis of methyl 16- (phosphonooxy) hexadecanoate (8.3).

To a solution of 8.2 (50 mg,0.174 mmol) in THF (3 mL) and triethylamine (35 mg,0.349 mmol) was added dropwise a solution of phosphorus oxychloride (54 mg,0.349 mmol) in THF (1 mL), the solution was stirred at 0 ℃ for 1h, then water was added, and the resulting mixture was stirred at 25 ℃ for 16h. The solution was extracted with diethyl ether (5 mL. Times.3). The combined organic phases were dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give 8.3 (50 mg,70% yield) as a white solid. MS (ESI): the calculated m/z for C ₁₇H₃₅O₆ P was 366.43, found to be 365.0[ M-H ] ^-.

Step 3.synthesis of methyl 16- ((((3 aR,4R,6 aR) -6- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxan-4-yl) methoxy) (hydroxy) phosphoryl) oxy) hexadecanoate (8.4).

To a solution of 8.3 (50 mg,0.136 mmol), 4 (50 mg,0.15 mmol) and 4-dimethylaminopyridine (15 mg,0.122 mmol) in pyridine (5 mL) was added DCC (59 mg, 0.284 mmol) and the resulting mixture was stirred at 90℃for 16h. The solution was concentrated under reduced pressure to a residue, which was purified by preparative HPLC to give 8.4 (150 mg,33% yield) as a white solid. MS (ESI): the calculated m/z for C ₃₂H₅₀N₅O₉ P was 679.75, found to be 678.0[ M-H ] ^-.

Step 4.synthesis of 16- (((((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) (hydroxy) phosphoryl) oxy) hexadecanoic acid.

To a solution of 8.4 (400 mg,0.588 mmol) in THF (5 mL) at 0deg.C was added dropwise HCl (5 mL, 12M) and the mixture was stirred at 25deg.C for 16h. The reaction was quenched with NaHCO ₃ (saturated aqueous solution, 10 mL) and concentrated under reduced pressure to give the crude product. The residue was redispersed in MeOH (5 mL) and purified by preparative HPLC to give the title compound as a white solid (85.0 mg,23% yield). MS (ESI): for a calculated m/z of C ₂₈H₄₄N₅O₉ P of 625.66, the actual measurement was 624.3[M-H]^-.¹H NMR(400MHz,MeOD)δ7.78(s,1H),6.89(d,J＝5.2Hz,1H),6.80(d,J＝5.2Hz,1H),4.75(d,J＝5.2Hz,1H),4.25-4.20(m,1H),4.16(t,J＝5.2Hz,1H),3.94-3.90(m,2H),3.60-3.58(m,2H),2.19(t,J＝7.2Hz,2H),1.51-1.48(m,2H),1.38-1.35(m,2H),1.25-1.12(m,22H).³¹P NMR(162MHz,CD₃OD)δ0.54.

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 3-methylbutanoate (Compound 9).

The title compound was prepared according to the procedure of step 4 of example 5 using 6.3 and 3-methylbutyryl chloride. MS (ESI): the calculated mass for C ₁₇H₂₁N₅O₅ was 375.15, m/z found to be 376.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ7.92(br s,3H),6.90(d,J＝4.4Hz,1H),6.80(d,J＝4.4Hz,1H),6.32(d,J＝6Hz,1H),5.37(d,J＝6Hz,1H),4.68(d,J＝5.2Hz,1H),4.3(d,J＝6Hz,1H),4.1-4.2(m,2H),3.91(m,1H),2.15(m,2H),1.92(m,1H),0.86(m,6H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2-cyclohexylacetate (Compound 10).

The title compound was prepared according to the procedure for step 4 of example 5 using 6.3 and cyclohexylacetyl chloride. MS (ESI): the calculated mass for C ₂₀H₂₅N₅O₅ was 415.19, the measured m/z was 416.2[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ7.92(br s,3H),6.91(d,J＝4.4Hz,1H),6.80(d,J＝4.4Hz,1H),6.31(d,J＝6Hz,1H),5.37(d,J＝6Hz,1H),4.68(d,J＝5.2Hz,1H),4.22(d,J＝6Hz,1H),3.9-4.15(m,2H),3.92(m,1H),2.07(m,2H),1.5(br m,6H),1.0-1.2(m,3H),0.86-1.1(m,2H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2-phenylacetate (Compound 12).

The title compound was prepared according to the procedure for step 4 of example 5 using 6.3 and phenylacetyl chloride. MS (ESI): the calculated mass for C ₂₀H₁₉N₅O₅ was 409.14 and the measured m/z was 410.0[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ8.13(br s,2H),7.95(s,1H),7;.21-7.28(m,5H),6.91(d,J＝4.4Hz,1H),6.79(d,J＝4.4Hz,1H),6.3(br s,1H),5.39(br s,1H),4.65(d,J＝4.8Hz,1H),4.35(m,1H),3.9-4.2(m,2H),3.67(m,2H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl isobutyrate (Compound 14).

The title compound was prepared according to the procedure of step 4 of example 5 using 6.3 and isobutyryl chloride. MS (ESI): the calculated mass for C ₁₆H₁₉N₅O₅ was 361.1 and the measured m/z was 362.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ7.92(br s,3H),6.90(d,J＝4.8Hz,1H),6.80(d,J＝4.8Hz,1H),6.31(d,J＝6Hz,1H),5.37(d,J＝6Hz,1H),4.68(d,J＝5.2Hz,1H),4.1-4.3(m,3H),3.93(m,1H),2.53(m,1H),1.05(m,6H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methylpropionate (Compound 15).

The title compound was prepared according to the procedure of step 4 of example 5 using 6.3 and propionyl chloride. MS (ESI): the calculated mass for C ₁₅H₁₇N₅O₅ was 347.1, m/z found to be 347.9[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ7.92(br s,3H),6.91(d,J＝4.4Hz,1H),6.80(d,J＝4.4Hz,1H),6.31(d,J＝6Hz,1H),5.37(d,J＝6Hz,1H),4.68(d,J＝5.2Hz,1H),4.34(d,J＝6Hz,1H),3.9-4.2(m,2H),3.91(m,1H),2.3(q,J＝7.6Hz,2H),1.0(t,J＝7.6Hz,3H).

EXAMPLE 14 Synthesis of (2R, 3S,4R, 5R) -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-4-hydroxy-2- { [ (3-methylbutanoyl) oxy ] methyl } oxa-3-yl (2S) -2-amino-3-methylbutanoate (Compound 19).

Synthesis of [ (2R, 3S,4R, 5R) -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -3- { [ (2S) -2- { [ (tert-butoxy) carbonyl ] amino } -3-methylbutanoyl ] oxy } -5-cyano-4-hydroxyoxolan-2-yl ] methyl 3-methylbutanoate (19.1).

To a solution of [ (2R, 3S,4R, 5R) -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-3, 4-dihydroxyoxacyclopent-2-yl ] methyl 3-methylbutanoate (9, 300mg,0.799 mmol) in THF (15 mL) was added (2S) -2- { [ (tert-butoxy) carbonyl ] amino } -3-methylbutanoate (173.43 mg,0.799 mmol), EDCI (459.62 mg,2.397 mmol) and DMAP (292.91 mg,2.397 mmol) and the mixture was stirred at 25℃for 16h. The reaction was washed with EtOAc (5 ml. Times.3). The combined organics were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by preparative HPLC to give 19.1 (70 mg,14% yield) as a white solid. MS (ESI): the calculated m/z for C ₂₇H₃₈N₆O₈ was 574.28, found to be 575.2[ M+H ] ⁺. Synthesis of (2R, 3S,4R, 5R) -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-4-hydroxy-2- { [ (3-methylbutanoyl) oxy ] methyl } oxa-n-3-yl (2S) -2-amino-3-methylbutanoate (19).

To a solution of [ (2R, 3S,4R, 5R) -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -3- { [ (2S) -2- { [ (tert-butoxy) carbonyl ] amino } -3-methylbutanoyl ] oxy } -5-cyano-4-hydroxyoxa-pent-2-yl ] methyl 3-methylbutanoate (19.1, 100mg,0.174 mmol) in THF (5 mL) was added HCl in dioxane (4M, 3 mL) and the mixture stirred at 25℃for 4h. The mixture was stirred at 25℃for 16h. The reaction was concentrated in vacuo and purified by prep HPLC to give 19 (35.89 mg,39% yield) as a white solid. MS (ESI): for a calculated m/z of C ₂₂H₃₀N₆O₆ of 474.22, the actual measurement was 475.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.93-7.90(br,s,3H),6.93(d,J＝4.8Hz,1H),6.87(d,J＝4.8Hz,1H),6.62-6.60(m,1H),5.12-5.10(m,2H),4.45-4.43(m,1H),4.27(dd,J＝12.0,4.4Hz,1H),4.24(dd,J＝12.0,4.8Hz,1H),3.23(d,J＝5.2Hz,1H),2.16-2.15(m,2H),1.99-1.97(m,1H),1.93-1.91(m,1H),0.93-0.83(m,12H).

Example 15 synthesis of (((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-3- ((pivaloyloxy) methoxy) tetrahydrofuran-2-yl) methyl 3-methylbutanoate (compound 24).

To a suspension of 9 (100 mg,0.266 mmol), dibutyltin oxide (86.2 mg,0.346 mmol) and tetrabutylammonium bromide (112 mg, 0.348 mmol) in DCE (1.0 mL) was added iodomethyl pivalate (161 mg,0.266 mmol). The reaction mixture was stirred under nitrogen at 75 ℃ for 2h. The reaction mixture was diluted with EA (5.0 mL) and washed with saturated aqueous Na ₂S₂O₃ (3.0 mL x 2) then water (3.0 mL x 2), brine (3.0 mL). The organic phase was dried over anhydrous Na ₂SO₄ and filtered. The filtrate was concentrated to dryness. The residue was purified by preparative HPLC to give 24 (22.09 mg,16% yield) as a white solid. MS (ESI): for a calculated m/z of C ₂₃H₃₁N₅O₇ of 489.22, the actual measurement was 490.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92(br s,3H),6.92(d,J＝4.4Hz,1H),6.83(d,J＝4.8Hz,1H),6.50(d,J＝6.0Hz,1H),5.32(dd,J＝23.2,6.4Hz,2H),5.00–4.95(dd,J＝6.0,4.8Hz,1H),4.37–4.28(m,2H),4.18–4.09(m,2H),2.14(d,J＝7.2Hz,2H),1.97–1.86(m,1H),1.11(s,9H),0.86(dd,J＝6.8,4.0Hz,6H).

Synthesis of (2R, 3S,4R, 5R) -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-2- { [ (2-cyclohexylacetyl) oxy ] methyl } -4-hydroxyoxa-pent-3-yl (2S) -2-amino-3-methylbutanoate (Compound 27).

Synthesis of (2R, 3S,4R, 5R) -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-2- { [ (2-cyclohexylacetyl) oxy ] methyl } -4-hydroxyoxolan-3-yl (2S) -2-amino-3-methylbutanoate (27.1).

Compound 27.1 was prepared according to the procedure of step 1 of example 19 using 10 and (2S) -2- { [ (tert-butoxy) carbonyl ] amino } -3-methylbutanoic acid. MS (ESI): the calculated mass for C ₃₀H₄₂N₆O₈ was 614.31 and the m/z found was 615.3[ M+H ] ⁺.

Synthesis of (2R, 3S,4R, 5R) -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-2- { [ (2-cyclohexylacetyl) oxy ] methyl } -4-hydroxyoxolan-3-yl (2S) -2-amino-3-methylbutanoate (27).

The title compound 27 was prepared according to the procedure for step 2 of example 19 using 27.1. MS (ESI): the calculated mass for C ₂₅H₃₄N₆O₆ was 514.25, the measured m/z was 515.4[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92-7.90(br,s,3H),6.93(d,J＝4.8Hz,1H),6.82(d,J＝4.4Hz,1H),6.60(d,J＝2.8Hz,1H),5.12-5.09(m,2H),4.44-4.40(m,1H),4.29(dd,J＝12.0,3.6Hz,1H),4.22(dd,J＝12.0,4.8Hz,1H),3.23(d,J＝5.2Hz,1H),2.19–2.12(m,2H),2.03–1.96(m,1H),1.57-1.50(m,6H),1.15-1.05(m,3H),0.94-0.85(m,8H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-3- ((3-methylbutanoyl) oxy) tetrahydrofuran-2-yl) methyl L-valine ester (Compound 33).

Synthesis of (((3 aR,4R,6 aR) -6- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) methyl (tert-butoxycarbonyl) -L-valine ester (33.1).

The title compound was prepared according to step 1 of example 16 using intermediate acetonate 6.4.

Synthesis of (((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl (tert-butoxycarbonyl) -L-valine ester (33.2).

To a solution of 33.1 (3.50 g,6.6 mmol) in MeOH (70 mL) was added TsOH. H ₂ O (2.51 g,13.2 mmol) at 0deg.C. The mixture was stirred at 0 ℃ for 30 minutes, then warmed to 20 ℃ and stirred for 16h. After completion, the mixture was concentrated in vacuo to give a residue, which was purified by preparative HPLC [ gradient: 40-60% ACN in water (0.1% FA) ] to obtain 33.2 (1.25 g,2.5mmol,37.8% yield) as a white solid. MS (ESI): for a calculated m/z of C ₂₂H₃₀N₆O₇ of 490.22, the actual measurement was 491.10[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.05(d,J＝70.8Hz,3H),7.17–7.09(m,1H),6.97(d,J＝4.4Hz,1H),6.84(d,J＝4.4Hz,1H),6.34(s,1H),5.40(s,1H),4.68(d,J＝4.8Hz,1H),4.38–4.18(m,3H),3.98–3.83(m,2H),1.96(d,J＝6.8Hz,1H),1.34(d,J＝32.4Hz,9H),0.82(t,J＝6.0Hz,6H).

Synthesis of (((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-3- ((3-methylbutanoyl) oxy) tetrahydrofuran-2-yl) methyl (tert-butoxycarbonyl) -L-valine ester (33.3).

To a solution of 33.2 (200 mg,0.40 mmol) in NMP (1 mL) was added HCl in dioxane (4M, 0.5 mL) and the solution was stirred at 20deg.C for 15 min. The reaction mixture was cooled at 0deg.C, and 3-methylbutyryl chloride (0.25 mL,2.0 mmol) was added immediately. The reaction was stirred at 20℃for 16 hours. The reaction was diluted with ACN (2 mL) and purified by preparative HPLC to give 33.3 (90 mg,37.3% yield) as a white solid. MS (ESI): for a calculated m/z of C ₂₇H₃₈N₆O₈ of 574.28, the actual measurement was 575.2[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ7.93(br s,3H),7.16(d,J＝8.2Hz,1H),6.93(d,J＝4.8Hz,1H),6.87(d,J＝4.8Hz,1H),6.63(d,J＝6.0Hz,1H),5.17–4.99(m,2H),4.49–4.44(m,1H),4.31(t,J＝7.2Hz,2H),3.80(dd,J＝44.0,37.6Hz,1H),2.26(d,J＝7.2Hz,2H),2.10–2.02(m,1H),1.99–1.88(m,1H),1.30(d,J＝52.8Hz,9H),0.93(d,J＝6.8Hz,6H),0.86(d,J＝26.4Hz,1H),0.78(t,J＝6.8Hz,5H).

Synthesis of (((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-3- ((3-methylbutanoyl) oxy) tetrahydrofuran-2-yl) methyl L-valine ester (33).

To a solution of 33.3 (60 mg,0.104 mmol) in DCM (0.5 mL) at 0deg.C was added HCl in 1, 4-dioxane (0.5 mL, 4M) and the reaction was stirred at 20deg.C for 1 h. The reaction was diluted with ACN (2 mL) and purified by preparative HPLC to give 33 (37.6 mg,71.1% yield) as a white solid. MS (ESI): for a calculated m/z of C ₂₂H₃₀N₆O₆ of 474.22, the actual measurement was 475.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ7.93(br s,3H),6.93(d,J＝4.8Hz,1H),6.87(d,J＝4.8Hz,1H),6.64(s,1H),5.15–5.07(m,2H),4.47(q,J＝4.4Hz,1H),4.37–4.24(m,2H),3.14(d,J＝5.2Hz,1H),2.26(d,J＝7.2Hz,2H),2.15–2.01(m,1H),1.85–1.75(m,1H),0.95–0.91(m,6H),0.84–0.68(m,6H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3- (2-cyclohexylacetoxy) -4-hydroxytetrahydrofuran-2-yl) methyl L-valine ester (Compound 34).

Synthesis of (((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3- (2-cyclohexylacetoxy) -4-hydroxytetrahydrofuran-2-yl) methyl (tert-butoxycarbonyl) -L-valine ester (34.1).

The title compound was prepared according to the procedure for step 2 of example 33 using 33.2 and 2-cyclohexylacetyl chloride. MS (ESI): for a calculated m/z of C ₃₀H₄₂N₆O₈ of 614.31, the actual measurement was 615.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.93(br s,3H),8.10-7.80(m,3H),7.17(d,J＝8.0Hz,1H),6.93(d,J＝4.4Hz,2H),6.87(d,J＝4.4Hz,1H),6.64(d,J＝5.6Hz,1H),5.08(s,2H),4.45(d,J＝3.2Hz,1H),4.30(s,2H),3.84(t,J＝7.2Hz,1H),2.25(d,J＝6.8Hz,2H),1.93(dd,J＝13.2,6.8Hz,1H),1.75-1.55(m,6H),1.37(s,7H),1.25-1.11(m4H),0.94(d,J＝12.0Hz,2H),0.77(t,J＝7.2Hz,6H).

Synthesis of (((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3- (2-cyclohexylacetoxy) -4-hydroxytetrahydrofuran-2-yl) methyl L-valine ester (34).

The title compound was prepared according to the procedure for step 3 of example 33 using 34.1. MS (ESI): for a calculated m/z of C ₂₅H₃₄N₆O₆ of 514.25, the actual measurement was 515.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92(br s,3H),6.93(d,J＝4.8Hz,1H),6.86(d,J＝4.8Hz,1H),6.63(s,1H),5.16–5.04(m,2H),4.47(q,J＝4.4Hz,1H),4.33–4.24(m,2H),3.12(d,J＝5.2Hz,1H),2.26(d,J＝6.8Hz,2H),1.80–1.57(m,7H),1.27–1.06(m,3H),1.00–0.89(m,2H),0.84–0.73(m,6H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-3- (2-phenylacetyloxy) tetrahydrofuran-2-yl) methyl L-valine ester (Compound 36).

Synthesis of (((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-3- (2-phenylacetyloxy) tetrahydrofuran-2-yl) methyl (tert-butoxycarbonyl) -L-valine ester (36.1).

The title compound was prepared according to the procedure for step 2 of example 33 using 33.2 and 2-phenylacetyl chloride. MS (ESI): for a calculated m/z of C ₃₀H₃₆N₆O₈ of 608.26, the actual measurement was 609.15[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92(s,3H),7.32(d,J＝4.4Hz,4H),7.28–7.23(m,1H),7.15(d,J＝8.0Hz,1H),6.93(d,J＝4.4Hz,1H),6.87(d,J＝4.4Hz,1H),6.69(d,J＝6.0Hz,1H),5.11(t,J＝5.2Hz,2H),4.48(d,J＝4.0Hz,1H),4.33–4.24(m,2H),3.88–3.66(m,3H),1.91(dt,J＝13.2,6.8Hz,1H),1.40–1.20(m,9H),0.75(dd,J＝8.8,7.2Hz,6H).

Synthesis of (((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-3- (2-phenylacetyloxy) tetrahydrofuran-2-yl) methyl L-valine ester (36).

The title compound was prepared according to the procedure for step 3 of example 33 using 36.1. MS (ESI): for a calculated m/z of C ₂₅H₂₈N₆O₆ of 508.21, the actual measurement was 509.25[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92(s,3H),7.32(d,J＝4.0Hz,4H),7.30–7.23(m,1H),6.93(d,J＝4.8Hz,1H),6.87(d,J＝4.8Hz,1H),6.69(d,J＝6.4Hz,1H),5.18–5.08(m,2H),4.49(q,J＝4.4Hz,1H),4.28(d,J＝4.4Hz,2H),3.76(q,J＝16.0Hz,2H),3.10(d,J＝5.2Hz,1H),1.82–1.70(m,,1H),0.78(d,J＝6.8,3H),0.72(d,J＝6.8Hz,3H).

Synthesis of((2R, 3S,4R, 5R) -3-acetoxy-5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxytetrahydrofuran-2-yl) methyl L-valine ester (Compound 37).

Synthesis of (((2R, 3S,4R, 5R) -3-acetoxy-5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxytetrahydrofuran-2-yl) methyl (tert-butoxycarbonyl) -L-valine ester (37.1).

The title compound was prepared according to the procedure for step 2 of example 33 using 33.2 and acetyl chloride .¹H NMR(400MHz,DMSO)δ7.93(br s,3H),7.15(d,J＝8.0Hz,1H),6.93(d,J＝4.8Hz,1H),6.86(d,J＝4.8Hz,1H),6.63(d,J＝6.0Hz,1H),5.13–5.00(m,2H),4.51–4.44(m,1H),4.35–4.23(m,2H),3.89–3.81(m,1H),2.08(s,3H),1.98–1.85(m,2H),1.37(s,9H),0.78(t,J＝6.8Hz,6H).

Synthesis of (((2R, 3S,4R, 5R) -3-acetoxy-5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxytetrahydrofuran-2-yl) methyl L-valine ester (37).

The title compound was prepared according to the procedure for step 3 of example 33 using 37.1. MS (ESI): for a calculated m/z of C ₁₉H₂₄N₆O₆ of 432.18, the observed value is 433.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.93(br s,3H),6.93(d,J＝4.4Hz,1H),6.86(d,J＝4.8Hz,1H),6.63(d,J＝4.4Hz,1H),5.16–4.99(m,2H),4.52–4.46(q,J＝4.4Hz,1H),4.35–4.24(m,2H),3.18–3.12(m,1H),2.09(s,3H),1.84–1.74(m,1H),0.81(d,J＝6.8Hz,3H),0.76(d,J＝6.8Hz,3H). synthesis of example 21 (((2 r,3s,4r,5 r) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-3- (isobutyryloxy) tetrahydrofuran-2-yl) methyl L-valine ester (compound 38).

Synthesis of (((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-3- (isobutyryloxy) tetrahydrofuran-2-yl) methyl (tert-butoxycarbonyl) -L-valine ester (38.1).

The title compound was prepared according to the procedure for step 2 of example 33 using 33.2 and 2-methylpropanoyl chloride. MS (ESI): for a calculated m/z of C ₂₆H₃₆N₆O₈ of 560.26, the actual measurement was 561.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92(br s,3H),7.16(d,J＝8.4Hz,1H),6.92(d,J＝4.8Hz,1H),6.87(d,J＝4.4Hz,1H),6.58(d,J＝6.0Hz,1H),5.17–5.07(m,2H),4.46(dd,J＝8.4,4.8Hz,1H),4.34–4.24(m,2H),3.88–3.82(m,1H),2.65–2.57(m,1H),1.98–1.86(m,1H),1.42–1.20(m,9H),1.14(t,J＝7.2Hz,6H),0.77(t,J＝7.2Hz,6H).

Synthesis of (((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-3- (isobutyryloxy) tetrahydrofuran-2-yl) methyl L-valine ester (38).

The title compound was prepared according to the procedure for step 3 of example 33 using 38.1. MS (ESI): for a calculated m/z of C ₂₁H₂₈N₆O₆ of 460.21, the actual measurement was 461.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92(br s,3H),6.93(d,J＝4.8Hz,1H),6.86(d,J＝4.4Hz,1H),6.57(d,J＝6.0Hz,1H),5.18–5.08(m,2H),4.50–4.43(m,1H),4.37–4.23(m,2H),3.12(d,J＝4.0Hz,1H),2.66–2.56(m,1H),1.83–1.72(m,1H),1.15(t,J＝7.2Hz,6H),0.77(dd,J＝22.8,6.8Hz,6H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-3- (propionyloxy) tetrahydrofuran-2-yl) methyl L-valine ester (Compound 39).

Synthesis of (((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-3- (propionyloxy) tetrahydrofuran-2-yl) methyl (tert-butoxycarbonyl) -L-valine ester (39.1).

The title compound was prepared according to the procedure for step 2 of example 33 using 33.2 and propionyl chloride. MS (ESI): for a calculated m/z of C ₂₅H₃₄N₆O₈ of 546.24, the actual measurement was 547.30[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.93(s,3H),7.16(d,J＝8.0Hz,1H),6.93(d,J＝4.4Hz,1H),6.86(d,J＝4.4Hz,1H),6.60(d,J＝6.0Hz,1H),5.17–5.03(m,2H),4.47(d,J＝4.4Hz,1H),4.30(d,J＝4.4Hz,2H),3.80(dd,J＝44.4,37.6Hz,1H),2.40(q,J＝7.6Hz,2H),1.93(dt,J＝13.2,6.4Hz,1H),1.37(s,9H),1.07(t,J＝7.6Hz,3H),0.78(t,J＝6.8Hz,6H).

Synthesis of (((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-3- (propionyloxy) tetrahydrofuran-2-yl) methyl L-valine ester (39).

The title compound was prepared according to the procedure for step 3 of example 33 using 39.1. MS (ESI): for a calculated m/z of C ₂₀H₂₆N₆O₆ of 446.19, the actual measurement was 447.25[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92(s,3H),6.93(d,J＝4.8Hz,1H),6.84(d,J＝4.4Hz,1H),6.61(d,J＝5.6Hz,1H),5.18–5.05(m,2H),4.49(q,J＝4.4Hz,1H),4.42–4.24(m,3H),3.32(d,J＝5.2Hz,1H),2.40(q,J＝7.6Hz,2H),1.92–1.81(m,1H),1.08(t,J＝7.6Hz,3H),0.86–0.75(m,6H).

EXAMPLE 23 Synthesis of (2R, 3S,4R, 5R) -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-4-hydroxy-2- { [ (2-phenylacetyl) oxy ] methyl } oxa-lan-3-yl (2S) -2-amino-3-methylbutanoate (Compound 43).

Synthesis of (2R, 3S,4R, 5R) -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-4-hydroxy-2- { [ (2-phenylacetyl) oxy ] methyl } oxa-lan-3-yl (2S) -2- { [ (tert-butoxy) carbonyl ] amino } -3-methylbutanoate (43.1).

Compound 43.1 was prepared according to the procedure of step 1 of example 19 using 12 and (2S) -2- { [ (tert-butoxy) carbonyl ] amino } -3-methylbutanoic acid. MS (ESI): the calculated mass for C ₃₀H₃₆N₆O₈ was 608.26 and the m/z found was 608.3[ M+H ] ⁺.

Synthesis of (2R, 3S,4R, 5R) -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-4-hydroxy-2- { [ (2-phenylacetyl) oxy ] methyl } oxa-lan-3-yl (2S) -2-amino-3-methylbutanoate (43).

The title compound 27 was prepared according to the procedure for step 2 of example 19 using 43.1. MS (ESI): synthesis of { [ (2R, 3S,4R, 5R) -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-4-hydroxy-2- { [ (2-phenylacetyl) oxy ] methyl } oxacyclopent-3-yl ] oxy } methyl 2, 2-dimethylpropionate (compound 48) for mass calculated for C ₂₅H₂₈N₆O₆ as 508.21, m/z found as 509.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.93(br,s,3H),7.30–7.17(m,5H),6.94(d,J＝4.8Hz,1H),6.84(d,J＝4.8Hz,1H),6.58(d,J＝5.6Hz,1H),5.17–5.11(m,1H),5.08-5.07(m,1H),4.46-4.44(m,1H),4.34(dd,J＝12.0,3.6Hz,1H),4.25(dd,J＝12.4,5.2Hz,1H),3.66(s,2H),3.24(d,J＝5.2Hz,1H),2.00-1.97(m,1H),0.92(d,J＝6.8Hz,3H),0.88(d,J＝6.8Hz,3H). example 24.

To a solution of [ (2 r,3s,4r,5 r) -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-3, 4-dihydroxyoxapent-2-yl ] methyl 2-phenylacetate (12, 150mg, 0.365 mmol) in DCE (10 mL) under an atmosphere of N ₂ was added tetrabutylammonium bromide (153.55 mg,0.476 mmol), DBTO (118.60 mg,0.476 mmol) and iodomethyl pivalate (221.67 mg, 0.912 mmol) and the resulting mixture was stirred at 75 ℃ for 2h. The reaction was washed with DCM (5 mL. Times.3). The combined organics were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by preparative HPLC to give 48 (12 mg,6% yield) as a white solid. MS (ESI): for a calculated m/z of C ₂₆H₂₉N₅O₇ of 523.21, the actual measurement was 524.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.93(br,s,3H),7.29-7.24(m,3H),7.23–7.18(m,2H),6.94(d,J＝4.4Hz,1H),6.81(d,J＝4.4Hz,1H),6.48(d,J＝6.4Hz,1H),5.32(d,J＝6.4Hz,1H),5.26(d,J＝6.4Hz,1H),4.96–4.88(t,J＝5.6Hz,1H),4.34-4.30(m,2H),4.16-4.13(m,2H),3.65(s,2H),1.10(s,9H).

Synthesis of (2R, 3S,4R, 5R) -2- (acetoxymethyl) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxytetrahydrofuran-3-yl 3-methylbutanoate (Compound 49).

To a solution of 13 (100 mg,0.30 mmol) in NMP (1.0 mL) was added HCl/dioxane (0.5 mL, 4M). The mixture solution was stirred at 20℃for 15 minutes. The reaction mixture was cooled at 0deg.C, and 3-methylbutyryl chloride (0.29 mL,2.4 mmol) was added immediately. The reaction was stirred at 20℃for 16 hours. The reaction was diluted with ACN (2.0 mL) and purified by preparative HPLC to give 49 (11.3 mg,8.80% yield) as a white solid. MS (ESI): for a calculated m/z of C ₁₉H₂₃N₅O₆ of 417.16, the actual measurement was 418.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ7.93(br s,3H),6.93(d,J＝4.8Hz,1H),6.86(d,J＝4.8Hz,1H),6.59(d,J＝6.0Hz,1H),5.11(m,2H),4.44(dd,J＝8.8,4.0Hz,1H),4.31(dd,J＝12.2,3.6Hz,1H),4.19(dd,J＝12.2,5.2Hz,1H),2.27(d,J＝7.2Hz,2H),2.07(dt,J＝13.6,6.8Hz,1H),2.00(s,3H),0.94(dd,J＝6.8,0.8Hz,6H).

Synthesis of (2R, 3S,4R, 5R) -2- (acetoxymethyl) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxytetrahydrofuran-3-yl 2-cyclohexylacetate (Compound 50).

The title compound was prepared according to the procedure for step 1 of example 49 using compound 13 and 2-cyclohexylacetyl chloride. MS (ESI): the calculated mass for C ₂₂H₂₇N₅O₆ was 457.20 and the measured m/z was 458.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ7.93(br s,3H),6.93(d,J＝4.4Hz,1H),6.86(d,J＝4.4Hz,1H),6.62–6.53(m,1H),5.12–5.07(m,2H),4.43(dd,J＝8.4,4.4Hz,1H),4.31(dd,J＝12.0,3.6Hz,1H),4.19(dd,J＝12.0,5.2Hz,1H),2.26(d,J＝6.8Hz,2H),2.00(s,3H),1.81–1.58(m,6H),1.28–1.10(m,3H),1.01–0.90(m,2H).

Synthesis of (2R, 3S,4R, 5R) -2- [ (acetoxy) methyl ] -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-4-hydroxyoxa-pent-3-yl (2S) -2-amino-3-methylbutanoate (Compound 51).

Synthesis of (2R, 3S,4R, 5R) -2- [ (acetoxy) methyl ] -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-4-hydroxyoxa-pent-3-yl (2S) -2- { [ (tert-butoxy) carbonyl ] amino } -3-methylbutanoate (51.1).

Compound 51.1 was prepared according to the procedure of step 1 of example 19 using 13 and (2S) -2- { [ (tert-butoxy) carbonyl ] amino } -3-methylbutanoic acid. MS (ESI): the calculated mass for C ₂₄H₃₂N₆O₈ was 532.23 and the m/z found was 533.2[ M+H ] ⁺.

Synthesis of (2R, 3S,4R, 5R) -2- [ (acetoxy) methyl ] -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-4-hydroxyoxa-pent-3-yl (2S) -2-amino-3-methylbutanoate (51).

The title compound 51 was prepared according to the procedure for step 2 of example 19 using 51.1. MS (ESI): the calculated mass for C ₁₉H₂₄N₆O₆ was 432.18, the measured m/z was 433.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.90(br,s,3H),6.94(d,J＝4.4Hz,1H),6.88(d,J＝4.8Hz,1H),6.61-6.55(m,1H),5.20–5.09(m,2H),4.43-4.40(m,1H),4.31(dd,J＝12.0,3.6Hz,1H),4.20(dd,J＝12.0,5.2Hz,1H),3.23(d,J＝5.2Hz,1H),2.05-2.02(m,1H),2.00(s,3H),0.92(d,J＝6.8Hz,3H),0.86(d,J＝6.8Hz,3H).

Synthesis of (2R, 3S,4R, 5R) -2- (acetoxymethyl) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxytetrahydrofuran-3-yl 2-phenylacetate (Compound 52).

The title compound was prepared according to the procedure for example 17 using 13 and 2-phenylacetyl chloride. MS (ESI): for a calculated m/z of C ₂₂H₂₁N₅O₆ of 451.15, the actual measurement was 452.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.93(br s,3H),7.35–7.20(m,5H),6.93(d,J＝4.4Hz,1H),6.87(d,J＝4.4Hz,1H),6.66(d,J＝6.0Hz,1H),5.12(p,J＝5.6Hz,2H),4.46(dd,J＝9.2,4.0Hz,1H),4.31(dd,J＝12.0,3.6Hz,1H),4.17(dd,J＝12.0,5.2Hz,1H),3.77(q,J＝16.0Hz,2H),1.98(s,3H).

Synthesis of((2R, 3S,4R, 5R) -3-acetoxy-5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxytetrahydrofuran-2-yl) methyl acetate (Compound 53).

To a solution of 6.3 (2.00 g,6.90 mmol) in DMPU (6 mL) was added HCl/dioxane (2.6 mL, 4M). The mixture solution was stirred at 20℃for 15 minutes. The reaction mixture was cooled at 0deg.C and acetyl chloride (0.98 mL,13.8 mmol) was added immediately. The reaction was stirred at 0 ℃ for 1 hour. The reaction was diluted with ACN (4.0 mL) and purified by preparative HPLC to give 53 (380 mg,15.2% yield) as a white solid. MS (ESI): for a calculated m/z of C ₁₆H₁₇N₅O₆ of 375.12, the actual measurement was 376.0[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ7.94(br s,3H),6.93(dd,J＝4.8,2.0Hz,1H),6.86(d,J＝4.8Hz,1H),6.63–6.58(m,1H),5.09–5.04(m,2H),4.49–4.36(m,1H),4.37–4.24(m,1H),4.17(dt,J＝11.2,5.6Hz,1H),2.18–2.07(m,3H),2.01(d,J＝8.0Hz,3H).

Synthesis of (2R, 3S,4R, 5R) -2- (acetoxymethyl) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxytetrahydrofuran-3-yl isobutyrate (Compound 54).

The title compound was prepared according to the procedure for example 17 using 13 and isobutyryl chloride. MS (ESI): for a calculated m/z of C ₁₈H₂₁N₅O₆ of 403.15, the actual measurement was 404.20[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.93(s,3H),6.93(d,J＝4.4Hz,1H),6.87(d,J＝4.8Hz,1H),6.54(d,J＝6.0Hz,1H),5.18–5.08(m,2H),4.50–4.41(m,1H),4.31(dd,J＝12.4,4.0Hz,1H),4.20(dd,J＝12.0,5.2Hz,1H),2.63(q,J＝6.8Hz,1H),2.00(s,3H),1.15(dd,J＝7.2,6.0Hz,6H).

Synthesis of (2R, 3S,4R, 5R) -2- (acetoxymethyl) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxytetrahydrofuran-3-yl propionate (Compound 55).

The title compound was prepared according to the procedure for example 17 using 13 and propionyl chloride. MS (ESI): for a calculated m/z of C ₁₇H₁₉N₅O₆ of 389.13, the actual measurement was 390.10[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.93(s,3H),6.93(d,J＝4.8Hz,1H),6.86(d,J＝4.8Hz,1H),6.58(d,J＝4.8Hz,1H),5.10(p,J＝5.6Hz,2H),4.45(q,J＝4.0Hz,1H),4.32(dd,J＝12.0,3.6Hz,1H),4.18(dd,J＝12.0,5.2Hz,1H),2.40(q,J＝7.6Hz,2H),2.00(s,3H),1.08(t,J＝7.6Hz,3H).

Example 32 synthesis of { [ (2R, 3S,4R, 5R) -2- [ (acetoxy) methyl ] -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-4-hydroxyoxolan-3-yl ] oxy } methyl 2, 2-dimethylpropionate (compound 56).

Compound 56 was prepared according to the procedure of step 1 of example 48 using 13 and iodomethyl pivalate. MS (ESI): the calculated mass for C ₂₀H₂₅N₅O₇ was 447.18, the measured m/z was 448.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92(br,s,3H),6.92(d,J＝4.8Hz,1H),6.83(d,J＝4.8Hz,1H),6.49(d,J＝6.4Hz,1H),5.35(d,J＝6.4Hz,1H),5.28(d,J＝6.4Hz,1H),5.02–4.93(m,1H),4.39–4.25(m,2H),4.19–4.06(m,2H),2.00(s,3H),1.11(s,9H).

Example 33 synthesis of (2 r,3s,4r,5 r) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-2- ((isobutyryloxy) methyl) tetrahydrofuran-3-yl 3-methylbutanoate (compound 57).

The title compound was prepared according to the procedure for example 17 using 15 and 3-methylbutyryl chloride. MS (ESI): for a calculated m/z of C ₂₁H₂₇N₅O₆ of 445.20, the actual measurement was 446.20[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.93(s,3H),6.93(d,J＝4.8Hz,1H),6.85(d,J＝4.8Hz,1H),6.61(d,J＝6.4Hz,1H),5.17–5.12(m,1H),5.10–5.05(m,1H),4.46(q,J＝4.4Hz,1H),4.26(qd,J＝12.0,4.0Hz,2H),2.54(q,J＝6.8Hz,1H),2.27(d,J＝7.2Hz,2H),2.07(dt,J＝13.6,6.8Hz,1H),1.04(dd,J＝6.8,4.8Hz,6H),0.94(d,J＝6.4Hz,6H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3- (2-cyclohexylacetoxy) -4-hydroxytetrahydrofuran-2-yl) methyl isobutyrate (Compound 58).

The title compound was prepared according to the procedure for step 1 of example 49 using compound 14 and 2-cyclohexylacetyl chloride. MS (ESI): the calculated mass for C ₂₄H₃₁N₅O₆ was 485.23 and the measured m/z was 486.2[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ7.93(br s,3H),6.93(d,J＝4.4Hz,1H),6.85(d,J＝4.8Hz,1H),6.61(d,J＝6.4Hz,1H),5.16–5.11(m,1H),5.07(t,J＝6.0Hz,1H),4.45(q,J＝4.4Hz,1H),4.25(qd,J＝12.0,4.4Hz,2H),2.57–2.51(m,1H),2.28(d,J＝6.8Hz,2H),1.82–1.58(m,6H),1.23–0.90(m,11H).

Synthesis of (2R, 3S,4R, 5R) -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-4-hydroxy-2- { [ (2-methylpropanoyl) oxy ] methyl } oxa-lan-3-yl (2S) -2-amino-3-methylbutanoate (Compound 59).

Synthesis of (2R, 3S,4R, 5R) -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-4-hydroxy-2- { [ (2-methylpropanoyl) oxy ] methyl } oxa-lan-3-yl (2S) -2- { [ (tert-butoxy) carbonyl ] amino } -3-methylbutanoate (59.1).

Compound 59.1 was prepared according to the procedure of step 1 of example 19 using 14 and (2S) -2- { [ (tert-butoxy) carbonyl ] amino } -3-methylbutanoic acid. MS (ESI): the calculated mass for C ₂₆H₃₆N₆O₈ was 560.26 and the m/z found was 561.2[ M+H ] ⁺.

Step 2: synthesis of (2R, 3S,4R, 5R) -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-4-hydroxy-2- { [ (2-methylpropanoyl) oxy ] methyl } oxa-lan-3-yl (2S) -2-amino-3-methylbutanoate (59).

The title compound 59 was prepared according to the procedure of step 2 of example 19 using 59.1. MS (ESI): the calculated mass for C ₂₁H₂₈N₆O₆ was 460.21 and the measured m/z was 461.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.90(br,s,3H),6.93(d,J＝4.8Hz,1H),6.86(d,J＝4.4Hz,1H),6.62 -6.60(m,1H),5.14-5.10(m,2H),4.46-4.45(m,1H),4.27(d,J＝4.0Hz,1H),4.24(d,J＝4.8Hz,1H),3.23(d,J＝5.2Hz,1H),2.53-2.51(m,1H),1.99-1.90(m,1H),1.06–1.00(m,6H),0.92(d,J＝6.8Hz,3H).0.85(d,J＝6.8Hz,3H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-3- (2-phenylacetyloxy) tetrahydrofuranyl-2-yl) methyl isobutyrate (Compound 60).

The title compound was prepared according to the procedure for step 1 of example 49 using compound 14 and 2-phenylacetyl chloride. MS (ESI): the calculated mass for C ₂₄H₂₅N₅O₆ was 479.18, found m/z 480.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ7.93(br s,3H),7.33–7.29(m,4H),7.29–7.24(m,1H),6.93(d,J＝4.8Hz,1H),6.86(d,J＝4.8Hz,1H),6.68(d,J＝6.4Hz,1H),5.13(dt,J＝12.0,5.6Hz,2H),4.48(q,J＝4.4Hz,1H),4.30–4.18(m,2H),3.77(q,J＝15.8Hz,2H),2.47–2.44(m,1H),1.04–1.00m,6H).

Synthesis of((2R, 3S,4R, 5R) -3-acetoxy-5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxytetrahydrofuran-2-yl) methyl isobutyrate (Compound 61).

The title compound was prepared according to the procedure for example 17 using 15 and acetyl chloride. MS (ESI): for a calculated m/z of C ₁₈H₂₁N₅O₆ of 403.15, the actual measurement was 404.00[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.93(s,3H),6.93(d,J＝4.4Hz,1H),6.85(d,J＝4.4Hz,1H),6.63(d,J＝6.0Hz,1H),5.07(dt,J＝19.2,5.2Hz,2H),4.48(q,J＝4.8Hz,1H),4.33–4.27(m,1H),4.25–4.16(m,1H),2.53(q,J＝7.2Hz,1H),2.09(s,3H),1.05(d,J＝4.8Hz,3H),1.03(d,J＝4.8Hz,3H).

Example 38 synthesis of (2 r,3s,4r,5 r) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-2- ((isobutyryloxy) methyl) tetrahydrofuran-3-yl isobutyrate (compound 62).

The title compound was prepared according to the procedure for example 17 using 15 and isobutyryl chloride. MS (ESI): for a calculated m/z of C ₂₀H₂₅N₅O₆ of 431.18, the actual measurement was 432.05[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92(s,3H),6.93(d,J＝4.4Hz,1H),6.85(d,J＝4.4Hz,1H),6.57(d,J＝6.4Hz,1H),5.20–5.06(m,2H),4.46(q,J＝4.2Hz,1H),4.25(qd,J＝12.0,4.0Hz,2H),2.67–2.58(m,1H),2.54(q,J＝7.2Hz,1H),1.15(t,J＝7.2Hz,6H),1.04(dd,J＝6.8,5.6Hz,6H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-3- (propionyloxy) tetrahydrofuran-2-yl) methyl isobutyrate (Compound 63).

The title compound was prepared according to the procedure for example 17 using 15 and propionyl chloride. MS (ESI): for a calculated m/z of C ₁₉H₂₃N₅O₆ of 417.16, the actual measurement was 418.05[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.93(s,3H),6.93(d,J＝4.4Hz,1H),6.85(d,J＝4.8Hz,1H),6.59(d,J＝6.0Hz,1H),5.16–5.11(m,1H),5.09–5.04(m,1H),4.47(q,J＝4.4Hz,1H),4.26(qd,J＝12.0,3.6Hz,2H),2.54(q,J＝6.8Hz,1H),2.40(q,J＝7.6Hz,2H),1.10–1.02(m,9H).

Example 40 synthesis of (((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-2- ((isobutyryloxy) methyl) tetrahydrofuran-3-yl) oxy) methyl pivalate (Compound 64).

The title compound was prepared according to the procedure for example 24 using 15 and iodomethyl pivalate. MS (ESI): for a calculated m/z of C ₂₂H₂₉N₅O₆ of 475.21, the actual measurement was 476.30[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92(s,3H),6.92(d,J＝4.4Hz,1H),6.83(d,J＝4.4Hz,1H),6.50(d,J＝6.4Hz,1H),5.40–5.25(m,2H),4.98(dd,J＝6.0,5.2Hz,1H),4.41–4.23(m,2H),4.23–4.07(m,2H),2.47(q,J＝7.2Hz,1H),1.11(s,9H),1.05(q,J＝3.6Hz,6H).

Synthesis of (2R, 3S,4R, 5R) -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-4-hydroxy-2- [ (propionyloxy) methyl ] oxa-pent-3-yl 3-methylbutanoate (Compound 65).

Synthesis of (2R, 3S,4R, 5R) -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-4-hydroxy-2- [ (propionyloxy) methyl ] oxa-3-yl 3-methylbutanoate (65).

To a solution of [ (2R, 3S,4R, 5R) -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-3, 4-dihydroxyoxazin-2-yl ] methylpropionate (15, 80mg,0.230 mmol) in NMP (3 mL) was added HCl in dioxane (4M, 0.1 mL) and the reaction was stirred at 25℃for 15 min. 3-methylbutyryl chloride (138.18 mg,1.151 mmol) was then added to the above solution at 0deg.C and the resulting mixture was stirred at 25deg.C for 16h. The reaction was quenched with water (1 mL) and purified by preparative HPLC to give the title compound as a white solid (38.0 mg,37% yield). MS (ESI): for a calculated m/z of C ₂₀H₂₅N₅O₆ of 431.18, the actual measurement was 432.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.93(br,s,3H),6.93(d,J＝4.4Hz,1H),6.85(d,J＝4.8Hz,1H),6.60(d,J＝6.4Hz,1H),5.11-5.06(m,2H),4.45(dd,J＝8.4,4.8Hz,1H),4.32(dd,J＝12.0,3.6Hz,1H),4.21(dd,J＝12.0,5.2Hz,1H),2.41–2.19(m,4H),2.07-2.04(m,1H),0.99(t,J＝7.6Hz,3H),0.94(dd,J＝6.8,0.8Hz,6H).

EXAMPLE 42 Synthesis of [ (2R, 3S,4R, 5R) -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-3- [ (2-cyclohexylacetyl) oxy ] -4-hydroxyoxolan-2-yl ] methylpropionate (Compound 66).

The title compound 66 was prepared according to the procedure for step 1 of example 65 using 15 and 2-cyclohexylacetyl chloride. MS (ESI): the calculated mass for C ₂₃H₂₉N₅O₆ was 471.21 and the measured m/z was 472.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.93-7.91(br,s,3H),6.93(d,J＝4.4Hz,1H),6.85(d,J＝4.8Hz,1H),6.59(d,J＝6.0Hz,1H),5.12-5.06(m,2H),4.44 -4.43(m,1H),4.31(dd,J＝12.0,4.0Hz,1H),4.20(dd,J＝12.0,5.2Hz,1H),2.31–2.24(m,4H),1.79–1.60(m,6H),1.21–0.93(m,8H).

Synthesis of (2R, 3S,4R, 5R) -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-4-hydroxy-2- [ (propionyloxy) methyl ] oxa-pent-3-yl (2S) -2-amino-3-methylbutanoate (Compound 67).

Step 1: synthesis of (2R, 3S,4R, 5R) -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-4-hydroxy-2- [ (propionyloxy) methyl ] oxa-n-3-yl (2S) -2- { [ (tert-butoxy) carbonyl ] amino } -3-methylbutanoate (67.1).

Compound 67.1 was prepared according to the procedure of step 1 of example 19 using 15 and (2S) -2- { [ (tert-butoxy) carbonyl ] amino } -3-methylbutanoic acid. MS (ESI): the calculated mass for C ₂₅H₃₄N₆O₈ was 546.24 and the m/z found was 547.3[ M+H ] ⁺.

Step 2: synthesis of (2R, 3S,4R, 5R) -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-4-hydroxy-2- [ (propionyloxy) methyl ] oxa-pent-3-yl (2S) -2-amino-3-methylbutanoate (67).

The title compound 67 was prepared according to the procedure of step 2 of example 19 using 67.1. MS (ESI): the calculated mass for C ₂₀H₂₆N₆O₆ was 446.19, m/z found to be 447.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.93(br,s,3H),6.93(d,J＝4.8Hz,1H),6.87(d,J＝4.8Hz,1H),6.61-6.52(m,1H),5.13-5.10(m,2H),4.44-4.40(m,1H),4.32(dd,J＝12.4,4.0Hz,1H),4.21(dd,J＝12.0,5.2Hz,1H),3.25(d,J＝5.2Hz,1H),2.30-2.22(m,2H),2.01-1.95(m,1H),0.99(t,J＝7.6Hz,3H),0.92(d,J＝6.8Hz,3H),0.86(d,J＝6.8Hz,3H).

Synthesis of [ (2R, 3S,4R, 5R) -3- (acetyloxy) -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-4-hydroxyoxolan-2-yl ] methylpropionate (Compound 69).

Synthesis of [ (2R, 3S,4R, 5R) -3- (acetyloxy) -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-4-hydroxyoxolan-2-yl ] methylpropionate (69).

The title compound 69 was prepared according to the procedure for step 1 of example 65 using 15 and AcCl. MS (ESI): for a calculated m/z of C ₁₇H₁₉N₅O₆ of 389.13, the actual measurement was 390.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.93-7.90(br,s,3H),6.93(d,J＝4.4Hz,1H),6.85(d,J＝4.8Hz,1H),6.61(d,J＝6.0Hz,1H),5.07-5.05(m,2H),4.46-4.45(m,1H),4.33(dd,J＝12.4,3.6Hz,1H),4.20(dd,J＝12.4,5.2Hz,1H),2.30-2.28(m,2H),2.09(s,3H),0.99(t,J＝7.6Hz,3H).

Synthesis of [ (2R, 3S,4R, 5R) -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-4-hydroxy-3- [ (2-methylpropanoyl) oxy ] oxa-pent-2-yl ] methylpropanoate (Compound 70).

The title compound 70 was prepared according to the procedure for step 1 of example 65 using 15 and isobutyryl chloride. MS (ESI): the calculated mass for C ₁₉H₂₃N₅O₆ was 417.16, the measured m/z was 418.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92(br,s,3H),6.93(d,J＝4.4Hz,1H),6.86(d,J＝4.8Hz,1H),6.55(d,J＝6.0Hz,1H),5.20–5.06(m,2H),4.45(dd,J＝8.8,4.0Hz,1H),4.31(dd,J＝12.0,4.0Hz,1H),4.21(dd,J＝12.0,5.2Hz,1H),2.70–2.56(m,1H),2.29(d,J＝5.2Hz,2H),1.15(dd,J＝6.8,6.4Hz,6H),0.99(t,J＝7.6Hz,3H).

Synthesis of [ (2R, 3S,4R, 5R) -3- (acetyloxy) -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-4-hydroxyoxolan-2-yl ] methylpropionate (Compound 71).

The title compound 71 was prepared according to the procedure of step 1 of example 65 using 15 and propionyl chloride. MS (ESI): the calculated mass for C ₁₈H₂₁N₅O₆ was 403.15, the measured m/z was 404.0[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.93(br,s,3H),6.93(d,J＝4.4Hz,1H),6.85(d,J＝4.4Hz,1H),6.59(d,J＝6.0Hz,1H),5.10-5.05(m,2H),4.46(dd,J＝8.4,4.8Hz,1H),4.33(dd,J＝12.0,3.6Hz,1H),4.20(dd,J＝12.0,5.2Hz,1H),2.40-2.38(m,2H),2.35–2.24(m,2H),1.08(t,J＝7.6Hz,3H),0.99(t,J＝7.6Hz,3H).

EXAMPLE 47 Synthesis of { [ (2R, 3S,4R, 5R) -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-4-hydroxy-2- [ (propionyloxy) methyl ] oxa-n-3-yl ] oxy } methyl 2, 2-dimethylpropionate (Compound 72).

Step 1: synthesis of { [ (2R, 3S,4R, 5R) -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-4-hydroxy-2- [ (propionyloxy) methyl ] oxa-3-yl ] oxy } methyl 2, 2-dimethylpropionate (72).

Compound 72 was prepared according to the procedure of step 1 of example 48 using 15 and iodomethyl pivalate. MS (ESI): the calculated mass for C ₂₁H₂₇N₅O₇ was 461.19, the measured m/z was 462.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92(br,s,3H),6.92(d,J＝4.4Hz,1H),6.83(d,J＝4.8Hz,1H),6.49(d,J＝6.4Hz,1H),5.35(d,J＝6.4Hz,1H),5.28(d,J＝6.4Hz,1H),4.97-4.96(m,1H),4.39–4.28(m,2H),4.19–4.08(m,2H),2.28-2.26(m,2H),1.11(s,9H),1.00(t,J＝7.6Hz,3H).

Synthesis of (7- ((2R, 3R,4S, 5R) -2-cyano-3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) carbamic acid pentyl ester (Compound 81).

Synthesis of (3 aR,4R,6 aR) -4- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6- (((tert-butyldimethylsilyl) oxy) methyl) -2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxole-4-carbonitrile (81.1).

TBSCl (2.19 g,14.5 mmol) was slowly added to a mixture of 6.4 (4.00 g,12.1 mmol) and imidazole (2.06, 30.2 mmol) in DMF (20 mL) at 0deg.C. The mixture was then stirred at 20℃for 16 hours. TLC showed complete consumption of starting material. After completion, the mixture was quenched with water (300 mL) and extracted with ethyl acetate (200 ml×3). The organic layer was then dried over sodium sulfate and concentrated in vacuo to give a residue. The residue was purified by flash column chromatography (SiO ₂, ethyl acetate/petroleum ether=0-30%) to give 81.1 (4.8 g,88.4% yield) as a colorless oil, which was confirmed by ¹ H NMR and LCMS. MS (ESI): calculated mass for C ₂₁H₃₁N₅O₄ Si was 445.21, m/z found to be 446.25[M+H]⁺.¹HNMR(400MHz,DMSO-d₆)δ7.94(s,3H),6.90(d,J＝4.4Hz,1H),6.84(d,J＝4.4Hz,1H),5.33(d,J＝6.4Hz,1H),4.85(dd,J＝6.4,2.8Hz,1H),4.37(dd,J＝7.6,4.8Hz,1H),4.03(q,J＝7.2Hz,1H),3.70(dd,J＝4.8,1.2Hz,2H),1.63(s,3H),1.37(s,3H),0.76(s,9H),-0.03(s,3H),-0.08(s,3H).

Synthesis of (7- ((3 aR,4R,6 aR) -6- (((tert-butyldimethylsilyl) oxy) methyl) -4-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) carbamic acid pentyl ester (81.2).

To a mixture of 81.1 (200 mg,0.45 mmol), DMAP (274.15 mg,2.24 mmol) and DIEA (0.37 mL,2.24 mmol) in DCM (2 mL) was added amyl chloroformate (0.19 mL,1.35 mmol) at 0deg.C, and the reaction was stirred at 20deg.C for 16 h. The reaction mixture was poured into 50mL of water, and the organic layer was separated. The aqueous phase was extracted twice with DCM (50 mL). The organic phase was washed with brine (50 ml×3), then dried over anhydrous sodium sulfate, filtered and concentrated to remove the solvent. The residue was purified by flash column chromatography (0% to 8% petroleum ether/ethyl acetate) to give 81.2 (125 mg,44.8% yield) as a white solid. MS (ESI): the calculated m/z for C ₂₇H₄₁N₅O₆ Si was 559.28, found to be 560.2[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.90(s,1H),8.40(s,1H),7.30(d,J＝4.8Hz,1H),7.06(d,J＝4.8Hz,1H),5.30(d,J＝6.2Hz,1H),4.86(dd,J＝6.2,2.4Hz,1H),4.44(d,J＝2.4Hz,1H),4.18(t,J＝6.8Hz,2H),3.70(d,J＝4.4Hz,2H),1.70–1.63(m,5H),1.39–1.32(m,7H),0.89(t,J＝7.2Hz,3H),0.73(s,9H),-0.08(d,J＝17.6Hz,6H).

Synthesis of (7- ((2R, 3R,4S, 5R) -2-cyano-3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) carbamic acid pentyl ester.

To a solution of 81.2 (65.0 mg,0.12 mmol) in THF (1 mL) at 0deg.C was added HCl (1 mL, 6M), and the reaction was stirred at 20deg.C for 1 hour. The reaction was diluted with ACN (1.0 mL) and purified by preparative HPLC to give 81 (22.8 mg,48.5% yield) as a white solid. MS (ESI): for a calculated m/z of C ₁₈H₂₃N₅O₆ of 405.16, the actual measurement was 406.0[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.97(s,1H),8.32(s,1H),7.25(d,J＝4.4Hz,1H),7.08(d,J＝4.8Hz,1H),6.21(d,J＝6.4Hz,1H),5.24(d,J＝5.6Hz,1H),4.91(t,J＝5.6Hz,1H),4.70–4.55(m,1H),4.16(t,J＝6.8Hz,2H),4.07(dd,J＝9.2,4.4Hz,1H),3.95(dd,J＝10.8,5.2Hz,1H),3.69–3.60(m,1H),3.56–3.47(m,1H),1.67(p,J＝7.2Hz,2H),1.41–1.30(m,4H),0.90(t,J＝7.2Hz,3H).

EXAMPLE 49 Synthesis of (2S) -2-amino-N- {7- [ (2R, 3R,4S, 5R) -2-cyano-3, 4-dihydroxy-5- (hydroxymethyl) oxacyclopent-2-yl ] pyrrolo [2,1-f ] [1,2,4] triazin-4-yl } -3-methylbutanamide (Compound 83).

Synthesis of tert-butyl N- [ (1S) -1- ({ 7- [ (3 aR,4R,6 aR) -6- { [ (tert-butyldimethylsilyl) oxy ] methyl } -4-cyano-2, 2-dimethyl-dihydro-3 aH-furo [3,4-d ] [1,3] dioxol-4-yl ] pyrrolo [2,1-f ] [1,2,4] triazin-4-yl } carbamoyl) -2-methylpropyl ] carbamate (83.1).

To a solution of (3 aR,4R,6 aR) -4- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -6- { [ (tert-butyldimethylsilyl) oxy ] methyl } -2, 2-dimethyl-dihydro-3 aH-furo [3,4-d ] [1,3] dioxole-4-carbonitrile (81.1, 200mg,0.4488 mmol) in THF (10 mL) was added (2S) -2- { [ (tert-butoxy) carbonyl ] amino } -3-methylbutanoic acid (146.08 mg,0.6732 mmol), HOBT (90.96 mg,0.67 mmol), EDCI (129.05 mg,0.67 mmol) and DIEA (174.01 mg,1.3464 mmol), and the mixture was stirred at 25℃for 16h. The reaction was extracted with EA (5 ml. Times.3). The combined organics were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (2% to 20% EA/PE) to give 83.1 (190 mg,59% yield) as a white solid. MS (ESI): the calculated mass for C ₃₁H₄₈N₆O₇ Si was 644.34 and the m/z found was 645.3[ M+H ] ⁺.

Synthesis of (2S) -2-amino-N- {7- [ (2R, 3R,4S, 5R) -2-cyano-3, 4-dihydroxy-5- (hydroxymethyl) oxacyclopenta-2-yl ] pyrrolo [2,1-f ] [1,2,4] triazin-4-yl } -3-methylbutanamide (83).

To a solution of tert-butyl N- [ (1S) -1- ({ 7- [ (3 aR,4R,6 aR) -6- { [ (tert-butyldimethylsilyl) oxy ] methyl } -4-cyano-2, 2-dimethyl-dihydro-3 aH-furo [3,4-d ] [1,3] dioxol-4-yl ] pyrrolo [2,1-f ] [1,2,4] triazin-4-yl } carbamoyl) -2-methylpropyl ] carbamate (83.1, 100mg,0.155 mmol) in THF (3 mL) at 0deg.C was added HCl (12M, 1 mL) and the mixture was stirred at 25deg.C for 6h. The reaction was concentrated in vacuo and purified by preparative HPLC to give the salt forming compound. The compound was basified with NaHCO ₃ (saturated aqueous solution, 1 mL) and purified by preparative HPLC to give 83 (9.85 mg,12% yield) as a white solid. MS (ESI): the calculated mass for C ₁₇H₂₂N₆O₅ was 390.17 and the measured m/z was 391.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.21(d,J＝8.4Hz,1H),7.97(s,1H),7.56(s,1H),7.23(d,J＝4.4Hz,1H),7.13(s,1H),6.89(d,J＝4.8Hz,1H),6.12(d,J＝6.0Hz,1H),5.20(d,J＝5.2Hz,1H),4.90(t,J＝5.6Hz,1H),4.64-4.60(m,2H),4.05-4.01(m,1H),3.94-3.90(m,1H),3.74–3.59(m,1H),3.57–3.47(m,1H),2.18-2.05(m,1H),0.96-0.85(m,6H).

EXAMPLE 50 Synthesis of (S) -2-amino-N- (7- ((2R, 3R,4S, 5R) -2-cyano-3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) -3- (4-fluorophenyl) acrylamide (Compound 84).

Synthesis of tert-butyl (S) -1- ((7- ((3 aR,4R,6 aR) -6- (((tert-butyldimethylsilyl) oxy) methyl) -4-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) amino) -3- (4-fluorophenyl) -1-oxopropan-2-yl) carbamate (84.2).

To a solution of 81.1 (2.00 g,4.5 mmol), 84.1 (1.28 g,4.5 mmol) and DIPEA (0.87 g,6.7 mmol) in dry DMF (20 mL) was added HATU (2.57 g,6.7 mmol) at 0deg.C. The reaction mixture was stirred at 20℃for 16h. The reaction mixture was poured into ice water (40 mL) and extracted with EA (20 ml×2). The combined organic phases were washed with water (15 mL), then brine (15 ml×3), dried over anhydrous Na ₂SO₄, and filtered. The filtrate was concentrated to dryness. The residue was purified by FCC (gradient: 5% ea in PE) to give 84.2 (2.47 g,78% yield) as a white solid. MS (ESI): the calculated m/z for C ₃₅H₄₇FN₆O₇ Si was 710.33, found to be 711.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ11.17(s,1H),8.51(s,1H),7.42(dd,J＝8.0,5.6Hz,2H),7.33–7.20(m,2H),7.15–7.07(m,3H),5.31(d,J＝6.0Hz,1H),4.87(dd,J＝6.0,2.4Hz,1H),4.49–4.44(m,1H),3.71(d,J＝4.4Hz,1H),3.12–3.00(m,1H),2.86–2.75(m,1H),1.66(s,3H),1.38(s,3H),1.32(s,9H),0.73(s,9H),-0.07(d,J＝18.0Hz,6H).

Synthesis of (S) -2-amino-N- (7- ((2R, 3R,4S, 5R) -2-cyano-3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) -3- (4-fluorophenyl) propanamide (84).

To a solution of 84.2 (50 mg,0.07 mmol) in dry THF (0.5 mL) was added dropwise concentrated HCl (0.25 mL, 12M) under nitrogen at 0deg.C. The reaction mixture was stirred at 0 ℃ for 2h. The reaction mixture was basified with aqueous NaHCO ₃ at 0 ℃ and the pH was adjusted to 8.LC-MS shows peak shift and new peaks have the same MS, possibly in different salt forms with different pH values. The organic solvent was removed with flowing nitrogen. The residue was diluted with ACN and purified by preparative HPLC to give the title compound 84 as a white solid (4.52 mg,14% yield). MS (ESI): for a calculated m/z of C ₂₁H₂₁FN₆O₅ of 456.16, the actual measurement was 457.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.56(d,J＝8.4Hz,1H),7.90(s,1H),7.68(s,1H),7.42–7.34(m,2H),7.17(s,1H),7.09–7.02(m,3H),6.86(d,J＝4.4Hz,1H),6.11(d,J＝6.0Hz,1H),5.22(d,J＝4.0Hz,1H),4.98–4.85(m,2H),4.60(t,J＝5.6Hz,1H),4.04(dd,J＝9.2,4.4Hz,1H),3.93(dd,J＝10.4,5.2Hz,1H),3.66–3.59(m,1H),3.53–3.45(m,1H),3.18(dd,J＝14.0,4.0Hz,1H),3.02(dd,J＝13.6,11.2Hz,1H).¹⁹F NMR(377MHz,DMSO)δ-116.76.

EXAMPLE 51 Synthesis of N- (7- ((2R, 3R,4S, 5R) -2-cyano-3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) benzamide (Compound 85).

Synthesis of N- (7- ((3 aR,4R,6 aR) -6- (((tert-butyldimethylsilyl) oxy) methyl) -4-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) benzamide (85.1).

To a solution of 81.1 (2.00 g,4.50 mmol) and DMAP (750 mg,6.75 mmol) in dry DCM (20 mL) was added benzoyl chloride (950 mg,6.75 mmol) dropwise at 0deg.C. The reaction mixture was stirred at 20℃for 16h. The mixture was washed with water (10 ml×2), then brine (10 mL), dried over anhydrous Na ₂SO₄, and filtered. The filtrate was concentrated to dryness. The residue was purified by FCC (gradient: 5% EA in PE) to give 85.1 (1.99 g,80% yield) as a white solid. MS (ESI): the calculated m/z for C ₂₈H₃₅N₅O₅ Si was 549.24, found to be 550.4[M+H]⁺.¹H NMR(400MHz,DMSO)δ11.38(s,1H),8.65-7.84(m,3H),7.66(t,J＝6.8Hz,1H),7.55(t,J＝7.6Hz,2H),7.22-6.94(m,2H),5.34(d,J＝6.4Hz,1H),4.88(dd,J＝6.0,2.8Hz,1H),4.46(d,J＝2.0Hz,1H),3.72(d,J＝4.8Hz,2H),1.66(s,3H),1.38(s,3H),0.75(s,9H),-0.03(s,3H),-0.07(s,3H).

Synthesis of N- (7- ((2R, 3R,4S, 5R) -2-cyano-3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) benzamide (85).

To a solution of 85.1 (0.10 g,0.18 mmol) in MeOH (1.0 mL) was added dropwise aqueous HCl (1.0 mL, 6M) at 0deg.C. The reaction mixture was stirred at 0℃for 3h. The organic solvent was removed with flowing nitrogen. The residue was purified by preparative HPLC to give the title compound 85 (23.55 mg,33% yield) as a white solid. MS (ESI): for a calculated m/z of C ₁₉H₁₇N₅O₅ of 395.12, the actual measurement was 396.0[M+H]⁺.¹H NMR(400MHz,DMSO)δ11.36(s,1H),8.65–7.85(m,3H),7.70–7.61(m,1H),7.59–7.52(m,2H),7.27–7.04(m,2H),6.24(d,J＝6.4Hz,1H),5.26(d,J＝5.6Hz,1H),4.92(t,J＝5.6Hz,1H),4.63(t,J＝5.6Hz,1H),4.12–4.06(m,1H),3.97(dd,J＝10.4,5.2Hz,1H),3.69–3.62(m,1H),3.56–3.48(m,1H).

Synthesis of((2R, 3S,4R, 5R) -5-cyano-3, 4-dihydroxy-5- (4- (((pentoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuranyl) methyl acetate (Compound 87).

/>

To a solution of pentyl 81 (80 mg,0.19 mmol) in DMPU (1 mL) was added dropwise 4M dioxane HCl (0.2 mL) at 0deg.C. The mixture was then stirred for 30min, and acetyl chloride (0.2 mL) was added dropwise and stirred for an additional 30min. After completion, the mixture was purified by preparative HPLC to give 87 (30 mg,33.6% yield) as a white solid. MS (ESI): for a calculated m/z of C ₂₀H₂₅N₅O₇ of 447.18, the actual measurement was 448.25[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.98(s,1H),8.34(s,1H),7.29(d,J＝4.4Hz,1H),7.02(d,J＝4.8Hz,1H),6.40(d,J＝6.0Hz,1H),5.44(d,J＝6.0Hz,1H),4.68(t,J＝5.6Hz,1H),4.32(dd,J＝12.0,2.8Hz,1H),4.28–4.23(m,1H),4.20–4.11(m,3H),3.93(q,J＝6.0Hz,1H),2.01(s,3H),1.67(p,J＝6.8Hz,2H),1.41–1.28(m,4H),0.90(t,J＝6.8Hz,3H).

Example 53 synthesis of ((2R, 3S,4R, 5R) -5-cyano-3, 4-dihydroxy-5- (4- (((pentoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuranyl-2-yl) methyl 2-cyclohexylacetate (compound 88).

To a solution of 81 (60.0 mg,0.16 mmol) in DMPU (1 mL) was added HCl/dioxane (0.2 mL, 4M). The mixture solution was stirred at 20℃for 15 minutes. The reaction mixture was cooled at 0deg.C, and 2-cyclohexylacetyl chloride (0.11 mL,0.74 mmol) was added immediately. The reaction was stirred at 0 ℃ for 2 hours. The reaction was diluted with ACN (2.0 mL) and purified by preparative HPLC to give 88 (28.8 mg,36.6% yield) as a white solid. MS (ESI): for a calculated m/z of C ₂₆H₃₅N₅O₇ of 529.25, the actual measurement was 530.2[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.97(s,1H),8.33(s,1H),7.29(d,J＝4.0Hz,1H),7.01(d,J＝4.8Hz,1H),6.41(d,J＝6.0Hz,1H),5.43(d,J＝6.0Hz,1H),4.83–4.58(m,1H),4.33–4.28(m,1H),4.27–4.22(m,1H),4.20–4.13(m,3H),3.95(dd,J＝11.2,6.0Hz,1H),2.18–2.05(m,2H),1.71–1.55(m,8H),1.40–1.30(m,4H),1.22–1.05(m,3H),0.92–0.80(m,5H).

Example 54 synthesis of ((2R, 3S,4R, 5R) -5-cyano-3, 4-dihydroxy-5- (4- (((pentoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuranyl-2-yl) methyl 2-phenylacetate (Compound 89).

The title compound was prepared according to the procedure for step 1 of example 88 using compound 81 and 2-phenylacetyl chloride. MS (ESI): the calculated mass for C ₂₆H₂₉N₅O₇ was 523.21, the measured m/z was 524.2[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.99(s,1H),8.33(s,1H),7.33–7.19(m,6H),6.97(d,J＝4.8Hz,1H),6.40(d,J＝6.0Hz,1H),5.45(d,J＝5.6Hz,1H),4.64(t,J＝5.6Hz,1H),4.34(dd,J＝12.0,2.4Hz,1H),4.29–4.25(m,1H),4.24–4.14(m,3H),3.97–3.91(m,1H),3.66(s,2H),1.73–1.60(m,2H),1.44–1.29(m,4H),0.89(t,J＝7.2Hz,3H).

Synthesis of (((2R, 3S,4R, 5R) -5-cyano-3, 4-dihydroxy-5- (4- (((pentoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuranyl) methylpropionate (Compound 91).

The title compound was prepared according to the procedure for step 1 of example 88 using compound 81 and propionyl chloride. MS (ESI): the calculated mass for C ₂₁H₂₇N₅O₇ was 461.19, the measured m/z was 462.2[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.98(s,1H),8.33(s,1H),7.28(d,J＝4.8Hz,1H),7.00(d,J＝4.8Hz,1H),6.41(d,J＝6.0Hz,1H),5.43(d,J＝6.0Hz,1H),4.86–4.46(m,1H),4.33(dd,J＝12.0,2.8Hz,1H),4.28–4.22(m,1H),4.19–4.13(m,3H),3.94(dd,J＝11.6,6.0Hz,1H),2.35–2.24(m,2H),1.71–1.63(m,2H),1.46–1.26(m,4H),0.99(t,J＝7.6Hz,3H),0.90(t,J＝7.2Hz,3H).

Example 56 synthesis of ((2R, 3S,4R, 5R) -5-cyano-3, 4-dihydroxy-5- (4- (((pentoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuranyl) methyl isobutyrate (compound 92).

The title compound was prepared according to the procedure for step 1 of example 87 using compound 81 and 2-methylpropanoyl chloride. MS (ESI): the calculated mass for C ₂₂H₂₉N₅O₇ was 475.21 and the measured m/z was 476.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.95(s,1H),8.33(s,1H),7.27(d,J＝4.4Hz,1H),7.00(d,J＝4.8Hz,1H),6.41(d,J＝6.4Hz,1H),5.42(d,J＝6.0Hz,1H),4.68(t,J＝5.6Hz,1H),4.33–4.23(m,2H),4.20–4.14(m,3H),3.95(dd,J＝11.2,6.0Hz,1H),2.52(s,1H),1.71–1.62(m,2H),1.41–1.29(m,4H),1.04(m,6H),0.89(t,J＝7.2Hz,3H).

Synthesis of((2R, 3S,4R, 5R) -5-cyano-3, 4-dihydroxy-5- (4- (((pentoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuranyl) methyl 3-methylbutanoate (Compound 93).

The title compound was prepared according to the procedure for step 1 of example 87 using compound 81 and 3-methylbutyryl chloride. MS (ESI): the calculated mass for C ₂₃H₃₁N₅O₇ was 489.22, the measured m/z was 490.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.99(s,1H),8.33(s,1H),7.29(d,J＝4.8Hz,1H),7.01(d,J＝4.8Hz,1H),6.42(d,J＝6.0Hz,1H),5.43(d,J＝5.2Hz,1H),4.68(t,J＝5.6Hz,1H),4.34–4.28(m,2H),4.20–4.13(m,3H),3.94(dd,J＝11.6,6.0Hz,1H),2.17–2.12(m,,2H),1.95–1.85(m,1H),1.73–1.62(m,2H),1.42–1.29(m,4H),0.94–0.81(m,9H).

Synthesis of((2R, 3S,4R, 5R) -5- (4- ((S) -2-amino-3- (4-fluorophenyl) propanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2-phenylacetate (Compound 97).

Synthesis of tert-butyl (S) -1- ((7- ((3 aR,4R,6 aR) -4-cyano-6- (hydroxymethyl) -2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) amino) -3- (4-fluorophenyl) -1-oxopropan-2-yl) carbamate (97.1).

To a solution of 84.2 (1.40 g,1.97 mmol) in dry THF (15 mL) was added TBAF (3.0 mL,1m in THF) dropwise at 0 ℃. The reaction mixture was stirred at 0 ℃ for 2h and at 25 ℃ for an additional 5h. The mixture was quenched with saturated aqueous NH ₄ Cl (15 mL) and extracted with EA (10 ml×2). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na ₂SO₄ and filtered. The filtrate was concentrated to dryness. The residue was purified by FCC (gradient: 35% ea in PE) to give 97.1 (820 mg,70% yield) as a yellow solid. MS (ESI): for a calculated m/z of C ₂₉H₃₃FN₆O₇ of 596.24, the actual measurement was 597.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ11.20(s,1H),8.51(s,1H),7.43(dd,J＝8.4,6.0Hz,2H),7.33–7.06(m,5H),5.36(d,J＝6.4Hz,1H),5.02(t,J＝5.6Hz,1H),4.94–4.79(m,2H),4.40–4.33(m,1H),3.59–3.45(m,2H),3.10(dd,J＝13.2,3.2Hz,1H),2.81(dd,J＝13.2,11.2Hz,1H),1.65(s,3H),1.38(s,3H),1.34–1.20(m,9H).

Synthesis of((3 aR,4R,6 aR) -6- (4- ((S) -2- ((tert-butoxycarbonyl) amino) -3- (4-fluorophenyl) propanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) methyl 2-phenylacetate (97.2).

To a solution of 97.1 (200 mg,0.335 mmol) and DIPEA (86.5 mg,0.669 mmol) in dry DCM (1.5 mL) was added dropwise 2-phenylacetyl chloride (77.6 mg,0.502 mmol) at 0 ℃. The reaction mixture was stirred at 20℃for 2h. The mixture was diluted with EA (5.0 mL) and washed with water (2.5 mL), then brine (2.5 mL), dried over anhydrous Na ₂SO₄, filtered. The filtrate was concentrated to dryness. The residue was purified by FCC (gradient: 30% EA in PE) to give 97.2 (122 mg,85% yield) as a white solid. MS (ESI): the calculated m/z for C ₃₇H₃₉FN₆O₈ was 714.28, found 715.2[ M+H ] ⁺.

Synthesis of((2R, 3S,4R, 5R) -5- (4- ((S) -2-amino-3- (4-fluorophenyl) propanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2-phenylacetate (97).

To a solution of 97.2 (50.0 mg,0.07 mmol) in THF (0.4 mL) and water (0.2 mL) at 0deg.C was added dropwise HCl/1, 4-dioxane (0.3 mL, 4M). The reaction mixture was stirred at 20℃for 3h. The reaction mixture was adjusted to pH 8 with saturated aqueous NaHCO ₃ at 0 ℃. The organic solvent was removed with flowing nitrogen. The residue was purified by preparative HPLC to give the title compound as a white solid (4.41 mg,11% yield). MS (ESI): for a calculated m/z of C ₂₉H₂₇FN₆O₆ of 574.20, the actual measurement was 575.1[M+H]⁺.¹HNMR(400MHz,DMSO)δ8.58(d,J＝8.4Hz,1H),7.92(s,1H),7.69(s,1H),7.39(dd,J＝8.4,6.0Hz,2H),7.32–7.13(m,6H),7.11–7.01(m,3H),6.78(d,J＝4.8Hz,1H),6.33(s,1H),5.43(s,1H),4.98–4.89(m,1H),4.63(t,J＝5.2Hz,1H),4.33(d,J＝10.8Hz,1H),4.25–4.15(m,2H),3.96–3.87(m,1H),3.66(s,2H),3.22–3.15(m,1H),3.07–2.98(m,1H).¹⁹F NMR(377MHz,DMSO)δ-116.75.

Synthesis of((2R, 3S,4R, 5R) -5- (4- ((S) -2-amino-3- (4-fluorophenyl) propanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 3-methylbutanoate (Compound 101).

Synthesis of((3 aR,4R,6 aR) -6- (4- ((S) -2- ((tert-butoxycarbonyl) amino) -3- (4-fluorophenyl) propanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) methyl 3-methylbutanoate (101.1).

To a solution of 97.1 (200 mg,0.335 mmol) and DIPEA (64.9 mg,0.502 mmol) in dry DCM (2.0 mL) was added 3-methylbutyryl chloride (60.5 mg,0.502 mmol) dropwise at 0 ℃. The reaction mixture was stirred at 25℃for 16h. The organic solvent was removed with flowing nitrogen. The residue was purified by preparative HPLC to give 101.1 (62.2 mg, crude) as a white solid. MS (ESI): the calculated m/z for C ₃₄H₄₁FN₆O₈ was 680.30, found to be 681.4[ M+H ] ⁺.

Synthesis of((2R, 3S,4R, 5R) -5- (4- ((S) -2-amino-3- (4-fluorophenyl) propanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 3-methylbutanoate (101).

To a solution of 101.1 (62.2 mg, crude) in THF (0.6 mL) was added dropwise aqueous HCl (0.3 mL,12 m) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 2h. The organic solvent was removed with flowing nitrogen. The residue was purified by preparative HPLC to give the title compound as a white solid (4.32 mg,8.5% yield). MS (ESI): for a calculated m/z of C ₂₆H₂₉FN₆O₆ of 540.21, the actual measurement was 541.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ11.04(s,1H),8.69(d,J＝7.6Hz,1H),7.91(s,1H),7.47(t,J＝6.4Hz,2H),7.15–6.99(m,3H),6.89(d,J＝3.6Hz,1H),6.09(d,J＝6.0Hz,1H),5.48–5.30(m,1H),5.19(d,J＝4.8Hz,1H),4.93–4.81(m,1H),4.65–4.53(m,1H),4.08–3.99(m,1H),3.97–3.90(m,1H),3.65–3.59(m,1H),3.51–3.48(m,1H),3.18–3.13(m,1H),3.05–2.97(m,1H),2.41(d,J＝6.8Hz,2H),2.11–2.00(m,1H),0.93(d,J＝6.4Hz,6H).¹⁹F NMR(377MHz,DMSO)δ-116.44.

Synthesis of((2R, 3S,4R, 5R) -5- (4-benzoylamino pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl acetate (Compound 103).

To a solution of 85 (80.0 mg,0.20 mmol) in DMPU (0.5 mL) was added HCl/dioxane (0.1 mL, 4M). The mixture solution was stirred at 0 ℃ for 15 minutes. Acetyl chloride (47.6 mg,0.61 mmol) was then added at 0deg.C. The resulting mixture was stirred at 20 ℃ for an additional 2 hours. The reaction was diluted with ACN (2.0 mL) and purified by preparative HPLC to give the title compound as a white solid (21.1 mg,23.8% yield). MS (ESI): for a calculated m/z of C ₂₁H₁₉N₅O₆ of 437.13, the actual measurement was 438.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ11.71(s,1H),8.39(s,1H),8.07(s,2H),7.66(t,J＝6.8Hz,1H),7.55(t,J＝7.6Hz,2H),7.17(d,J＝4.4Hz,1H),7.06(s,1H),6.43(d,J＝6.0Hz,1H),5.46(d,J＝5.6Hz,1H),4.79–4.61(m,1H),4.39–4.24(m,2H),4.22–4.12(m,1H),4.01–3.93(m,1H),2.02(s,3H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-benzoylamino pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2-phenylacetate (Compound 105).

The title compound was prepared according to the procedure for step 1 of example 88 using compound 85 and 2-phenylacetyl chloride. MS (ESI): the calculated mass for C ₂₇H₂₃N₅O₆ was 513.16, the measured m/z was 514.2[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ11.88(s,1H),8.36(s,1H),8.07(d,J＝7.6Hz,2H),7.64(t,J＝7.2Hz,1H),7.55(t,J＝7.6Hz,2H),7.36–7.19(m,5H),7.16(d,J＝4.8Hz,1H),7.02(d,J＝4.8Hz,1H),6.42(d,J＝6.0Hz,1H),5.46(d,J＝5.6Hz,1H),4.66(t,J＝5.6Hz,1H),4.36(dd,J＝12.0,2.4Hz,1H),4.32–4.26(m,1H),4.22(dd,J＝12.0,5.2Hz,1H),3.99–3.94(m,1H),3.68(s,2H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-benzoylamino pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methylpropionate (Compound 107).

The title compound was prepared according to the procedure for step 1 of example 88 using compound 85 and propionyl chloride. MS (ESI): the calculated mass for C ₂₂H₂₁N₅O₆ was 451.15 and the measured m/z was 452.0[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ11.81(s,1H),8.37(s,1H),8.06(d,J＝7.2Hz,2H),7.65(t,J＝7.6Hz,1H),7.55(t,J＝7.6Hz,2H),7.16(d,J＝4.8Hz,1H),7.04(d,J＝4.8Hz,1H),6.44(d,J＝6.0Hz,1H),5.45(d,J＝6.0Hz,1H),4.78–4.62(m,1H),4.35(dd,J＝12.0,2.8Hz,1H),4.31–4.25(m,1H),4.21–4.15(m,1H),3.96(dd,J＝11.6,6.0Hz,1H),2.34–2.26(m,2H),1.00(t,J＝7.6Hz,3H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-benzoylamino pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl isobutyrate (Compound 108).

The title compound was prepared according to the procedure for step 1 of example 103 using compound 85 and 2-methylpropanoyl chloride. MS (ESI): the calculated mass for C ₂₃H₂₃N₅O₆ was 465.16, the measured m/z was 466.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ11.80(s,1H),8.37(s,1H),8.06(d,J＝7.2Hz,2H),7.65(t,J＝7.2Hz,1H),7.55(t,J＝7.6Hz,2H),7.16(d,J＝4.0Hz,1H),7.04(d,J＝4.4Hz,1H),6.44(d,J＝6.0Hz,1H),5.45(d,J＝5.6Hz,1H),4.70(t,J＝5.2Hz,1H),4.37-4.14(m,3H),4.02-3.93(m,1H),2.55-2.51(m,1H),1.05(dd,J＝6.8,2.4Hz,6H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-benzoylamino pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2-cyclohexylacetate (Compound 109).

The title compound was prepared according to the procedure for step 1 of example 103 using compound 85 and 3-methylbutyryl chloride. MS (ESI): the calculated mass for C ₂₄H₂₅N₅O₆ was 479.18, found m/z 480.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ11.75(s,1H),8.38(s,1H),8.02(d,J＝7.2Hz,2H),7.66(t,J＝7.6Hz,1H),7.55(t,J＝7.6Hz,2H),7.18(d,J＝4.8Hz,1H),7.06(d,J＝4.4Hz,1H),6.45(d,J＝6.0Hz,1H),5.45(d,J＝6.0Hz,1H),4.71(s,1H),4.37–4.25(m,2H),4.18(dd,J＝12.0,5.2Hz,1H),3.99–3.94(m,1H),2.51(s,2H),2.00–1.83(m,1H),0.86(dd,J＝6.8,3.2Hz,6H).

Example 65 synthesis of (((2R, 3S,4R, 5R) -5- (4- ((S) -2-amino-3-methylbutanamide) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl L-valine ester (Compound 110).

Synthesis of (((3 aR,4R,6 aR) -6- (4- ((S) -2- ((tert-butoxycarbonyl) amino) -3-methylbutanamide) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) methyl (tert-butoxycarbonyl) -L-valine ester (110.1).

To a solution of 6.4 (1.00 g,3 mmol) in THF (15 mL) at 0deg.C was added (2S) -2- { [ (tert-butoxy) carbonyl ] amino } -3-methylbutanoic acid (0.65 g,3 mmol), HOBt (0.41 g,3 mmol) and DIEA (0.58 g,4.5 mmol), and the mixture was stirred at 0deg.C for 5min. EDCI was then slowly added to the mixture and stirred for 16 hours. After completion, the mixture was washed with water (50 mL) and extracted with ethyl acetate (50 ml×3). The organic layer was dried over sodium sulfate and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC to give 110.1 (230 mg,10.4% yield) as a white solid. MS (ESI): for a calculated m/z of C ₃₅H₅₁N₇O₁₀ of 729.37, the actual measurement was 730.25[M+H]⁺.¹H NMR(400MHz,DMSO)δ11.02(s,1H),8.47(s,1H),7.20(d,J＝4.4Hz,1H),7.17–6.70(m,3H),5.42(d,J＝6.4Hz,1H),4.92(dd,J＝6.4,2.8Hz,1H),4.63(s,1H),4.42(s,1H),4.25(dd,J＝12.0,3.6Hz,1H),4.14(dd,J＝12.0,6.4Hz,1H),3.71(dd,J＝46.0,38.8Hz,1H),2.09(dd,J＝13.2,6.8Hz,1H),1.79(dd,J＝13.6,6.8Hz,1H),1.66(s,3H),1.45–1.23(m,21H),0.94(dd,J＝14.4,6.8Hz,6H),0.76(dd,J＝15.2,6.8Hz,6H).

Synthesis of (((2R, 3S,4R, 5R) -5- (4- ((S) -2-amino-3-methylbutanamide) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl L-valine ester (110).

To a solution of 110.1 (100 mg,0.13 mmol) in DCM (5 mL) was added dropwise 1mL of HCl/dioxane (5 mL) at 0deg.C. The mixture was then stirred at 0 ℃ for 2 hours. After completion, the mixture was dried by a nitrogen stream to obtain a residue. The residue was purified by prep HPLC to give 110 (15 mg.22.1% yield) as a white solid. MS (ESI): for a calculated m/z of C ₂₂H₃₁N₇O₆ of 489.23, the actual measurement was 490.15[M+H]⁺.¹H NMR(400MHz,DMSO)8.23(d,J＝8.8Hz,1H),7.98(s,1H),7.56(s,1H),7.25(d,J＝4.4Hz,1H),7.13(s,1H),6.83(d,J＝4.4Hz,1H),6.36(d,J＝6.0Hz,1H),5.40(d,J＝5.6Hz,1H),4.72–4.61(m,2H),4.37–4.22(m,3H),3.94(q,J＝4.8Hz,1H),3.30(s,1H),2.23–2.13(m,1H),1.92–1.80(m,1H),0.96(dd,J＝6.8,4.0Hz,6H),0.83(dd,J＝16.4,6.8Hz,6H).

Example 66 synthesis of [ (2R, 3S,4R, 5R) -5- {4- [ (2S) -2-amino-3-methylbutanamide ] pyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-3, 4-dihydroxyoxacyclopent-2-yl ] methyl 2-cyclohexylacetate (compound 112).

Synthesis of tert-butyl (S) -1- ((7- ((3 aR,4R,6 aR) -4-cyano-6- (hydroxymethyl) -2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) amino) -3-methyl-1-oxobutan-2-yl) carbamate (112.1).

To a solution of tert-butyl N- [ (1S) -1- ({ 7- [ (3 aR,4R,6 aR) -6- { [ (tert-butyldimethylsilyl) oxy ] methyl } -4-cyano-2, 2-dimethyl-dihydro-3 aH-furo [3,4-d ] [1,3] dioxol-4-yl ] pyrrolo [2,1-f ] [1,2,4] triazin-4-yl } carbamoyl) -2-methylpropyl ] carbamate (83.1, 450mg,0.697 mmol) in THF (5 mL) was added TBAF in THF (1M, 3.5 mL) and the mixture was stirred at 25℃for 2h. The reaction was extracted with EA (5 ml. Times.3). The combined organics were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (2% to 50% EA/PE) to give 112.1 (320 mg,82% yield) as a white solid. MS (ESI): the calculated mass for C ₂₅H₃₄N₆O₇ was 530.25 and the m/z found was 531.2[ M+H ] ⁺.

Synthesis of((3 aR,4R,6 aR) -6- (4- ((S) -2- ((tert-butoxycarbonyl) amino) -3-methylbutanamide) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) methyl 2-cyclohexylacetate (112.2).

Compound 112.2 was prepared according to the procedure of step 4 of example 1 using 112.1 and 2-cyclohexylacetyl chloride. MS (ESI): the calculated mass for C ₃₃H₄₆FN₆O₈ is 654.34 and the m/z found is 655.3[ M+H ] ⁺.

Synthesis of [ (2R, 3S,4R, 5R) -5- {4- [ (2S) -2-amino-3-methylbutanamide ] pyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-3, 4-dihydroxyoxacyclopent-2-yl ] methyl 2-cyclohexylacetate (112).

To a solution of [ (3 aR,4R,6 aR) -6- {4- [ (2S) -2- { [ (tert-butoxy) carbonyl ] amino } -3-methylbutanamidyl ] pyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -6-cyano-2, 2-dimethyl-dihydro-3 aH-furo [3,4-d ] [1,3] dioxol-4-yl ] methyl 2-cyclohexyl acetate (112.2, 80mg,0.122 mmol) in THF (2 mL) and water (1 mL) was added HCl in dioxane (4M, 2 mL) and the mixture was stirred at 25℃for 6h. The reaction was concentrated in vacuo and purified by preparative HPLC to give the salt forming compound. The compound was filtered and the filter cake was washed with water (5 ml×3). The product was then dried by freeze drying to give the title compound (26.02 mg, 41%) as a white solid. MS (ESI): the calculated mass for C ₂₅H₃₄N₆O₆ was 514.25, the measured m/z was 515.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.22(d,J＝8.8Hz,1H),7.98(s,1H),7.55(s,1H),7.24(d,J＝4.4Hz,1H),7.13(s,1H),6.81(d,J＝4.4Hz,1H),6.32(d,J＝6.0Hz,1H),5.38(d,J＝6.0Hz,1H),4.65-4.63(m,2H),4.35–4.26(m,1H),4.22-4.20(m,1H),4.16(dd,J＝12.0,5.2Hz,1H),3.92-3.90(m,1H),2.17-2.14(m,3H),1.61-1.59(m,6H),1.14-1.06(m,3H),0.96(dd,J＝6.8,4.0Hz,6H),0.90–0.87(m,2H).

Synthesis of (2R, 3S,4R, 5R) -5- {4- [ (2S) -2-amino-3-methylbutanamide ] pyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-3, 4-dihydroxyoxapent-2-yl ] methyl 2-phenylacetate (Compound 113).

Synthesis of [ (3 aR,4R,6 aR) -6- {4- [ (2S) -2- { [ (tert-butoxy) carbonyl ] amino } -3-methylbutanamidyl ] pyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -6-cyano-2, 2-dimethyl-dihydro-3 aH-furo [3,4-d ] [1,3] dioxol-4-yl ] methyl 2-phenylacetate (113.1).

Compound 113.1 was prepared according to the procedure of step 4 of example 1 using 112.1 and 2-phenylacetyl chloride. MS (ESI): the calculated mass for C ₃₃H₄₀N₆O₈ was 648.29 and the m/z found was 649.3[ M+H ] ⁺.

Synthesis of (2R, 3S,4R, 5R) -5- {4- [ (2S) -2-amino-3-methylbutanamido ] pyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-3, 4-dihydroxyoxacyclopent-2-yl ] methyl 2-phenylacetate (113).

Compound 113 was prepared according to the procedure of step 3 of example 112 using 113.1. MS (ESI): the calculated mass for C ₂₅H₂₈N₆O₆ was 508.21 and the measured m/z was 509.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.27(d,J＝8.8Hz,1H),7.98(s,1H),7.58(s,1H),7.32–7.21(m,6H),7.12(s,1H),6.79(d,J＝4.4Hz,1H),6.40(d,J＝5.2Hz,1H),5.49(d,J＝5.2Hz,1H),4.65(t,J＝8.0Hz,2H),4.34(dd,J＝11.6,2.4Hz,1H),4.28–4.15(m,2H),3.94-3.92(m,1H),3.66(s,2H),2.20-2.15(m,1H),0.96(dd,J＝6.8,4.4Hz,6H).

Synthesis of [ (2R, 3S,4R, 5R) -5- {4- [ (2S) -2-amino-3-methylbutanamide ] pyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-3, 4-dihydroxyoxapent-2-yl ] methyl 2-methylpropionate (Compound 116).

Synthesis of [ (3 aR,4R,6 aR) -6- {4- [ (2S) -2- { [ (tert-butoxy) carbonyl ] amino } -3-methylbutanamino ] pyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -6-cyano-2, 2-dimethyl-dihydro-3 aH-furo [3,4-d ] [1,3] dioxol-4-yl ] methyl 2-methylpropionate (116.1).

Compound 116.1 was prepared according to the procedure of step 4 of example 1 using 112.1 and 2-methylpropanoyl chloride. MS (ESI): the calculated mass for C ₂₉H₄₀N₆O₈ was 600.29 and the m/z found was 601.3[ M+H ] ⁺.

Step 2: synthesis of [ (2R, 3S,4R, 5R) -5- {4- [ (2S) -2-amino-3-methylbutanamide ] pyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-3, 4-dihydroxyoxacyclopent-2-yl ] methyl 2-methylpropionate (116).

Compound 116 was prepared according to the procedure of step 3 of example 112 using 116.1. MS (ESI): the calculated mass for C ₂₁H₂₈N₆O₆ was 460.21 and the measured m/z was 461.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.21(d,J＝8.8Hz,1H),7.98(s,1H),7.56(s,1H),7.24(d,J＝4.4Hz,1H),7.13(s,1H),6.81(d,J＝4.8Hz,1H),6.34-6.25(m,1H),5.39-5.25(m,1H),4.66-4.62(m,2H),4.31(dd,J＝12.0,2.4Hz,1H),4.23-4.21(m,1H),4.16(dd,J＝12.0,5.2Hz,1H),3.95(d,J＝5.2Hz,1H),2.53-2.50(m,1H),2.18-2.15(m,1H),1.05(dd,J＝7.2,2.8Hz,6H),0.96(dd,J＝6.8,3.2Hz,6H).

Synthesis of [ (2R, 3S,4R, 5R) -5- {4- [ (2S) -2-amino-3-methylbutanamide ] pyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-3, 4-dihydroxyoxacyclopent-2-yl ] methyl 3-methylbutanoate (compound 117).

Synthesis of [ (3 aR,4R,6 aR) -6- {4- [ (2S) -2- { [ (tert-butoxy) carbonyl ] amino } -3-methylbutanamino ] pyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -6-cyano-2, 2-dimethyl-dihydro-3 aH-furo [3,4-d ] [1,3] dioxol-4-yl ] methyl 3-methylbutanoate (117.1).

Compound 117.1 was prepared according to the procedure of step 4 of example 1 using 117.1 and 3-methylbutyryl chloride. MS (ESI): the calculated mass for C ₃₀H₄₂N₆O₈ was 614.31 and the m/z found was 615.3[ M+H ] ⁺.

Synthesis of [ (2R, 3S,4R, 5R) -5- {4- [ (2S) -2-amino-3-methylbutanamide ] pyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-3, 4-dihydroxyoxacyclopent-2-yl ] methyl 3-methylbutanoate (117).

Compound 117 was prepared according to the procedure of step 1 of example 112 using 117.1 and 3-methylbutyryl chloride. MS (ESI): the calculated mass for C ₂₂H₃₀N₆O₆ was 474.22 and the measured m/z was 475.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.23(d,J＝8.4Hz,1H),7.98(s,1H),7.56(s,1H),7.24(d,J＝4.4Hz,1H),7.13(s,1H),6.81(d,J＝4.8Hz,1H),6.36(d,J＝6.0Hz,1H),5.40(d,J＝6.0Hz,1H),4.69–4.60(m,2H),4.33(dd,J＝12.0,2.4Hz,1H),4.26–4.19(m,1H),4.16(dd,J＝12.0,5.6Hz,1H),3.93-3.92(m,1H),2.18-2.15(m,3H),1.98–1.87(m,1H),0.96(dd,J＝6.8,3.6Hz,6H),0.87(dd,J＝6.8,2.4Hz,6H).

EXAMPLE 70 Synthesis of (2R, 3S,4R, 5R) -5- {4- [ (2S) -2-amino-3-methylbutanamide ] pyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-4-hydroxy-2- (hydroxymethyl) oxacyclopent-3-yl (2S) -2-amino-3-methylbutanoate (compound 129).

Synthesis of (2R, 3S,4R, 5R) -5- {4- [ (2S) -2- { [ (tert-butoxy) carbonyl ] amino } -3-methylbutanamino ] pyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -2- ({ 1- [ tert-butyl (hydroxy) phenylsilyl ] phenyl } methyl) -5-cyano-4-hydroxyoxolan-3-yl (2S) -2- { [ (tert-butoxy) carbonyl ] amino } -3-methylbutanoate (129.1).

Compound 129.1 was prepared according to the procedure of step 1 of example 83 using 129.1 and (2S) -2-cyclohexylpropionic acid. MS (ESI): the calculated mass for C ₄₈H₆₅N₇O₁₀ Si was 927.46 and the m/z found was 928.5[ M+H ] ⁺.

(2R, 3S,4R, 5R) -5- {4- [ (2S) -2-amino-3-methylbutanamide ] pyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-4-hydroxy-2- (hydroxymethyl) oxacyclopent-3-yl (2S) -2-amino-3-methylbutanoate (129).

To a solution of (2R, 3S,4R, 5R) -5- {4- [ (2S) -2- { [ (tert-butoxy) carbonyl ] amino } -3-methylbutanamino ] pyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -2- { [ (tert-butyldiphenylsilyl) oxy ] methyl } -5-cyano-4-hydroxyoxa-3-yl (2S) -2- { [ (tert-butoxy) carbonyl ] amino } -3-methylbutanoate (129.2, 100mg,0.107 mmol) in THF (2 mL) was added HCl in dioxane (4M, 3 mL) and TBAF in THF (1M, 4 mL) and the mixture was stirred at 25℃for 16h. The reaction was concentrated in vacuo and purified by preparative HPLC to give the salt forming compound. The compound was basified with NaHCO ₃ (saturated aqueous solution, 1 mL) and purified by preparative HPLC to give 129 (11.58 mg,22% yield) as a white solid. MS (ESI): the calculated mass for C ₂₂H₃₁N₇O₆ was 489.23 and the measured m/z was 490.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.26(d,J＝8.0Hz,1H),7.98(s,1H),7.56(s,1H),7.26(d,J＝4.4Hz,1H),7.14(s,1H),6.90(d,J＝4.4Hz,1H),6.4-6.45(m,1H),5.19(dd,J＝5.6,3.6Hz,1H),5.02-5.00(m,2H),4.66(t,J＝8.0Hz,1H),4.25-4.23(m,1H),3.59-3.55(m,2H),3.23(d,J＝5.2Hz,1H),2.18-2.14(m,1H),2.0-1.98(m,1H),0.97–0.85(m,12H).

Synthesis of [ (2R, 3R,4R, 5R) -5- [ 2-amino-6- (methylamino) purin-9-yl ] -4-fluoro-3-hydroxy-4-methyloxypent-2-yl ] methyl (2S) -2-amino-3-methylbutanoate (Compound 176).

Synthesis of([ (2R, 3R,4R, 5R) -5- [ 2-amino-6- (methylamino) purin-9-yl ] -4-fluoro-3-hydroxy-4-methyloxypent-2-yl ] methyl (2S) -2- { [ (tert-butoxy) carbonyl ] amino } -3-methylbutanoate methane (176.1).

Compound 176.1 was prepared according to the procedure of step 1 of example 19 using 3.3 and (2S) -2- { [ (tert-butoxy) carbonyl ] amino } -3-methylbutanoic acid. MS (ESI): the calculated mass for C ₂₂H₃₄FN₇O₆ was 511.26 and the measured m/z was 512.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.81(s,1H),7.30(s,1H),7.19(d,J＝8.0Hz,1H),6.03-6.00(m,3H),5.80(d,J＝6.8Hz,1H),4.50(d,J＝11.2Hz,1H),4.37(dd,J＝12.0,7.2Hz,1H),4.06(t,J＝8.0Hz,1H),3.86(t,J＝8.0Hz,1H),3.30-3.25(m,1H),2.87(s,3H),2.02-1.98(m,1H),1.36(s,9H),1.09(d,J＝22.4Hz,3H),0.86(dd,J＝6.8,2.4Hz,6H).

Synthesis of [ (2R, 3R,4R, 5R) -5- [ 2-amino-6- (methylamino) purin-9-yl ] -4-fluoro-3-hydroxy-4-methyloxypent-2-yl ] methyl (2S) -2-amino-3-methylbutanoate (176).

The title compound 176 was prepared according to the procedure for step 2 of example 19 using 176.1. MS (ESI): the calculated mass for C ₁₇H₂₆FN₇O₄ was 411.20 and the measured m/z was 412.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.83(s,1H),7.34(s,1H),6.12–5.97(m,3H),5.82-5.80(m,1H),4.52(d,J＝12.0Hz,1H),4.34(dd,J＝12.4,6.4Hz,2H),4.10–4.05(m,1H),3.18((d,J＝5.2Hz,1H),2.87(s,3H),1.86-1.83(m,1H),1.10(d,J＝22.4Hz,3H),0.85(dd,J＝17.2,6.8Hz,6H).¹⁹F NMR(376MHz,DMSO)δ-159.87(s,1H).

Synthesis of((2R, 3R,4R, 5R) -5- (2-amino-6- (methylamino) -9H-purin-9-yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methylpropionate (Compound 180).

The title compound was prepared according to the procedure for step 3 of example 3 using propionyl chloride. MS (ESI): the calculated mass for C ₁₅H₂₁FN₆O₄ was 368.16, the measured m/z was 369.2[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ7.81(s,1H),7.32(br s,1H),6.0-6.05(m,3H),5.76(br d,J＝6.8Hz,1H),4.29-4.47(m,4H),4.04(m,1H),2.87(br s,3H),2.34-2.40(m,2H),1.02-1.14(m,6H).

Synthesis of (2R, 3R,4R, 5R) -5- (2-amino-6- (methylamino) -9H-purin-9-yl) -2- ((2-cyclohexylacetoxy) methyl) -4-fluoro-4-methyltetrahydrofuran-3-yl 3-methylbutanoate (Compound 183).

To a solution of 175 (100 mg,0.22 mmol) in NMP was added dropwise 4M HCl/dioxane (0.1 mL) at 0deg.C. The mixture was then stirred at 0 ℃ for 30 minutes. Thereafter, 3-methylbutyryl chloride was slowly added to the mixture. The reaction mixture was stirred at 20 ℃ for 16 hours. After completion, the mixture was purified by preparative HPLC to give 183 (12 mg,9.9% yield) as a white solid. MS (ESI): for a calculated m/z of C ₂₅H₃₇FN₆O₅ of 520.28, the actual measurement was 521.20[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.88(s,1H),7.39(s,1H),6.13(d,J＝19.6Hz,1H),5.95(s,3H),4.45(d,J＝9.2Hz,1H),4.33(dd,J＝15.2,6.0Hz,2H),2.87(s,3H),2.37–2.31(m,2H),2.21(d,J＝6.4Hz,2H),2.03(dt,J＝13.6,6.8Hz,1H),1.62(dd,J＝21.2,10.4Hz,6H),1.24–1.09(m,6H),0.93(dt,J＝17.2,8.4Hz,8H).¹⁹F NMR(377MHz,DMSO)δ-156.31(s,1F).

EXAMPLE 74 Synthesis of (2R, 3R,4R, 5R) -5- (2-amino-6- (methylamino) -9H-purin-9-yl) -4-fluoro-4-methyl-2- ((2-phenylacetyloxy) methyl) tetrahydrofuran-3-yl 3-methylbutanoate (Compound 185).

The title compound was prepared according to the procedure for example 183 using 177 and 3-methylbutyryl chloride. MS (ESI): for a calculated m/z of C ₂₅H₃₁FN₆O₅ of 514.23, the actual measurement was 515.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.86(s,1H),7.48–7.13(m,6H),6.13(d,J＝19.6Hz,1H),6.04–5.74(m,3H),4.51–4.43(m,1H),4.41–4.28(m,2H),3.72(d,J＝2.8Hz,2H),2.87(s,3H),2.34–2.30(m,2H),2.06–1.97(m,1H),1.14(d,J＝23.2Hz,3H),0.94(dd,J＝6.8,1.2Hz,6H).¹⁹FNMR(377MHz,DMSO)δ-156.01.

Synthesis of (2R, 3R,4R, 5R) -2- (acetoxymethyl) -5- (2-amino-6- (methylamino) -9H-purin-9-yl) -4-fluoro-4-methyltetrahydrofuran-3-yl 3-methylbutanoate (Compound 186).

The title compound was prepared according to the procedure for example 183 using 178 and 3-methylbutyryl chloride. MS (ESI): for a calculated m/z of C ₁₉H₂₇FN₆O₅ of 438.20, the actual measurement was 439.10[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.05(d,J＝70.8Hz,3H),7.17–7.09(m,1H),6.97(d,J＝4.4Hz,1H),6.84(d,J＝4.4Hz,1H),6.34(s,1H),5.40(s,1H),4.68(d,J＝4.8Hz,1H),4.38–4.18(m,3H),3.98–3.83(m,2H),1.96(d,J＝6.8Hz,1H),1.34(d,J＝32.4Hz,9H),0.82(t,J＝6.0Hz,6H).¹⁹F NMR(377MHz,DMSO)δ-156.17(s,1F).

Synthesis of (2R, 3R,4R, 5R) -5- (2-amino-6- (methylamino) -9H-purin-9-yl) -4-fluoro-4-methyl-2- ((propionyloxy) methyl) tetrahydrofuran-3-yl 3-methylbutanoate (Compound 188).

The title compound was prepared according to the procedure for example 183 using 180 and 3-methylbutyryl chloride. MS (ESI): for a calculated m/z of C ₂₀H₂₉FN₆O₅ of 452.22, the actual measurement was 453.10[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.89(s,1H),7.39(s,1H),6.13(d,J＝19.2Hz,1H),5.90(s,3H),4.46(d,J＝9.6Hz,1H),4.39–4.27(m,2H),2.87(s,3H),2.39–2.30(m,4H),2.10–1.97(m,1H),1.15(d,J＝22.8Hz,3H),1.03(t,J＝7.6Hz,3H),0.94(dd,J＝6.8,2.0Hz,6H).¹⁹F NMR(377MHz,DMSO)δ-156.26.

Synthesis of((2R, 3R,4R, 5R) -5- (2-amino-6- (methylamino) -9H-purin-9-yl) -3- (2-cyclohexylacetoxy) -4-fluoro-4-methyltetrahydrof-n-2-yl) methyl 3-methylbutanoate (Compound 190).

The title compound was prepared according to the procedure for step 1 of example 183 using compound 174 and 2-cyclohexylacetyl chloride. MS (ESI): the calculated mass for C ₂₅H₃₇FN₆O₅ was 520.28, the measured m/z was 521.3[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ7.88(s,1H),7.39(s,1H),6.13(d,J＝19.6Hz,1H),6.02–5.74(m,3H),4.44(t,J＝8.4Hz,1H),4.37–4.23(m,2H),2.87(s,3H),2.33(d,J＝6.8Hz,2H),2.22(d,J＝6.8Hz,2H),1.98(dt,J＝13.6,6.8Hz,1H),1.76–1.58(m,6H),1.27–1.10(m,6H),1.05–0.93(m,2H),0.90(dd,J＝6.8,2.4Hz,6H).¹⁹F NMR(376MHz,DMSO)δ-156.30.

Synthesis of (2R, 3R,4R, 5R) -5- (2-amino-6- (methylamino) -9H-purin-9-yl) -2- ((2-cyclohexylacetoxy) methyl) -4-fluoro-4-methyltetrahydrof-n-3-yl 2-cyclohexylacetate (Compound 191).

The title compound was prepared according to the procedure for step 1 of example 183 using compound 175 and 2-cyclohexylacetyl chloride. MS (ESI): the calculated mass for C ₂₈H₄₁FN₆O₅ was 560.31, the measured m/z was 561.3[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ7.88(s,1H),7.39(s,1H),6.13(d,J＝19.6Hz,1H),6.05–5.80(m,3H),4.47–4.41(m,1H),4.35–4.27(m,2H),2.87(s,3H),2.33(d,J＝6.8Hz,2H),2.21(d,J＝6.8Hz,2H),1.74–1.61(m,11H),1.26–1.10(m,10H),1.02–0.86(m,4H).¹⁹F NMR(376MHz,DMSO)δ-156.30.

Synthesis of((2R, 3R,4R, 5R) -5- (2-amino-6- (methylamino) -9H-purin-9-yl) -3- (2-cyclohexylacetoxy) -4-fluoro-4-methyltetrahydrof-n-2-yl) methyl 2-phenylacetate (Compound 193).

The title compound was prepared according to the procedure for step 1 of example 183 using compound 177 and 2-cyclohexylacetyl chloride. MS (ESI): the calculated mass for C ₂₈H₃₅FN₆O₅ was 554.27, m/z found to be 555.2[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ7.86(s,1H),7.51–7.12(m,6H),6.13(d,J＝19.6Hz,1H),5.95–5.74(m,3H),4.48(dd,J＝12.4,2.8Hz,1H),4.42–4.25(m,2H),3.71(d,J＝2.8Hz,2H),2.87(s,3H),2.32(d,J＝6.8Hz,2H),1.70–1.63(m,6H),1.25–1.10(m,6H),1.09–0.92(m,2H).¹⁹F NMR(376MHz,DMSO)δ-155.98.

Example 80 synthesis of (2R, 3R,4R, 5R) -2- (acetoxymethyl) -5- (2-amino-6- (methylamino) -9H-purin-9-yl) -4-fluoro-4-methyltetrahydrof-n-3-yl 2-cyclohexylacetate (Compound 194).

The title compound was prepared according to the procedure for step 1 of example 183 using compound 178 and 2-cyclohexylacetyl chloride. MS (ESI): the calculated mass for C ₂₂H₃₁FN₆O₅ was 478.23 and the measured m/z was 479.2[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ7.90(s,1H),7.38(s,1H),6.13(d,J＝19.6Hz,1H),5.80–5.60(m,3H),4.46–4.42(m,1H),4.35–4.27(m,2H),2.87(s,3H),2.33(d,J＝6.8Hz,2H),2.04(s,3H),1.70–1.60(m,6H),1.24–1.10(m,6H),1.03–0.94(m,2H).¹⁹F NMR(376MHz,DMSO)δ-156.14.

Synthesis of((2R, 3R,4R, 5R) -5- (2-amino-6- (methylamino) -9H-purin-9-yl) -3- (2-cyclohexylacetoxy) -4-fluoro-4-methyltetrahydrofuran-2-yl) methylpropionate (Compound 196).

The title compound was prepared according to the procedure for step 1 of example 183 using compound 180 and 2-cyclohexylacetyl chloride. MS (ESI): the calculated mass for C ₂₃H₃₃FN₆O₅ was 492.25 and the measured m/z was 493.2[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ7.89(s,1H),7.39(s,1H),6.13(d,J＝19.6Hz,1H),6.05–5.80(m,3H),4.48–4.43(m,1H),4.39–4.26(m,2H),2.87(s,3H),2.39–2.30(m,4H),1.75–1.58(m,6H),1.28–1.10(m,6H),1.06–0.93(m,5H).¹⁹F NMR(376MHz,DMSO)δ-156.23.

EXAMPLE 82 synthesis of [ (2R, 3R,4R, 5R) -5- [ 2-amino-6- (methylamino) purin-9-yl ] -4-fluoro-4-methyl-3- [ (2-phenylacetyl) oxy ] oxa-pent-2-yl ] methyl 3-methylbutanoate (compound 206) and [ (2R, 3R,4R, 5R) -4-fluoro-3-hydroxy-4-methyl-5- [6- (methylamino) -2- (2-phenylacetylamino) purin-9-yl ] oxa-pent-2-yl ] methyl 3-methylbutanoate (compound 316).

The title compounds 206 and 316 were prepared according to the procedure for step1 of example 65 using 174 and 2 2-phenylacetyl chloride.

For compound 206: MS (ESI): the calculated mass for C ₂₅H₃₁FN₆O₅ was 514.23, m/z found to be 515.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.87(s,1H),7.40–7.25(m,6H),6.13(d,J＝19.6Hz,1H),5.92-5.90(m,3H),4.44(t,J＝7.2Hz,1H),4.35–4.29(m,2H),3.83(d,J＝2.0Hz,2H),2.86(s,3H),2.18(dd,J＝7.2,2.8Hz,2H),1.96-1.92(m,1H),1.12(d,J＝22.8Hz,3H),0.88(dd,J＝6.8,3.2Hz,6H).¹⁹F NMR(376MHz,DMSO)δ-156.22.

For compound 316: MS (ESI): the calculated mass for C ₂₅H₃₁FN₆O₅ was 514.23, m/z found to be 515.2[M+H]⁺.¹H NMR(400MHz)δ10.25(s,1H),8.13(s,1H),7.85(s,1H),7.33-7.21(m,5H),6.13(d,J＝20.0Hz,1H),5.66(d,J＝6.8Hz,1H),4.78-4.70(m,1H),4.47(dd,J＝12.4,2.0Hz,1H),4.33-4.30(m,1H),4.04(t,J＝7.6Hz,1H),3.83(s,2H),2.94(s,3H),2.20(d,J＝7.2Hz,2H),1.97-1.94(m,1H),1.12(d,J＝22.8Hz,3H),0.89(dd,J＝6.8,1.6Hz,6H).¹⁹F NMR(376MHz,DMSO)δ-158.53.

EXAMPLE 83 Synthesis of (2R, 3R,4R, 5R) -5- (2-amino-6- (methylamino) -9H-purin-9-yl) -4-fluoro-4-methyl-2- ((2-phenylacetyloxy) methyl) tetrahydrofuran-3-yl 2-phenylacetate (Compound 209).

The title compound was prepared according to the procedure for step 1 of example 183 using compound 177 and 2-phenylacetyl chloride. MS (ESI): the calculated mass for C ₂₈H₂₉FN₆O₅ was 548.22 and the measured m/z was 549.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ7.85(s,1H),7.44–7.18(m,11H),6.14(d,J＝19.6Hz,1H),5.91(s,3H),4.49–4.25(m,1H),4.40–4.29(m,2H),3.83(d,J＝2.0Hz,2H),3.68(d,J＝4.8Hz,2H),2.87(s,3H),1.12(d,J＝22.8Hz,3H).¹⁹F NMR(376MHz,DMSO)δ-155.94.

Synthesis of (2R, 3R,4R, 5R) -2- (acetoxymethyl) -5- (2-amino-6- (methylamino) -9H-purin-9-yl) -4-fluoro-4-methyltetrahydrofuran-3-yl 2-phenylacetate (Compound 210).

The title compound was prepared according to the procedure for example 183 using 178 and 2-phenylacetyl chloride. MS (ESI): for a calculated m/z of C ₂₂H₂₅FN₆O₅ of 472.19, the actual measurement was 473.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.88(s,1H),7.40–7.23(m,6H),6.13(d,J＝19.6Hz,1H),5.91(s,3H),4.48–4.41(m,1H),4.35–4.27(m,2H),3.83(d,J＝1.6Hz,2H),2.87(s,3H),2.01(s,3H),1.12(d,J＝22.8Hz,3H).¹⁹F NMR(377MHz,DMSO)δ-156.10.

Synthesis of((2R, 3R,4R, 5R) -5- (2-amino-6- (methylamino) -9H-purin-9-yl) -4-fluoro-4-methyl-3- (2-phenylacetyloxy) tetrahydrofuran-2-yl) methylpropionate (Compound 212).

The title compound was prepared according to the procedure for example 183 using 180 and 2-phenylacetyl chloride. MS (ESI): for a calculated m/z of C ₂₃H₂₇FN₆O₅ of 486.20, the actual measurement was 487.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.88(s,1H),7.40–7.23(m,6H),6.13(d,J＝19.2Hz,1H),5.92(s,3H),4.51–4.40(m,1H),4.36–4.28(m,2H),3.83(d,J＝2.8Hz,2H),2.87(s,3H),2.36–2.24(m,2H),1.12(d,J＝23.2Hz,3H),1.01(t,J＝7.2Hz,3H).¹⁹F NMR(377MHz,DMSO)δ-156.17.

Synthesis of((2R, 3R,4R, 5R) -3-acetoxy-5- (2-amino-6- (methylamino) -9H-purin-9-yl) -4-fluoro-4-methyltetrahydrof-n-2-yl) methyl 3-methylbutanoate (Compound 214).

The title compound was prepared according to the procedure for example 183 using 174 and acetyl chloride. MS (ESI): for a calculated m/z of C ₁₉H₂₇FN₆O₅ of 438.20, the actual measurement was 439.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.88(s,1H),7.39(s,1H),6.13(d,J＝19.2Hz,1H),6.04–5.65(m,3H),4.46(dd,J＝12.0,2.8Hz,1H),4.39–4.27(m,2H),2.87(s,3H),2.25–2.19(m,2H),2.15(s,3H),2.03–1.92(m,1H),1.15(d,J＝23.2Hz,3H),0.90(dd,J＝6.4,2.4Hz,6H).¹⁹F NMR(377MHz,DMSO)δ-156.44.

Synthesis of((2R, 3R,4R, 5R) -3-acetoxy-5- (2-amino-6- (methylamino) -9H-purin-9-yl) -4-fluoro-4-methyltetrahydrof-n-2-yl) methyl 2-cyclohexylacetate (Compound 215).

The title compound was prepared according to the procedure for example 183 using 175 and acetyl chloride. MS (ESI): for a calculated m/z of C ₂₂H₃₁FN₆O₅ of 478.23, the actual measurement was 479.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.88(s,1H),7.38(s,1H),6.12(d,J＝19.6Hz,1H),6.04–5.68(m,3H),4.49–4.41(m,1H),4.37–4.26(m,2H),2.87(s,3H),2.21(d,J＝6.8Hz,2H),2.15(s,3H),1.70–1.55(m,6H),1.25–1.04(m,6H),0.98–0.85(m,2H).¹⁹F NMR(377MHz,DMSO)δ-156.39.

Synthesis of((2R, 3R,4R, 5R) -3-acetoxy-5- (2-amino-6- (methylamino) -9H-purin-9-yl) -4-fluoro-4-methyltetrahydrofuran-2-yl) methyl 2-phenylacetate (Compound 217).

The title compound was prepared according to the procedure for example 183 using 177 and acetyl chloride. MS (ESI): for a calculated m/z of C ₂₂H₂₅FN₆O₅ of 472.19, the actual measurement was 473.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.86(s,1H),7.41–7.22(m,6H),6.13(d,J＝19.6Hz,1H),6.04–5.71(m,3H),4.49(dd,J＝12.4,2.8Hz,1H),4.42–4.27(m,2H),3.71(d,J＝2.4Hz,2H),2.87(s,3H),2.14(s,3H),1.15(d,J＝22.8Hz,3H).¹⁹F NMR(377MHz,DMSO)δ-156.12.

Synthesis of((2R, 3R,4R, 5R) -3-acetoxy-5- (2-amino-6- (methylamino) -9H-purin-9-yl) -4-fluoro-4-methyltetrahydrofuran-2-yl) methylacetate (Compound 218).

To a solution of 3.3 (500 mg,1.6 mmol) in DMA (1 mL) was added HCl/dioxane (0.8 mL, 4M). The mixture solution was stirred at 20℃for 15 minutes. The reaction mixture was cooled at 0deg.C and acetyl chloride (0.91 mL,12.8 mmol) was added immediately. The reaction was stirred at 0 ℃ for 1 hour. The reaction was diluted with ACN (2.0 mL) and purified by preparative HPLC to give 218 (24.5 mg,3.83% yield) as a white solid. MS (ESI): for a calculated m/z of C ₁₆H₂₁FN₆O₅ of 396.16, the actual measurement was 397.0[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ7.90(s,1H),7.38(s,1H),6.13(d,J＝19.6Hz,1H),5.93–5.80(m,3H),4.50–4.37(m,1H),4.38–4.26(m,2H),2.87(s,3H),2.15(s,3H),2.04(s,3H),1.15(d,J＝22.8Hz,3H).¹⁹F NMR(376MHz,DMSO)δ-156.30.

Example 90 synthesis of [ (2R, 3R,4R, 5R) -3- (acetoxy) -5- [ 2-amino-6- (methylamino) purin-9-yl ] -4-fluoro-4-methyloxypent-2-yl ] methyl 2-methylpropionate (compound 219) and [ (2R, 3R,4R, 5R) -3- (acetoxy) -5- [ 2-acetamido-6- (methylamino) purin-9-yl ] -4-fluoro-4-methyloxypent-2-yl ] methyl 2-methylpropionate (compound 323).

The title compounds 219 and 323 were prepared according to the procedure of step 1 of example 65 using 179 and acetyl chloride.

For compound 219: MS (ESI): the calculated mass for C ₁₈H₂₅FN₆O₅ was 424.19, the measured m/z was 425.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.89(s,1H),7.40(s,1H),6.13(d,J＝19.6Hz,1H),5.90-5.86(m,3H),4.45-4.44(m,1H),4.37-4.31(m,2H),2.87(s,3H),2.58-2.52(m,1H),2.15(s,3H),1.20–1.07(m,9H).¹⁹F NMR(376MHz,DMSO)δ-156.51.

For compound 323: MS (ESI): the calculated mass for C ₂₀H₂₇FN₆O₆ was 466.20 and the measured m/z was 467.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ9.94(s,1H),8.18(s,1H),7.91(s,1H),6.23(d,J＝19.6Hz,1H),6.11-6.08(m,1H),4.47–4.37(m,2H),4.36–4.29(m,1H),2.94(s,3H),2.55-2.51(m,1H),2.20(s,3H),2.14(s,3H),1.17(d,J＝23.2Hz,3H),1.08(dd,J＝7.2,1.2Hz,6H).¹⁹FNMR(376MHz,DMSO)δ-155.42.

Synthesis of((2R, 3R,4R, 5R) -3-acetoxy-5- (2-amino-6- (methylamino) -9H-purin-9-yl) -4-fluoro-4-methyltetrahydrofuran-2-yl) methylpropionate (Compound 220).

The title compound was prepared according to the procedure for example 183 using 180 and acetyl chloride. MS (ESI): for a calculated m/z of C ₁₇H₂₃FN₆O₅ of 410.17, the actual measurement was 411.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.89(s,1H),7.38(s,1H),6.13(d,J＝19.2Hz,1H),6.05–5.69(m,3H),4.51–4.43(m,1H),4.38–4.28(m,2H),2.87(s,3H),2.39–2.31(m,2H),2.15(s,3H),1.15(d,J＝22.8Hz,3H),1.03(t,J＝7.2Hz,3H).¹⁹F NMR(377MHz,DMSO)δ-156.39.

Synthesis of((2R, 3R,4R, 5R) -5- (2-amino-6- (methylamino) -9H-purin-9-yl) -4-fluoro-3- (isobutyryloxy) -4-methyltetrahydrofuran-2-yl) methyl 3-methylbutanoate (Compound 222).

The title compound was prepared according to the procedure for example 183 using 174 and 2-methylpropanoyl chloride. MS (ESI): for a calculated m/z of C ₂₁H₃₁FN₆O₅ of 466.23, the actual measurement was 467.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.88(s,1H),7.39(s,1H),6.13(d,J＝19.2Hz,1H),6.05–5.70(m,3H),4.49–4.39(m,1H),4.37–4.28(m,2H),2.87(s,3H),2.72–2.64(m,1H),2.22(dd,J＝6.8,1.2Hz,2H),2.03–1.92(m,1H),1.18–1.09(m,9H),0.89(dd,J＝6.8,2.4Hz,6H).¹⁹F NMR(377MHz,DMSO)δ-156.75.

Example 93: synthesis of (2R, 3R,4R, 5R) -5- [ 2-amino-6- (methylamino) purin-9-yl ] -2- { [ (2-cyclohexylacetyl) oxy ] methyl } -4-fluoro-4-methyloxolan-3-yl 2-methylpropanoate (Compound 223) and [ (2R, 3R,4R, 5R) -4-fluoro-3-hydroxy-4-methyl-5- [6- (methylamino) -2- (2-methylpropanamido) purin-9-yl ] oxolan-2-yl ] methyl 2-cyclohexylacetate (Compound 335).

The title compounds 223 and 335 were prepared according to the procedure for step 1 of example 65 using 175 and 2-methylpropanoyl chloride.

For compound 223: MS (ESI): the calculated mass for C ₂₄H₃₅FN₆O₅ was 506.27, the measured m/z was 507.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.88(s,1H),7.39(s,1H),6.13(d,J＝19.6Hz,1H),5.94-5.80(m,3H),4.45-4.44(m,1H),4.33-4.30(m,2H),2.87(s,3H),2.68-2.64(m,1H),2.19(dd,J＝6.8,2.0Hz,2H),1.76–1.58(m,6H),1.21–1.07(m,12H),0.97–0.88(m,2H).¹⁹F NMR(376MHz,DMSO)δ-156.70.

For compound 335: MS (ESI): the calculated mass for C ₂₄H₃₅FN₆O₅ was 506.27, the measured m/z was 507.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ9.93(s,1H),8.12(s,1H),7.80(s,1H),6.13(d,J＝19.6Hz,1H),5.64(d,J＝6.8Hz,1H),4.80-4.78(m,1H),4.44(dd,J＝12.4,2.0Hz,1H),4.3-4.30(m,1H),4.04(t,J＝8.0Hz,1H),2.94-2.90(m,4H),2.17(d,J＝6.8Hz,2H),1.62(d,J＝12.0Hz,6H),1.23–1.06(m,12H),0.95–0.86(m,2H).¹⁹F NMR(376MHz,DMSO)δ-158.73.

Example 94 synthesis of (2 r,3r,4r,5 r) -5- (2-amino-6- (methylamino) -9H-purin-9-yl) -4-fluoro-4-methyl-2- ((2-phenylacetyloxy) methyl) tetrahydrofuran-3-yl isobutyrate (compound 225).

The title compound was prepared according to the procedure for example 183 using 177 and isobutyryl chloride. MS (ESI): for a calculated m/z of C ₂₄H₂₉FN₆O₅ of 500.22, the actual measurement was 501.15[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.88(s,1H),7.38(s,1H),7.38–7.17(m,5H),6.16(d,J＝19.6Hz,1H),5.95(s,3H),4.66–4.23(m,3H),3.82–3.66(m,2H),2.90(s,3H),2.75–2.63(m,1H),1.30–1.08(m,9H).¹⁹F NMR(377MHz,DMSO)δ-156.45.

Example 95 synthesis of (2R, 3R,4R, 5R) -2- [ (acetoxy) methyl ] -5- [ 2-amino-6- (methylamino) purin-9-yl ] -4-fluoro-4-methyloxypent-3-yl 2-methylpropionate (Compound 226).

The title compound 226 was prepared according to the procedure for step 1 of example 65 using 178 and isobutyryl chloride. For compound 226: MS (ESI): the calculated mass for C ₁₈H₂₅FN₆O₅ was 424.19, the measured m/z was 425.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.90(s,1H),7.38(s,1H),6.13(d,J＝19.6Hz,1H),5.94-5.90(m,3H),4.44-4.40(m,1H),4.38–4.25(m,2H),2.87(s,3H),2.68-2.63(m,1H),2.02(s,3H),1.18–1.09(m,9H).¹⁹F NMR(376MHz,DMSO)δ-156.59.

Synthesis of [ (2R, 3R,4R, 5R) -5- [ 2-amino-6- (methylamino) purin-9-yl ] -4-fluoro-4-methyl-3- [ (2-methylpropanoyl) oxy ] oxa-pent-2-yl ] methylpropanoate (Compound 228) and [ (2R, 3R,4R, 5R) -4-fluoro-3-hydroxy-4-methyl-5- [6- (methylamino) -2- (2-methylpropanoyl) purin-9-yl ] oxa-pent-2-yl ] methylpropanoate (Compound 319).

The title compounds 228 and 319 were prepared according to the procedure of step 1 of example 65 using 180 and isobutyryl chloride.

For compound 228: MS (ESI): the calculated mass for C ₁₉H₂₇FN₆O₅ was 438.20, the measured m/z was 439.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.89(s,1H),7.38(s,1H),6.13(d,J＝19.6Hz,1H),5.95-5.80(m,3H),4.45-4.43(m,1H),4.34-4.30(m,2H),2.87(s,3H),2.72-2.65(m,1H),2.34-2.31(m,2H),1.15-1.11(m,9H),1.03(t,J＝7.6Hz,3H).¹⁹F NMR(376MHz,DMSO)δ-156.67.

For compound 319: MS (ESI): the calculated mass for C ₁₉H₂₇FN₆O₅ was 438.20, the measured m/z was 439.2[M+H]⁺.1H NMR(400MHz,DMSO)δ9.94(s,1H),8.12(s,1H),7.80(s,1H),6.13(d,J＝19.6Hz,1H),5.63(d,J＝6.8Hz,1H),4.85-4.80(m,1H),4.39-4.35(m,2H),4.06(t,J＝7.6Hz,1H),2.94(s,3H),2.51-2.49(m,1H),2.33-2.28(m,2H),1.16–1.06(m,9H),1.00(t,J＝7.6Hz,3H).¹⁹F NMR(376MHz,DMSO)δ-158.71.

Example 97 synthesis of [ (2R, 3R,4R, 5R) -5- [ 2-amino-6- (methylamino) purin-9-yl ] -4-fluoro-4-methyl-3- (propionyloxy) oxa-n-2-yl ] methyl 3-methylbutanoate (compound 230), [ (2R, 3R,4R, 5R) -4-fluoro-3-hydroxy-4-methyl-5- [6- (methylamino) -2-propionamido purin-9-yl ] oxa-n-2-yl ] methyl 3-methylbutanoate (compound 310) and [ (2R, 3R,4R, 5R) -4-fluoro-4-methyl-5- [6- (methylamino) -2-propionamido purin-9-yl ] -3- (propionyloxy) oxa-n-2-yl ] methyl 3-methylbutanoate (compound 311).

The title compounds 230, 310 and 311 were prepared according to the procedure of step 1 of example 65 using 174 and propionyl chloride.

For compound 230: MS (ESI): the calculated mass for C ₂₀H₂₉FN₆O₅ was 452.22 and the measured m/z was 453.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.88(s,1H),7.39(s,1H),6.13(d,J＝19.6Hz,1H),5.94-5.90(m,3H),4.46(dd,J＝12.0,2.4Hz,1H),4.40–4.26(m,2H),2.87(s,3H),2.45(d,J＝7.2Hz,2H),2.25–2.17(m,2H),1.98-1.94(m,1H),1.14(d,J＝22.8Hz,3H),1.08(t,J＝7.6Hz,3H),0.90(dd,J＝6.8,2.8Hz,6H).¹⁹F NMR(376MHz,DMSO)δ-156.52.

For compound 310: MS (ESI): the calculated mass for C ₂₀H₂₉FN₆O₅ was 452.22 and the measured m/z was 453.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ9.94(s,1H),8.11(s,1H),7.82(s,1H),6.12(d,J＝20.0Hz,1H),5.66(d,J＝7.2Hz,1H),4.79-4.76(m,1H),4.48(dd,J＝12.4,2.0Hz,1H),4.35-4.32(m,1H),4.05(t,J＝8.0Hz,1H),2.93(s,3H),2.52-2.50(m,2H),2.18(d,J＝6.8Hz,2H),1.96-1.93(m,1H),1.13(d,J＝22.8Hz,3H),1.06(t,J＝7.6Hz,3H),0.88(dd,J＝6.8,1.6Hz,6H).¹⁹F NMR(376MHz,DMSO)δ-158.47.

For compound 311: MS (ESI): the calculated mass for C ₂₃H₃₃FN₆O₆ was 508.24 and the m/z found was 509.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ9.86(s,1H),8.18(s,1H),7.89(s,1H),6.23(d,J＝20.0Hz,1H),6.08(d,J＝15.6Hz,1H),4.42-4.37(m,2H),4.35–4.27(m,1H),2.94(s,3H),2.54-2.51(m,2H),2.45-2.42(m,2H),2.19(d,J＝7.2Hz,2H),1.96-1.90(m,1H),1.18(d,J＝23.6Hz,3H),1.06-1.03(m,6H),0.89(dd,J＝6.8,2.0Hz,6H).¹⁹F NMR(376MHz,DMSO)δ-155.59.

Example 98 synthesis of [ (2R, 3R,4R, 5R) -5- [ 2-amino-6- (methylamino) purin-9-yl ] -4-fluoro-4-methyl-3- (propionyloxy) oxacyclopent-2-yl ] methylcyclohexane carboxylic acid ester (compound 231) and [ (2R, 3R,4R, 5R) -4-fluoro-3-hydroxy-4-methyl-5- [6- (methylamino) -2-propionamidoprozin-9-yl ] oxapent-2-yl ] methylcyclohexane carboxylic acid ester (compound 327).

The title compounds 231 and 327 were prepared according to the procedure of step 1 of example 65 using 175 and propionyl chloride.

For compound 231: MS (ESI): the calculated mass for C ₂₃H₃₃FN₆O₅ was 492.25 and the measured m/z was 493.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.88(s,1H),7.38(s,1H),6.13(d,J＝19.6Hz,1H),5.93-5.80(m,3H),4.45(d,J＝8.0Hz,1H),4.33-4.25(m,2H),2.87(s,3H),2.44(d,J＝7.6Hz,2H),2.24–2.17(m,2H),1.74–1.58(m,6H),1.21–1.03(m,9H),0.97–0.86(m,2H).¹⁹F NMR(376MHz,DMSO)δ-156.46.

For compound 327: MS (ESI): the calculated mass for C ₂₃H₃₃FN₆O₅ was 492.25 and the measured m/z was 493.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ9.94(s,1H),8.11(s,1H),7.82(s,1H),6.12(d,J＝19.8Hz,1H),5.65(d,J＝6.8Hz,1H),4.78-4.75(m,1H),4.47(dd,J＝12.4,2.0Hz,1H),4.33(dd,J＝12.4,7.2Hz,1H),4.04(t,J＝7.8Hz,1H),2.93(s,3H),2.18(d,J＝6.8Hz,2H),1.62-1.60(m,6H),1.22–1.02(m,9H),0.98–0.85(m,2H).¹⁹F NMR(376MHz,DMSO)δ-158.51.

Example 99 synthesis of (2 r,3r,4r,5 r) -5- (2-amino-6- (methylamino) -9H-purin-9-yl) -4-fluoro-4-methyl-2- ((2-phenylacetyloxy) methyl) tetrahydrofuran-3-yl propionate (compound 233).

The title compound was prepared according to the procedure for example 183 using 177 and propionyl chloride. MS (ESI): for a calculated m/z of C ₂₃H₂₇FN₆O₅ of 486.20, the actual measurement was 487.15[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.86(s,1H),7.49–7.33(m,1H),7.33–7.21(m,5H),6.13(d,J＝19.6Hz,1H),5.93(s,3H),4.49(dd,J＝12.0,2.8Hz,1H),4.38(dd,J＝12.0,6.0Hz,1H),4.35–4.27(m,1H),3.77–3.64(m,2H),2.87(s,3H),2.45(q,J＝7.2Hz,2H),1.20–1.04(m,6H).¹⁹F NMR(377MHz,DMSO)δ-156.22.

Example 100 synthesis of (2 r,3r,4r,5 r) -5- (2-amino-6- (methylamino) -9H-purin-9-yl) -4-fluoro-4-methyl-2- ((propionyloxy) methyl) tetrahydrofuran-3-yl propionate (compound 236).

The title compound was prepared according to the procedure for example 183 using 180 and propionyl chloride. MS (ESI): for a calculated m/z of C ₁₈H₂₅FN₆O₅ of 424.19, the actual measurement was 425.10[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.89(s,1H),7.38(s,1H),6.13(d,J＝19.6Hz,1H),5.94(s,3H),4.47(d,J＝9.2Hz,1H),4.38–4.28(m,2H),2.88(s,3H),2.45(q,J＝7.6Hz,2H),2.39–2.30(m,2H),1.20–1.00(m,9H).¹⁹F NMR(377MHz,DMSO)δ-156.47.

Example 101 synthesis of (((2R, 3R,4R, 5R) -5- (2-amino-6- (methylamino) -9H-purin-9-yl) -4-fluoro-3-hydroxy-4-methyltetrahydrof-n-2-yl) methyl (2- (octadecyloxy) ethyl) hydrogen phosphate (compound 254).

The title compound was prepared according to the procedure for step 3 of example 6 using alcohol 3.2. MS (ESI): the calculated mass for C ₃₂H₅₈FN₆O₇ P was 688.41 and the measured m/z was 687.4[M-H]^-.¹H NMR(400MHz,DMSO-d₆)δ8.08(s,1H),6.14(d,J＝18Hz,1H),4.26-4.4(m,3H),4.2(m,1H),4.01(m,2H),3.62(m,2H),3.4(m,2H),3.0-3.3(m,3H),1.53(m,2H),1.2-1.35(br m,30H),1.19(d,J＝22Hz,3H),0.92(t,J＝7Hz,3H).

Example 102 synthesis of [ (2 r,3S,4r,5 r) -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-3, 4-dihydroxyoxacyclopenta-2-yl ] methyl (2S) -3-methyl-2- (3-methylbutanamide) butanoate (compound 255).

The title compound 255 was prepared according to the procedure of step 1 of example 65 using 11 and 3-methylbutyryl chloride. For compound 231: MS (ESI): the calculated mass for C ₂₂H₃₀FN₆O₆ was 474.22 and the measured m/z was 475.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.03(d,J＝8.0Hz,1H),7.92(br,s,3H),6.92(d,J＝4.4Hz,1H),6.83(d,J＝4.4Hz,1H),6.36-6.34(m,1H),5.40-5.35(m,1H),4.68-4.64(m,1H),4.35–4.18(m,4H),3.91-3.87(m,1H),2.06–1.97(m,4H),0.91–0.87(m,6H),0.85–0.81(m,6H).

Example 103 synthesis of [ (phosphoryl) oxy ] methyl 2, 2-dimethylpropionate (compound 256) ({ [ (2R, 3S,4R, 5R) -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-3, 4-dihydroxyoxapent-2-yl ] methoxy } ({ [ (2, 2-dimethylpropionyl) oxy ] methoxy }).

Synthesis of N' - (7- ((2R, 3R,4S, 5R) -2-cyano-3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) -N, N-dimethylformamide (256.1).

To a solution of 6.3 (5.00 g,17.2 mmol) in dry DMF (60 mL) was added DMF-DMA (2.46 g,20.6 mmol). The reaction mixture was stirred under nitrogen at 70 ℃ for 2h. The reaction mixture was diluted with EA (80 mL) and washed with water (150 ml×2), then brine (150 ml×2), dried over anhydrous Na ₂SO₄, and filtered. The filtrate was concentrated to dryness. The residue was slurried in MeOH (30 mL) for 1h and filtered. The filter cake was washed with MeOH (5.0 mL) and then dried in vacuo to give 256.1 (4.45 g,74% yield) as a white solid. MS (ESI): for a calculated m/z of C ₁₅H₁₈N₆O₄ of 346.14, the actual measurement was 347.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.95(s,1H),8.15(s,1H),6.99(d,J＝4.4Hz,1H),6.83(d,J＝4.4Hz,1H),6.12(d,J＝6.4Hz,1H),5.22(d,J＝5.2Hz,1H),4.92(t,J＝5.6Hz,1H),4.67(dd,J＝6.4,5.6Hz,1H),4.08(dd,J＝8.4,4.4Hz,1H),3.99(q,J＝5.2Hz,1H),3.68–3.61(m,1H),3.56–3.48(m,1H),3.25(s,3H),3.19(s 3H).

Synthesis of ((oxo-l 5-phosphanetrioyl) tris (oxy)) tris (methylene) tris (2, 2-dimethylpropionate) (256.4).

To a solution of 256.3 (5.00 g,35.7 mmol) in dry ACN (30 mL) was added sequentially 256.2 (21.5 g,0.143 mol) and sodium iodide (16.1 g,0.107 mol). The reaction mixture was stirred under nitrogen at 80 ℃ for 72h. TLC showed 256.3 complete consumption. The reaction mixture was diluted with Et ₂ O (150 mL) and washed with water (80 ml×2), then with saturated aqueous Na ₂S₂O₃ (80 ml×2), dried over anhydrous Na ₂SO₄, filtered. The filtrate was concentrated to dryness. The residue was purified by FCC (gradient: 20% EA in PE) to give 256.4 (8.65 g,55% yield) as a colorless oil ).¹H NMR(400MHz,CDCl₃)δ5.66(d,J＝13.6Hz,6H),1.24(s,27H).³¹P NMR(162MHz,CDCl₃)δ-5.22.

Synthesis of ((hydroxyphosphoryl) bis (oxy)) bis (methylene) bis (2, 2-dimethylpropionate) (256.5).

256.3 (8.65 G,20 mmol) was dissolved in piperidine (50 mL) and stirred under nitrogen at 20deg.C for 16h. TLC showed 256.3 complete consumption. The reaction mixture was concentrated to constant weight. The residue was dissolved in water (180 mL) and treated with Dowex W50 x 2H ⁺ type resin (150 g). The suspension was stirred at 20 ℃ for 1h and filtered. The filtrate was concentrated to remove the solvent. The residue was lyophilized to give 256.4 (7.46 g, crude product) as a white wax ).¹HNMR(400MHz,CDCl₃)δ5.57(d,J＝12.4Hz,6H),1.22(s,18H).³¹P NMR(162MHz,CDCl₃)δ-4.08.

Synthesis of [ (phosphoryl) oxy ] methyl 2, 2-dimethylpropionate (256.6) [ ({ [ (2R, 3S,4R, 5R) -5-cyano-5- (4- { [ (dimethylamino) methylene ] amino } pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3, 4-dihydroxyoxapent-2-yl ] methoxy } ({ [ (2, 2-dimethylpropionyl) oxy ] methoxy }).

To a solution of 256.1 (500 mg,1.44 mmol) in dry THF (20 mL) was added a solution of triethylammonium bis (POM) phosphate in THF (prepared from 265.5 (560 mg,1.73 mmol), THF (5.0 mL) and TEA (190 mg,1.88 mmol). The resulting mixture was cooled to 0deg.C in an ice bath and DIPEA (746 mg,5.77 mmol) was added followed by BOP-Cl (730 mg,2.89 mmol) and 3-nitro-l, 2, 4-triazole (399 mg,2.89 mmol). The reaction mixture was stirred at 0 ℃ for 2h. The reaction mixture was diluted with DCM (150 mL) and washed with saturated aqueous NaHCO ₃ (25 mL. Times.2) followed by brine (25 mL). The aqueous phase was extracted with DCM (25 mL). The combined organic phases were dried over anhydrous Na ₂SO₄ and filtered. The filtrate was concentrated to dryness. The residue was purified by FCC (gradient: 5% MeOH in DCM) to give 256.6 (71.1 mg,7.5% yield) as a white solid. MS (ESI): for a calculated m/z of C ₂₇H₃₉N₆O₁₁ P of 654.24, the actual measurement was 655.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.94(s,1H),8.14(s,1H),6.92(d,J＝4.8Hz,1H),6.81(d,J＝4.4Hz,1H),6.37(d,J＝6.0Hz,1H),5.57(s,2H),5.54(s,2H),5.44(d,J＝6.0Hz,1H),4.73–4.69(m,1H),4.32–4.23(m,2H),4.20–4.14(m,1H),3.96(dd,J＝11.2,5.6Hz,1H),3.25(s,3H),3.18(s,3H),1.14(d,J＝5.6Hz,18H).³¹P NMR(162MHz,DMSO)δ-3.93.

Synthesis of [ (phosphoryl) oxy ] methyl 2, 2-dimethylpropionate (Compound 256) [ ({ [ (2R, 3S,4R, 5R) -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-3, 4-dihydroxyoxapent-2-yl ] methoxy } ({ [ (2, 2-dimethylpropionyl) oxy ] methoxy }).

To a solution of 256.6 (71.1 mg,0.109 mmol) in dry THF (1.0 mL) was added aqueous HCl (0.5 mL, 1M). The reaction mixture was irradiated in a microwave reactor at 60 ℃ for 10min under nitrogen. The organic solvent was removed with flowing nitrogen. The residue was purified by preparative HPLC to give the title compound 256 (30.6 mg,47% yield) as a white solid. MS (ESI): for a calculated m/z of C ₂₄H₃₄N₅O₁₁ P of 599.20, the actual measurement was 600.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92(br s,3H),6.90(d,J＝4.4Hz,1H),6.81(d,J＝4.4Hz,1H),6.36(d,J＝6.0Hz,1H),5.56(dd,J＝14.0,1.2Hz,4H),5.43(d,J＝5.6Hz,1H),4.68(t,J＝5.6Hz,1H),4.31–4.21(m,2H),4.19–4.12(m,1H),3.96–3.90(m,1H),1.14(d,J＝5.2Hz,18H).³¹P NMR(162MHz,DMSO)δ-3.93.

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2- (tetrahydro-2H-pyran-4-yl) acetate (Compound 257).

Step 1.2 Synthesis of acetyl chloride (257.2) (tetrahydro-2H-pyran-4-yl).

To a solution of 257.1 (500 mg,3.47 mmol) in dry DCM (7.0 mL) was added dropwise oxalyl chloride (660 mg,5.20 mmol) at 0deg.C. The reaction mixture was stirred at 20℃for 16h. The reaction mixture was concentrated to dryness to give 257.2 (510 mg, crude) as a yellow oil, which was used directly in the next step.

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2- (tetrahydro-2H-pyran-4-yl) acetate (257).

To a solution of 6.3 (100 mg,0.343 mmol) in DMPU (1.0 mL) was added dropwise HCl/1, 4-dioxane (0.1 mL, 4M) at 0deg.C. The reaction mixture was stirred at 0deg.C for 15min, then 257.2 (510 mg, crude) was added dropwise to the flask. The reaction mixture was stirred at 20℃for 2h. The reaction mixture was purified by preparative HPLC to give the title compound 257 as a white solid (22.39 mg,16% yield). MS (ESI): for a calculated m/z of C ₁₉H₂₃N₅O₆ of 417.16, the actual measurement was 418.0[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92(br s,3H),6.92(d,J＝4.8Hz,1H),6.80(d,J＝4.4Hz,1H),6.32(d,J＝6.0Hz,1H),5.38(d,J＝5.6Hz,1H),4.69(t,J＝5.6Hz,1H),4.32(dd,J＝11.6,2.4Hz,1H),4.25–4.14(m,2H),3.94(dd,J＝11.2,6.0Hz,1H),3.76(dd,J＝11.2,2.8Hz,2H),3.23(t,J＝11.6Hz,2H),2.19(dd,J＝6.8,2.4Hz,2H),1.89–1.77(m,1H),1.51(d,J＝11.6Hz,2H),1.22–1.10(m,2H).

Synthesis of [ (2R, 3S,4R, 5R) -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-3, 4-dihydroxyoxacyclopent-2-yl ] methyl 2-cyclopropylacetate (compound 258).

Step 1.2 Synthesis of Cyclopropylacetoachloro (258.2).

To a solution of 2-cyclopropylacetic acid (258.1, 500mg,5.0 mmol) in DCM (3 mL) was added oxalyl chloride (0.48 mL,5.64 mmol) followed by a few drops of DMF at 0deg.C. The resulting solution was stirred at 20℃for 1h. The mixture was concentrated in vacuo and the resulting acid chloride was used in the next step without further purification.

Synthesis of [ (2R, 3S,4R, 5R) -5- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -5-cyano-3, 4-dihydroxyoxacyclopent-2-yl ] methyl 2-cyclopropylacetate (258).

Compound 258 was prepared according to the procedure of step4 of example 1 using 6.3 and 258.2. MS (ESI): the calculated mass for C ₁₇H₁₉N₅O₅ was 373.14, m/z found to be 374.2[M+H]⁺.1H NMR(400MHz,DMSO)δ7.92(br,s,3H),6.90(d,J＝4.4Hz,1H),6.80(d,J＝4.4Hz,1H),6.31(d,J＝6.4Hz,1H),5.38(d,J＝5.6Hz,1H),4.68(t,J＝5.6Hz,1H),4.34(dd,J＝12.0,2.8Hz,1H),4.26–4.20(m,1H),4.16(dd,J＝12.0,5.6Hz,1H),3.95-3.91(m,1H),2.25–2.18(m,2H),0.95–0.84(m,1H),0.4-0.40(m,2H),0.13–0.06(m,2H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2-cyclopentylacetate (Compound 259).

The title compound was prepared according to the procedure of step 4 of example 5 using 6.3 and 2-cyclopentylacetoachloro. MS (ESI): the calculated mass for C ₁₉H₂₃N₅O₅ was 401.17 and the measured m/z was 402.0[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ7.92(br s,3H),6.91(d,J＝4.4Hz,1H),6.80(d,J＝4.4Hz,1H),6.32(d,J＝6.0Hz,1H),5.38(d,J＝6.0Hz,1H),4.69(t,J＝5.6Hz,1H),4.31(dd,J＝12.0,2.8Hz,1H),4.22(dd,J＝10.4,4.4Hz,1H),4.15(dd,J＝12.0,5.6Hz,1H),3.94(dd,J＝11.2,6.0Hz,1H),2.27(dd,J＝7.6,2.0Hz,2H),2.06(dt,J＝15.6,8.0Hz,1H),1.75–1.65(m,2H),1.60–1.42(m,4H),1.12–1.01(m,2H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2- (2, 3-dihydro-1H-inden-2-yl) acetate (Compound 260).

The title compound was prepared according to the procedure of step 4 of example 5 using 6.3 and 2- (2, 3-dihydro-1H-inden-2-yl) acetyl chloride (prepared according to j.am. Chem. Soc. (2019), 141 (9), 3849-3853). MS (ESI): the calculated mass for C ₂₃H₂₃N₅O₅ was 449.17, the measured m/z was 450.0[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ7.91(br s,3H),7.19–7.08(m,4H),6.90(d,J＝4.4Hz,1H),6.81(d,J＝4.4Hz,1H),6.32(d,J＝6.0Hz,1H),5.40(d,J＝5.2Hz,1H),4.71(t,J＝5.2Hz,1H),4.34(dd,J＝11.2,2.0Hz,1H),4.27–4.17(m,2H),3.99–3.93(d,J＝4.0Hz,1H),3.05–2.96(m,2H),2.69(dt,J＝14.8,7.6Hz,1H),2.60–2.52(m,2H),2.47(d,J＝1.8Hz,2H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2-cycloheptylacetate (Compound 261).

Step 1: synthesis of cycloheptanecarbonyl chloride (261.2).

A solution of 261.1 (500 mg,3.2 mmol) in SOCl ₂ (1.33 g,11.2 mmol) was stirred at 90℃for 1.5 h. The crude product (530 mg,93.8% yield) was used in the next step without any purification.

Step 2: synthesis of (((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2-cycloheptylacetate (261).

To a solution of 6.3 (100 mg,0.34 mmol) in DMPU (1 mL) was added dropwise 0.3mL of 4M HCl dioxane at 0deg.C, and the mixture was stirred for 30 minutes. 261.2 (299 mg,1.71 mmol) was then added dropwise to the mixture and stirred for 3 hours. After completion, the mixture was diluted with water (2 mL) and purified by preparative HPLC to give 261 (90 mg, 60.4%) as a white solid. MS (ESI): for a calculated m/z of C ₂₁H₂₇N₅O₅ of 429.20, the actual measurement was 430.25[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92(s,3H),6.91(d,J＝4.4Hz,1H),6.80(d,J＝4.8Hz,1H),6.33(d,J＝5.6Hz,1H),5.38(s,1H),4.69(d,J＝4.8Hz,1H),4.30(dd,J＝11.6,2.4Hz,1H),4.25–4.12(m,2H),3.94(t,J＝5.6Hz,1H),2.26–2.12(m,2H),1.93–1.78(m,1H),1.65–1.27(m,10H),1.23–1.06(m,2H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2- (4, 4-difluorocyclohexyl) acetate (compound 262).

Step 1.2 Synthesis of (4, 4-difluorocyclohexyl) acetyl chloride (262.2).

To a solution of 262.1 (400 mg,2.25 mmol) in dry DCM (4.5 mL) was added dropwise oxalyl chloride (427 mg,3.37 mmol) at 0deg.C. The reaction mixture was stirred at 20℃for 16h. The reaction mixture was concentrated to dryness to give 262.2 (431 mg, crude) as a yellow oil, which was used directly in the next step.

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2- (4, 4-difluorocyclohexyl) acetate (262).

To a solution of 6.3 (100 mg,0.343 mmol) in DMPU (1.0 mL) was added dropwise HCl/1, 4-dioxane (0.1 mL, 4M) at 0deg.C. The reaction mixture was stirred at 0 ℃ for 15min, and 262.2 (431 mg, crude) was added dropwise to the flask. The reaction mixture was stirred at 20℃for 2h. The reaction mixture was purified by preparative HPLC to give the title compound 262 (22.70 mg,14% yield) as a white solid. MS (ESI): for a calculated m/z of C ₂₀H₂₃F₂N₅O₅ of 451.17, the actual measurement was 452.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92(br s,3H),6.91(d,J＝4.4Hz,1H),6.80(d,J＝4.4Hz,1H),6.31(d,J＝6.0Hz,1H),5.38(d,J＝6.0Hz,1H),4.70(t,J＝5.6Hz,1H),4.32(dd,J＝11.2,2.4Hz,1H),4.25–4.15(m,2H),3.94(dd,J＝11.2,6.0Hz,1H),2.30–2.19(m,2H),1.99–1.87(m,2H),1.84–1.65(m,5H),1.23–1.11(m,2H).¹⁹F NMR(377MHz,DMSO)δ-89.81(d,J＝231.9Hz,1F),-99.51(d,J＝234.1Hz,1F).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2- ((3R, 5R, 7R) -adamantan-1-yl) acetate (Compound 263).

The title compound was prepared according to the procedure of step 4 of example 5 using 6.3 and 2- (adamantan-1-yl) acetyl chloride. MS (ESI): for a calculated m/z of C ₂₄H₂₉N₅O₅ of 467.22, the actual measurement was 468.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.91(br s,3H),6.91(d,J＝4.4Hz,1H),6.81(d,J＝4.4Hz,1H),6.30(d,J＝6.0Hz,1H),5.37(d,J＝5.6Hz,1H),4.72(t,J＝5.6Hz,1H),4.29–4.13(m,3H),3.95(dd,J＝10.8,5.6Hz,1H),2.00(d,J＝2.4Hz,2H),1.86(s,3H),1.65–1.47(m,12H).

EXAMPLE 111 Synthesis of N- (7- ((2R, 3R,4S, 5R) -2-cyano-3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) pentanamide (Compound 264).

Synthesis of N- (7- ((3 aR,4R,6 aR) -6- (((tert-butyldimethylsilyl) oxy) methyl) -4-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) pentanamide (264.1).

To a mixture of 81.1 (100 mg,0.22 mmol) and DMAP (41 mg,0.33 mmol) in DCM (1 mL) was added pentanoyl chloride (35 mg,0.29 mmol) dropwise at 0deg.C. The mixture was then stirred at 20℃for 1 hour. After completion, the reaction was quenched with water (10 mL) and extracted with ethyl acetate (10 ml×3). The organic layer was dried over sodium sulfate and concentrated in vacuo to give a residue. The residue was purified by flash column chromatography to give 264.1 (111 mg,92.4% yield) as a white solid. MS (ESI): the calculated m/z for C ₂₆H₃₉N₅O₅ Si was 529.27, found to be 530.40[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.99(s,1H),8.52(s,1H),7.36(d,J＝4.8Hz,1H),7.18(d,J＝4.8Hz,1H),5.40(d,J＝6.2Hz,1H),4.95(dd,J＝6.2,2.4Hz,1H),4.57–4.52(m,1H),3.80(d,J＝4.4Hz,2H),2.80(t,J＝7.2Hz,2H),1.74(s,3H),1.73–1.65(m,2H),1.49–1.39(m,5H),1.00(t,J＝7.2Hz,3H),0.84–0.80(m,9H),0.02(d,J＝16.8Hz,6H).

Synthesis of N- (7- ((2R, 3R,4S, 5R) -2-cyano-3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) pentanamide (264).

To a solution of 264.1 (80.0 mg,0.15 mmol) in THF (2.0 mL) at 0 ℃ was added 6M HCl (2.0 mL) dropwise, and the mixture was stirred at 20 ℃ for 2 hours. After completion, the reaction mixture was purified by preparative HPLC to give 264 as a white solid (16 mg,27.9% yield). MS (ESI): for a calculated m/z of C ₁₇H₂₁N₅O₅ of 375.15, the actual measurement was 376.15[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.94(s,1H),8.39(s,1H),7.30(d,J＝4.8Hz,1H),7.14(d,J＝4.8Hz,1H),4.61(d,J＝4.8Hz,1H),4.11–4.05(m,1H),3.96–3.93(m,1H),3.65(dd,J＝12.0,3.2Hz,1H),3.51(dd,J＝12.4,4.4Hz,1H),2.72(t,J＝7.2Hz,2H),1.66–1.55(m,2H),1.41–1.30(m,2H),0.91(t,J＝7.6Hz,3H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2-cyclobutylacetate (Compound 265).

Step 1.2 Synthesis of cyclobutylacetyl chloride (265.2).

To a solution of cyclobutylacetic acid (250 mg,2.20 mmol) in dry DCM (4.5 mL) was added oxalyl chloride (418 mg,3.30 mmol) dropwise at 0deg.C. The reaction mixture was stirred at 20℃for 16h. The reaction mixture was concentrated to dryness to give 265.2 (270 mg, crude) as a yellow oil, which was used directly in the next step.

To a solution of 6.3 (100 mg,0.343 mmol) in DMPU (1.0 mL) was added dropwise HCl/1, 4-dioxane (0.1 mL, 4M) at 0deg.C. The reaction mixture was stirred at 0 ℃ for 15min, and 265.2 (270 mg, crude) was added dropwise to the flask. The reaction mixture was stirred at 20℃for 2h. The reaction mixture was purified by prep. to give the title compound 265 (34.75 mg,26% yield) as a white solid. MS (ESI): for a calculated m/z of C ₁₈H₂₁N₅O₅ of 387.15, the actual measurement was 388.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92(br s,3H),6.92(d,J＝4.4Hz,1H),6.80(d,J＝4.4Hz,1H),6.35(s,1H),5.38(s,1H),4.73–4.65(m,1H),4.30(dd,J＝12.0,2.8Hz,1H),4.23–4.09(m,2H),3.97–3.89(m,1H),2.58–2.51(m,1H),2.42–2.35(m,2H),2.06–1.94(m,2H),1.86–1.70(m,2H),1.67–1.54(m,2H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2- ((1 r, 4R) -4-aminocyclohexyl) acetate (Compound 266).

Synthesis of((3 aR,4R,6 aR) -6- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) methyl 2- ((1 r, 4R) -4- ((tert-butoxycarbonyl) amino) cyclohexyl) acetate (266.2).

To a solution of (3 aR,4R,6 aR) -4- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -6- (hydroxymethyl) -2, 2-dimethyl-dihydro-3 aH-furo [3,4-d ] [1,3] dioxole-4-carbonitrile (6.3, 200mg,0.603 mol) in THF (20 mL) was added (4- { [ tert-butyl (formyl) - $l {3} -oxyalkyl ] amino } cyclohexyl) acetic acid (202.71mg, 0.784 mol), EDCI (347.13 mg, 1.810mol) and DMAP (221.23 mg, 1.810mmol), and the mixture was stirred at 25℃for 16h. The reaction was washed with EtOAc (5 mL. Times.3). The combined organics were dried over sodium sulfate and concentrated in vacuo. The crude product was purified to give 266.2 (250 mg,65% yield) as a white solid. MS (ESI): for a calculated m/z of C ₂₈H₃₈N₆O₇ of 570.23, the actual measurement was 571.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.96(br,s,3H),6.91(d,J＝4.4Hz,1H),6.81(d,J＝4.8Hz,1H),6.66(d,J＝8.0Hz,1H),5.40(d,J＝6.4Hz,1H),4.92(dd,J＝6.4,2.8Hz,1H),4.57(dd,J＝7.6,4.8Hz,1H),4.19(dd,J＝12.0,4.4Hz,1H),4.08(dd,J＝12.0,5.6Hz,1H),3.11-3.09(m,1H),2.08(dd,J＝15.6,6.8Hz,1H),1.98(dd,J＝15.6,7.2Hz,1H),1.70(d,J＝10.8Hz,2H),1.64(s,3H),1.59(d,J＝12.0Hz,2H),1.42-1.40(m,1H),1.37(s,12H),1.08-1.05(m,2H),0.98–0.84(m,2H).

To a solution of [ (3 ar,4r,6 ar) -6- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -6-cyano-2, 2-dimethyl-dihydro-3 aH-furo [3,4-d ] [1,3] dioxol-4-yl ] methyl 2- (4- { [ (tert-butoxy) carbonyl ] amino } cyclohexyl) acetate (266.2, 80mg,0.140 mmol) in THF (2 mL) and water (1 mL) was added HCl in dioxane (4 m,2 mL) and the mixture was stirred for 4h at 25 ℃. The reaction was concentrated in vacuo. The crude product was purified to give 266 as a white solid (45.5 mg,73% yield). MS (ESI): for a calculated m/z of C ₂₀H₂₆N₆O₅ of 430.20, the actual measurement was 431.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.85(br,s,3H),6.94(d,J＝4.4Hz,1H),6.80(d,J＝4.4Hz,1H),6.47-6.45(m,1H),5.51-5.47(m,1H),4.68(d,J＝4.8Hz,1H),4.31(dd,J＝11.6,2.4Hz,1H),4.25–4.08(m,2H),3.93-3.90(m,1H),2.82-2.80(m,1H),2.20-2.18(m,2H),1.87(d,J＝10.0Hz,2H),1.70(d,J＝12.8Hz,2H),1.65–1.49(m,1H),1.25-1.20(m,2H),1.00-0.90(m,2H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2-cyclohexylacetate (267).

Step 1.synthesis of tert-butyl 4- (2- (((3 aR,4R,6 aR) -6- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) methoxy) -2-oxoethyl) piperidine-1-carboxylate (compound 267.1).

Compound 267.1 was prepared according to the procedure of step 1 of example 266 using 6.3 and 2- (1- (tert-butoxycarbonyl) piperidin-4-yl) acetic acid. MS (ESI): the calculated mass for C ₂₇H₃₆N₆O₇ was 556.26 and the measured m/z was 557.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.96(br s,3H),6.91(d,J＝4.4Hz,1H),6.82(d,J＝4.8Hz,1H),5.41(d,J＝6.4Hz,1H),4.94(dd,J＝6.4,2.8Hz,1H),4.64–4.49(m,1H),4.22(dd,J＝12.0,4.0Hz,1H),4.10(dd,J＝12.0,6.4Hz,1H),3.85(d,J＝11.2Hz,2H),2.63-2.60(m,2H),2.16(dd,J＝15.6,7.2Hz,1H),2.11–2.02(m,1H),1.68-1.65(m,1H),1.64(s,3H),1.52(d,J＝10.8Hz,2H),1.40(s,12H),1.06–0.89(m,2H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2-cyclohexylacetate (Compound 267).

The title compound 267 was prepared according to the procedure of step 2 of example 266 using 267.1. MS (ESI): the calculated mass for C ₁₉H₂₄N₆O₅ was 416.18, the measured m/z was 417.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92-7.90(br,s,3H),6.93(d,J＝4.8Hz,1H),6.81(d,J＝4.4Hz,1H),6.49-6.40(m,1H),5.50-5.40(m,1H),4.70(d,J＝4.8Hz,1H),4.32(dd,J＝11.2,2.0Hz,1H),4.27–4.15(m,2H),3.93(t,J＝5.2Hz,1H),3.10-3.05(m,2H),2.72-2.68(m,2H),2.26(d,J＝7.2Hz,2H),1.87-1.80(m,1H),1.70(d,J＝12.0Hz,2H),1.25-1.20(m,2H).

Example 115 synthesis of ((2 r,3s,4r,5 r) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2- (1- (methylsulfonyl) piperidin-4-yl) acetate (compound 268).

Synthesis of((3 aR,4R,6 aR) -6- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) methyl 2- (1- (methylsulfonyl) piperidin-4-yl) acetate (268.1).

To a mixture of 6.4 (300 mg,0.90 mmol), (1-methanesulfonylpiperidin-4-yl) acetic acid (200 mg,0.90 mmol) and EDCI (520 mg,2.71 mmol) in THF was slowly added DMAP (331 mmol,2.71 mmol) at 0deg.C, and the mixture was stirred for 16 hours. After completion, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 ml×3). The organic layer was dried over sodium sulfate and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC to give 268.1 (302 mg,61.3% yield) as a white solid. MS (ESI): for C ₂₃H₃₀N₆O₇ S calculated m/z was 534.19, found to be 535.30[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.97(s,3H),6.91(d,J＝4.4Hz,1H),6.83(d,J＝4.4Hz,1H),5.42(d,J＝6.4Hz,1H),4.95(dd,J＝6.4,2.8Hz,1H),4.60–4.55(m,1H),4.23(dd,J＝12.0,4.0Hz,1H),4.10(dd,J＝12.0,5.6Hz,1H),3.47(d,J＝11.6Hz,2H),2.82(s,3H),2.61(dd,J＝16.8,7.6Hz,2H),2.22(dd,J＝15.6,6.8Hz,1H),2.16–2.06(m,1H),1.65(d,J＝10.4Hz,6H),1.38(s,3H),1.22–1.09(m,2H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2- (1- (methylsulfonyl) piperidin-4-yl) acetate (268).

To a solution of 268.1 (200 mg,0.37 mmol) in THF (2.0 mL) at 0 ℃ was added 6M HCl (2.0 mL) dropwise, and the mixture was stirred at 20 ℃ for 2 hours. The mixture was quenched with water (2 mL) and dried with a stream of nitrogen to remove the solvent. The residue was purified by preparative HPLC to give 268 (130 mg,69.5% yield) as a white solid. MS (ESI): for C ₂₀H₂₆N₆O₇ S calculated m/z was 494.16, found to be 495.20[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.28–7.87(m,3H),6.96(d,J＝4.4Hz,1H),6.83(d,J＝4.8Hz,1H),6.33(s,1H),5.41(s,1H),4.69(d,J＝4.8Hz,1H),4.33(dd,J＝11.6,2.4Hz,1H),4.26–4.15(m,2H),3.98–3.90(m,1H),3.50(s,2H),2.83(s,3H),2.65(dt,J＝12.0,2.0Hz,2H),2.28(dd,J＝6.8,2.4Hz,2H),1.80–1.66(m,3H),1.27–1.12(m,2H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2-cyclohexyl-2-methylpropionate (Compound 269).

Step 1: synthesis of methyl 2-cyclohexyl-2-methylpropionate (269.3).

To a solution of LDA (5.40 mL, 2M) in THF (30 mL) at 0deg.C under N ₂ was added methyl 269.2 (1.00 g,9.80 mmol), and the reaction was stirred at 0deg.C for 30 min. 269.1 (1.4 mL,10.7 mmol) was then added to the mixture at 0deg.C, and the reaction was stirred at 20deg.C for 16 hours. The reaction was quenched with HCl (50 mL, 1M) and extracted with MTBE (50 mL. Times.3). The combined organics were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (0% to 0% EA/PE) to give 269.3 (500 mg,26.5% yield) as a yellow oil ).¹H NMR(400MHz,CDCl₃)δ3.65(s,3H),1.80–1.71(m,2H),1.68–1.62(m,1H),1.58–1.52(m,3H),1.29–1.23(m,2H),1.09(s,6H),1.04–0.95(m,2H),0.90–0.85(m,1H).

Step 2: synthesis of 2-cyclohexyl-2-methylpropanoic acid (269.4).

To a solution of 269.3 (500 mg,2.7 mmol) in DMSO (5 mL) was added NaOH (5 mL, 4M) and the reaction was stirred at 80deg.C for 16 h. The mixture was poured into ice water (50 mL) and acidified with aqueous HCl (50 mL,1m, ph=2-3), and a white solid formed in the aqueous layer, which was then filtered to obtain 269.4 (120 mg,24.7% yield) as a white solid ).¹H NMR(400MHz,CDCl₃)δ1.79–1.75(m,2H),1.71–1.55(m,4H),1.34–1.19(m,2H),1.12(s,6H),1.09–0.96(m,2H).

Step 3: synthesis of 2-cyclohexyl-2-methylpropionyl chloride (269.5).

To a round bottom flask equipped with a gas bubbler was added 269.4 (120 mg,0.70 mmol) and DCM (1 mL). Oxalyl chloride (0.12 mL,1.41 mmol) was added followed by a few drops of DMF at 20 ℃. The resulting solution was stirred at 20 ℃ until gas evolution ceased (-1 h). The mixture was concentrated 3 times from DCM to obtain 269.5 (100 mg, crude) and the resulting acid chloride was used for the above coupling without further purification.

Step 4: synthesis of (((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2-cyclohexyl-2-methylpropionate (269.5).

The title compound was prepared according to the procedure for step 4 of example 5 using 6.3 and 269.5. MS (ESI): the calculated mass for C ₂₂H₂₉N₅O₅ was 443.22 and the measured m/z was 444.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ7.92(br s,3H),6.91(d,J＝4.4Hz,1H),6.81(d,J＝4.4Hz,1H),6.35(d,J＝5.6Hz,1H),5.38(s,1H),4.71(d,J＝4.4Hz,1H),4.31–4.12(m,3H),3.97(s,1H),1.67–1.51(m,3H),1.48–1.37(m,3H),1.14–0.96(m,9H),0.93–0.80(m,2H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2- (4- (trifluoromethyl) cyclohexyl) acetate (Compound 270) and (2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-2- ((2- (4- (trifluoromethyl) cyclohexyl) acetoxy) methyl) tetrahydrofuran-3-yl 2- (4- (trifluoromethyl) cyclohexyl) acetate (Compound 271).

Step 1.2 Synthesis of ethyl (270.2) acetate (4- (trifluoromethyl) cyclohexylidene).

To a solution of ethyl 2- (diethoxyphosphoryl) acetate (810 mg,3.61 mmol) in dry THF (10 mL) was added sodium hydride (150 mg,60%,3.76 mmol). The reaction mixture was stirred at 20 ℃ for 1h, then a solution of 270.1 (500 mg,3.01 mmol) in dry THF (5.0 mL) was added dropwise to the solution. The reaction mixture was stirred at 20℃for 16h. The reaction mixture was quenched with water (30 mL) and extracted with EA (10 mL. Times.3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na ₂SO₄ and filtered. The filtrate was concentrated to dryness. The residue was purified by FCC (gradient: 5% EA in PE) to give 270.2 (560 mg,79% yield) as a colorless oil. MS (ESI): for a calculated m/z of C ₁₁H₁₅F₃O₂ of 236.10, the actual measurement was 237.0[M+H]⁺.¹H NMR(400MHz,CDCl₃)δ5.68(s,1H),4.15(q,J＝7.2Hz,2H),3.94(d,J＝14.4Hz,1H),2.39(d,J＝13.6Hz,1H),2.32–2.15(m,2H),2.13–2.05(m,2H),1.92(td,J＝14.0,4.4Hz,1H),1.53–1.40(m,2H),1.28(t,J＝7.2Hz,3H).¹⁹F NMR(377MHz,)δ-194.12.

Step 2.2 Synthesis of ethyl 2- (4- (trifluoromethyl) cyclohexyl) acetate (270.3).

To a solution of 270.2 (560 mg,2.37 mmol) in EtOH (10 mL) was added Pd/C (56 mg,10% w.t%). The reaction mixture was degassed three times with H ₂ and stirred at 40 ℃ for 16H under H ₂. TLC detected complete consumption of 270.2. The reaction mixture was filtered, and the filtrate was concentrated to dryness to give 270.3 (514 mg,91% yield) as a colorless oil ).¹H NMR(400MHz,CDCl₃)δ4.18–4.09(m,2H),2.36–2.18(m,2H),2.12–1.53(m,8H),1.41–1.29(m,1H),1.28–1.23(m,3H),1.07–0.95(m,1H).¹⁹F NMR(377MHz,CDCl₃)δ-73.82.

Step 3.2 Synthesis of (4- (trifluoromethyl) cyclohexyl) acetic acid (270.4).

To a solution of 270.3 (514 mg,2.16 mmol) in EtOH (8.0 mL) was added a solution of sodium hydroxide (173 mg,4.31 mmol) in H ₂ O (4.0 mL). The reaction mixture was stirred under nitrogen at 40 ℃ for 2h. TLC showed 270.3 complete consumption. The reaction mixture was diluted with water (10 mL). The aqueous solution was acidified with HCl (1M) and extracted with EA (5.0 ml×3). The combined organic phases were washed with brine (5.0 mL), dried over anhydrous Na ₂SO₄, and filtered. The filtrate was concentrated to dryness to give 270.4 (4635 mg,97% yield) as a white solid ).¹H NMR(400MHz,CDCl₃)δ5.92(br,1H),2.33(dd,J＝52.4,7.6Hz,2H),2.25–1.52(m,8H),1.42–1.25(m,1H),1.10–0.98(m,1H).¹⁹F NMR(377MHz,)δ-194.49.

Step 4.2 Synthesis of (4- (trifluoromethyl) cyclohexyl) acetyl chloride (270.5).

To a solution of 270.4 (4630 mg,2.20 mmol) in dry DCM (10 mL) was added dropwise oxalyl chloride (418 mg,3.30 mmol) at 0deg.C. The reaction mixture was stirred at 20℃for 16h. The reaction mixture was concentrated to dryness to give 270.5 (481 mg, crude), which was used directly in the next step.

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2- (4- (trifluoromethyl) cyclohexyl) acetate (270) and (2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-2- ((2- (4- (trifluoromethyl) cyclohexyl) acetoxy) methyl) tetrahydrofuran-3-yl 2- (4- (trifluoromethyl) cyclohexyl) acetate (271).

To a solution of 6.3 (100 mg,0.343 mmol) in DMPU (1.0 mL) was added dropwise HCl/1, 4-dioxane (0.1 mL, 4M) at 0deg.C. The reaction mixture was stirred at 0 ℃ for 15min, and 270.5 (481 mg, crude) was added dropwise to the flask. The reaction mixture was stirred at 20℃for 2h. The reaction mixture was purified by preparative HPLC to give title compounds 270 (60.50 mg,36% yield) and 271 (49.18 mg,21% yield) as white solids.

Compound 270: MS (ESI): for a calculated m/z of C ₂₁H₂₄F₃N₅O₅ of 483.17, the actual measurement was 484.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92(br s,3H),6.91(dd,J＝4.4,1.6Hz,1H),6.80(d,J＝4.4Hz,1H),6.32(d,J＝6.0Hz,1H),5.38(d,J＝6.0Hz,1H),4.69(q,J＝5.2Hz,1H),4.35–4.25(m,1H),4.25–4.13(m,2H),3.98–3.89(m,1H),2.35–2.09(m,3H),2.08–1.37(m,7H),1.26–1.13(m,1H),1.04–0.90(m,1H).¹⁹F NMR(377MHz,DMSO)δ-70.74,-72.30.

Compound 271: MS (ESI): for a calculated m/z of C ₃₀H₃₅F₆N₅O₆ of 675.25, the actual measurement was 676.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92(br s,3H),6.93(dd,J＝4.4,1.6Hz,1H),6.86(d,J＝4.8Hz,1H),6.66–6.59(m,1H),5.17–5.04(m,2H),4.46(dd,J＝8.4,4.0Hz,1H),4.33–4.21(m,2H),2.43(d,J＝7.2Hz,1H),2.33–2.27(m,2H),2.23–1.98(m,3H),1.90–1.36(m,13H),1.31–1.24(m,1H),1.21–0.85(m,6H).¹⁹F NMR(377MHz,DMSO)δ-70.83,-72.35.

Synthesis of ((2R, 3R,4R, 5R) -5- (2-amino-6- (methylamino) -9H-purin-9-yl) -3, 4-dihydroxy-4-methyltetrahydrof-n-2-yl) methyl isobutyrate ((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2- (4, 4-dimethylcyclohexyl) acetate (Compound 272).

Synthesis of((3 aR,4R,6 aR) -6- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) methyl 2- (4, 4-dimethylcyclohexyl) acetate (272.1).

Compound 272.1 was prepared according to the procedure of step 1 of example 266 using 6.3 and 2- (4, 4-dimethylcyclohexyl) acetic acid. MS (ESI): the calculated mass for C ₂₅H₃₃N₅O₅ was 483.25 and the measured m/z was 484.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.94(br,s,3H),6.91(d,J＝4.4Hz,1H),6.81(d,J＝4.8Hz,1H),5.39(d,J＝6.4Hz,1H),4.93(dd,J＝6.4,2.8Hz,1H),4.69–4.48(m,1H),4.21(dd,J＝12.0,4.0Hz,1H),4.09(dd,J＝12.0,5.6Hz,1H),2.06-2.00(m,2H),1.64(s,3H),1.37-1.34(m,6H),1.29–1.20(m,2H),1.13–0.96(m,4H),0.83(d,J＝14.8Hz,6H).

Synthesis of ((2R, 3R,4R, 5R) -5- (2-amino-6- (methylamino) -9H-purin-9-yl) -3, 4-dihydroxy-4-methyltetrahydrofuran-2-yl) methyl isobutyrate ((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2- (4, 4-dimethylcyclohexyl) acetate (272).

To a solution of [ (3 ar,4r,6 ar) -6- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -6-cyano-2, 2-dimethyl-dihydro-3 aH-furo [3,4-d ] [1,3] dioxol-4-yl ] methyl 2- (4, 4-dimethylcyclohexyl) acetate (272.1, 100mg,0.206 mmol) in THF (3 mL) at 0 ℃ was added HCl (12 m,1 mL) and the mixture stirred for 3h at 25 ℃. The reaction was concentrated in vacuo. The crude product was purified by prep HPLC to give 272 (83.32 mg,91% yield) as a white solid. MS (ESI): the calculated mass for C ₂₂H₂₉N₅O₅ was 443.22 and the measured m/z was 444.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92-7.90(br,s,3H),6.91(d,J＝4.4Hz,1H),6.80(d,J＝4.8Hz,1H),6.31(d,J＝6.0Hz,1H),5.37(d,J＝5.2Hz,1H),4.68(t,J＝5.2Hz,1H),4.30(dd,J＝11.2,2.4Hz,1H),4.25–4.19(m,1H),4.16(dd,J＝11.2,5.6Hz,1H),3.93-3.90(m,1H),2.19(dd,J＝7.2,2.0Hz,2H),1.53-1.48(m,3H),1.27-1.20(m,2H),1.18–1.05(m,4H),0.84(d,J＝10.8Hz,6H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2- (1-methylcyclohexyl) acetate (Compound 273).

Step 1: synthesis of ((3 aR,4R,6 aR) -6- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) methyl 2- (1-methylcyclohexyl) acetate (273.1).

To a solution of 6.4 (300 mg,0.91 mol) in THF (10 mL) were added (1-methylcyclohexyl) acetic acid (183.90 mg,1.18 mol), EDCI (520.75 mg,2.72 mol) and DMAP (331.87 mg,2.72 mmol), and the mixture was stirred at 25℃for 16 hours. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 ml×3). The organic phase was washed with brine (50 ml×3), then dried over anhydrous sodium sulfate, filtered and concentrated to remove the solvent. The residue was purified by flash column chromatography (0% to 15% EA/PE) to give 273.1 (450 mg,52.9% yield) as a white solid. MS (ESI): the calculated mass for C ₂₄H₃₁N₅O₅ was 469.23 and the m/z found was 470.1[ M+H ] ⁺.

Step 2: synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2- (1-methylcyclohexyl) acetate (273).

HCl (1 mL, 12M) was added to a solution of 273.1 (100 mg,0.213 mol) in THF (1 mL) at 0deg.C, the mixture was stirred at 0deg.C for 1.5h, and the reaction was stirred at 20deg.C for 0.5h. The reaction was diluted with ACN (2.0 mL) and purified by preparative HPLC to give 273 (34.0 mg,37.0% yield) as a white solid. MS (ESI): for a calculated m/z of C ₂₁H₂₇N₅O₅ of 429.20, the actual measurement was 430.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ7.92(br s,1H),6.91(d,J＝4.4Hz,1H),6.81(d,J＝4.4Hz,1H),6.31(d,J＝6.0Hz,1H),5.37(d,J＝6.0Hz,1H),4.70(t,J＝5.6Hz,1H),4.34–4.11(m,3H),3.94(d,J＝5.6Hz,1H),2.19(d,J＝2.4Hz,2H),1.40–1.30(m,8H),1.25–1.18(m,2H),0.91(s,3H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2- (4-phenyltetrahydro-2H-pyran-4-yl) acetate (Compound 274).

Step 1.2 Synthesis of Ethyl 2-cyano-2- (tetrahydro-4H-pyran-4-ylidene) acetate (274.2).

To a mixture of oxetan-4-one (274.1, 5g,0.049 mol) and ethyl cyanoacetate (5.64 g,0.049 mol) was added acetic acid (0.30 g,0.0045 mmol) and piperidine (0.425 g,0.0045 mol) at 0℃and then acetic acid (0.30 g,0.0045 mmol) and piperidine (0.425 g,0.0045 mmol) were added to the above solution at 25℃and the resulting mixture was stirred at 25℃for 0.5h. The reaction was quenched with NaHCO ₃ (saturated aqueous solution, 10 mL) and extracted with EtOAc (10 mL. Times.3). The combined organics were dried over sodium sulfate and concentrated in vacuo to give 274.2 (10 g,92% yield) as a pale yellow solid ).¹H NMR(400MHz,CDCl₃)δ4.43–4.24(m,2H),3.87(t,J＝5.6Hz,2H),3.80(t,J＝5.6Hz,2H),3.19(t,J＝5.6Hz,2H),2.80(t,J＝5.2Hz,2H),1.38(t,J＝3.2Hz,2H,3H).

Step 2.Synthesis of ethyl 2-cyano-2- (4-phenyltetrahydro-2H-pyran-4-yl) acetate (274.3).

To a solution of ethyl 2-cyano-2- (oxetan-4-ylidene) acetate (274.2, 3g,0.015 mol) in dry THF (30 mL) was added PhMgBr (1M in THF, 30.8 mL) dropwise at 0 ℃ and the solution was heated to 60 ℃ for 6h. The reaction was quenched with NH ₄ Cl (saturated aqueous solution, 10 mL) and extracted with EA (10 ml×3). The combined organics were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (2% to 20% EA/PE) to give 107.3 (1.5 g,48% yield) as a pale yellow solid ).¹H NMR(400MHz,CDCl₃)δ7.44 -7.30(m,5H),3.94-3.90(m,2H),3.85-3.82(m,2H),3.65(s,1H),3.59–3.41(m,2H),2.69–2.43(m,2H),2.21-2.09(m,2H),1.00(t,J＝7.2Hz,3H).

Step 3.2 synthesis of (4-phenyltetrahydro-2H-pyran-4-yl) acetic acid (274.4).

To a solution of ethyl 2-cyano-2- (4-phenyloxazin-4-yl) acetate (274.3, 250mg, 0.910 mmol) in ethylene glycol (5 mL) was added KOH (102.65 mg,1.83 mmol), and the resulting mixture was stirred at 160 ℃ for 16h and concentrated in vacuo. The reaction was washed with diethyl ether (5 ml×3) and dried in vacuo. The crude product was purified by preparative HPLC to give 274.4 as a white solid (160 mg,75% yield ).¹H NMR(400MHz,MeOD)δ7.44–7.31(m,4H),7.22(t,J＝7.2Hz,1H),3.81-3.79(m,2H),3.59-3.57(m,2H),2.63(s,2H),2.40–2.24(m,2H),2.18–2.03(m,2H).

Synthesis of((3 aR,4R,6 aR) -6- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) methyl 2- (4-phenyltetrahydro-2H-pyran-4-yl) acetate (274.5).

To a solution of (3 aR,4R,6 aR) -4- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -6- (hydroxymethyl) -2, 2-dimethyl-dihydroxy (dihy) (200 mg,0.603 mmol) in THF (15 mL) was added (4-phenyloxacyclohexan-4-yl) acetic acid (274.4, 132.79mg,0.603 mmol), EDCI (347.13 mg, 1.81mmol) and DMAP (221.23 mg, 1.81mmol) and the mixture was stirred at 25℃for 16h. The reaction was washed with EA (5 ml×3) and dried in vacuo. The crude product was purified by preparative HPLC to give 274.5 as a white solid (200 mg,59% yield). MS (ESI): for a calculated m/z of C ₂₈H₃₁N₅O₆ of 533.23, the actual measurement was 534.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.96(br,s,3H),7.31–7.22(m,4H),7.21–7.13(m,1H),6.92(d,J＝4.4Hz,1H),6.77(d,J＝4.8Hz,1H),5.24(d,J＝6.4Hz,1H),4.58(dd,J＝6.4,2.8Hz,1H),4.34-4.30(m,1H),3.95(dd,J＝12.0,4.0Hz,1H),3.82(dd,J＝12.0,5.6Hz,1H),3.62-3.60(m,2H),3.49–3.36(m,2H),2.54-2.50(m,2H),2.07-2.05(m,2H),1.94–1.79(m,2H),1.62(s,3H),1.36(s,3H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2- (4-phenyltetrahydro-2H-pyran-4-yl) acetate (274).

To a solution of [ (3 ar,4r,6 ar) -6- { 4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl } -6-cyano-2, 2-dimethyl-dihydro-3 aH-furo [3,4-d ] [1,3] dioxol-4-yl ] methyl 2- (4-phenyloxa-n-4-yl) acetate (274.5, 150mg, 0.281mmol) in THF (3 mL) at 0 ℃ was added HCl (12 m,1 mL) and the mixture stirred for 4h at 25 ℃. The reaction was dried in vacuo. The crude product was purified by prep HPLC to give the title compound 274 as a white solid (112.15 mg,81% yield). MS (ESI): for a calculated m/z of C ₂₅H₂₇N₅O₆ of 493.20, the actual measurement was 494.3[M+H].¹H NMR(400MHz,DMSO)δ7.93-7.90(br,s,3H),7.30–7.21(m,4H),7.16(t,J＝6.8Hz,1H),6.94(d,J＝4.4Hz,1H),6.75(d,J＝4.4Hz,1H),6.27-6.20(m,1H),5.28-5.20(m,1H),4.63-4.60(m,1H),4.08–4.00(m,2H),3.89(dd,J＝12.4,6.0Hz,1H),3.72(t,J＝5.6Hz,1H),3.69–3.60(m,2H),3.40-3.35(m,2H),2.63(s,2H),2.15–2.03(m,2H),2.02–1.88(m,2H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl (R) -2-cyclohexylpropionate (Compound 275).

Synthesis of((3 aR,4R,6 aR) -6- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) methyl (R) -2-cyclohexylpropionate (275.1).

The title compound was prepared according to the procedure for step 1 of example 273 using 6.4 and (R) -2-cyclohexylpropionic acid. MS (ESI): the calculated mass for C ₂₄H₃₁N₅O₅ was 469.23, found m/z was 470.2[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ7.96(br s,3H),6.91(d,J＝4.8Hz,1H),6.84(d,J＝4.8Hz,1H),5.43(d,J＝6.4Hz,1H),4.92(dd,J＝6.4,3.2Hz,1H),4.55(d,J＝3.2Hz,1H),4.22(dd,J＝12.0,4.4Hz,1H),4.11(dd,J＝12.0,6.0Hz,1H),2.16(t,J＝7.2Hz,1H),1.67–1.51(m,7H),1.47–1.30(m,5H),1.18–0.99(m,3H),0.94(d,J＝7.2Hz,3H),0.90–0.80(m,2H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl (R) -2-cyclohexylpropionate (275).

The title compound was prepared according to the procedure for step 2 of example 273 using 275.1. MS (ESI): the calculated mass for C ₂₁H₂₇N₅O₅ was 429.20 and the measured m/z was 430.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ7.92(br s,3H),6.91(d,J＝4.4Hz,1H),6.81(d,J＝4.4Hz,1H),6.32(d,J＝6.0Hz,1H),5.38(d,J＝5.6Hz,1H),4.69(t,J＝5.2Hz,1H),4.35–4.10(m,3H),3.96(d,J＝5.2Hz,1H),2.19(t,J＝7.2Hz,1H),1.60(d,J＝17.6Hz,4H),1.44(dd,J＝24.4,10.8Hz,2H),1.20–1.02(m,3H),0.98(d,J＝7.2Hz,3H),0.94–0.79(m,2H).

Synthesis of((2R, 3S,4R, 5R) -5-cyano-3, 4-dihydroxy-5- (4-pentanamido pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuranyl) methyl isobutyrate (Compound 276).

The title compound was prepared according to the procedure for step 1 of example 288 using compound 264 and 2-methylpropanoyl chloride. MS (ESI): the calculated mass for C ₂₁H₂₇N₅O₆ was 445.20 and the measured m/z was 446.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.88(s,1H),8.39(s,1H),7.27(d,J＝4.4Hz,1H),7.04(d,J＝4.8Hz,1H),6.42(d,J＝6.0Hz,1H),5.43(d,J＝6.0Hz,1H),4.68(t,J＝5.6Hz,1H),4.33–4.23(m,2H),4.17(dd,J＝11.6,4.4Hz,1H),3.95(dd,J＝11.2,6.0Hz,1H),2.70(m,2H),2.53(s,1H),1.66–1.53(m,2H),1.40–1.28(m,2H),1.03(dd,J＝7.2,3.6Hz,6H),0.90(t,J＝7.6Hz,3H).

Synthesis of((2R, 3S,4R, 5R) -5-cyano-3, 4-dihydroxy-5- (4-pentanamido pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuranyl-2-yl) methyl 2-phenylacetate (Compound 277).

The title compound was prepared according to the procedure for step 4 of example 5 using 264 and 2-phenylacetyl chloride. MS (ESI): the calculated mass for C ₂₅H₂₇N₅O₆ was 493.20 and the measured m/z was 494.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.89(s,1H),8.39(s,1H),7.32–7.20(m,6H),7.02(d,J＝4.8Hz,1H),6.43(d,J＝6.0Hz,1H),5.47(d,J＝5.6Hz,1H),4.64(t,J＝5.2Hz,1H),4.37–4.33(m,1H),4.31–4.25(m,1H),4.23–4.18(m,1H),3.94(dd,J＝11.2,6.0Hz,1H),2.72(t,J＝7.2Hz,2H),1.66–1.56(m,2H),1.40–1.31(m,2H),0.91(t,J＝7.2Hz,3H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2- ((1 r, 4R) -4-methylcyclohexyl) acetate (Compound 278).

Synthesis of (1 r,4 r) -4-methylcyclohexane-1-carbonyl chloride (278.2).

A solution of 4-methylcyclohexane-1-carboxylic acid (500 mg,3.52 mmol) in SOCl ₂ (2.5 mL) was stirred at 80℃for 2h. The reaction mixture was concentrated to dryness to give 278.2 (533 mg, crude) as a yellow oil, which was used directly in the next step.

Step 2.2 Synthesis of 2-diazo-1- ((1 r,4 r) -4-methylcyclohexyl) ethan-1-one (278.3).

TMSCHN ₂ (7.0 mL,14.0mmol,2M in hexanes) was added dropwise to a solution of 278.2 (533 mg, crude) in THF (10 mL) and ACN (10 mL) at 0deg.C. The reaction mixture was stirred at 20℃for 16h. The reaction mixture was concentrated to remove the solvent. The residue was diluted with EA (10 mL) and washed with water (5.0 mL x 2), then brine (5.0 mL), dried over anhydrous Na ₂SO₄, filtered. The filtrate was concentrated to dryness. The residue was purified by FCC (gradient: 10% EA in PE) to give 278.3 (354 mg,60% yield) as a yellow oil. MS (ESI): the calculated mass for C ₉H₁₄N₂ O was 166.11, the measured m/z was 167.0[M+H]⁺.¹H NMR(400MHz,CDCl₃)δ5.25(s,1H),2.15(s,1H),1.88–1.73(m,4H),1.48–1.28(m,3H),0.99–0.86(m,5H).

Step 3.2 Synthesis of- ((1 r,4 r) -4-methylcyclohexyl) acetic acid (278.4).

To a solution of 278.3 (354 mg,2.13 mmol) in 1, 4-dioxane (60 mL) and water (12 mL) under nitrogen was added silver benzoate (48.8 mg,0.21 mmol) and TEA (860 mg,8.52 mmol). The reaction mixture was sonicated at 20℃for 1h while protected from light, then stirred in the dark at 20℃for an additional 16h. TLC showed 278.3 complete consumption. The reaction mixture was filtered, and the filtrate was concentrated to remove the solvent. The residue was diluted with water (10 mL) and the pH was adjusted to 2-3 with HCl (1M) and extracted with EA (5.0 mL. Times.3). The combined organic phases were washed with brine (5.0 mL) and dried over anhydrous Na ₂SO₄, filtered. The filtrate was concentrated to dryness to give 278.4 (342 mg, crude product) as a yellow solid ).¹H NMR(400MHz,DMSO)δ12.06(s,1H),2.06(d,J＝6.8Hz,2H),1.73–1.47(m,5H),1.31–1.20(m,1H),0.99–0.82(m,7H).

Synthesis of((3 aR,4R,6 aR) -6- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) methyl 2- ((1 r, 4R) -4-methylcyclohexyl) acetate (278.5).

A solution of 278.4 (150 mg,0.96 mmol), EDCI (552 mg,2.9 mmol) and DMAP (352 mg,2.9 mmol) in dry THF (15 mL) was stirred at 20℃for 30min, then 6.4 (255 mg,0.77 mmol) was added. The reaction mixture was stirred at 20℃for 16h. The mixture was quenched with water (15 mL) and extracted with EA (5.0 mL. Times.2). The combined organic phases were washed with brine (5.0 mL), dried over anhydrous Na ₂SO₄, and filtered. The filtrate was concentrated to dryness. The residue was purified by FCC (gradient: 25% EA in PE) to give 278.5 (309 mg,69% yield) as a white solid. MS (ESI): the calculated mass for C ₂₄H₃₁N₅O₅ was 469.23, found m/z was 470.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92(br s,3H),6.90(d,J＝4.4Hz,1H),6.81(d,J＝4.4Hz,1H),5.39(d,J＝6.0Hz,1H),4.93(dd,J＝6.4,2.8Hz,1H),4.61–4.54(m,1H),4.20(dd,J＝12.0,4.0Hz,1H),4.09(dd,J＝12.0,5.6Hz,1H),2.10–1.93(m,2H),1.64(s,3H),1.61–1.50(m,4H),1.42–1.31(m,4H),1.22–1.18(m,1H),0.92–0.71(m,7H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2- ((1 r, 4R) -4-methylcyclohexyl) acetate (278).

To a solution of 278.5 (120 mg,0.26 mmol) in dry THF (1.2 mL) was added dropwise concentrated HCl (0.6 mL) at 0 ℃. The reaction mixture was stirred at 20℃for 30min. LC-MS showed complete consumption of 278.5. The organic solvent was removed with flowing nitrogen and the residue was diluted with ACN. The solution was purified by preparative HPLC to give the title compound as a white solid (61.23 mg,55% yield). MS (ESI): the calculated mass for C ₂₁H₂₇N₅O₅ was 429.20 and the measured m/z was 430.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92(br s,3H),6.91(d,J＝4.4Hz,1H),6.80(d,J＝4.4Hz,1H),6.31(d,J＝6.0Hz,1H),5.37(d,J＝6.0Hz,1H),4.69(t,J＝5.6Hz,1H),4.30(dd,J＝12.0,2.4Hz,1H),4.24–4.12(m,2H),3.94(dd,J＝11.2,5.6Hz,1H),2.19–2.08(m,2H),1.65–1.47(m,5H),1.28–1.15(m,1H),0.97–0.77(m,7H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2- (spiro [4.5] decan-8-yl) acetate (Compound 279).

Step 1.2 Synthesis of ethyl 2- (spiro [4.5] decan-8-ylidene) acetate (279.2).

To a solution of ethyl 2- (diethoxyphosphoryl) acetate (884 mg,3.94 mmol) in dry THF (5.0 mL) was added sodium hydride (158 mg,60%,3.94 mmol) in an ice bath. The reaction mixture was stirred at 20 ℃ for 1h, then a solution of 279.1 (500 mg,3.28 mmol) in dry THF (1.0 mL) was added dropwise. The reaction mixture was stirred at 20℃for 16h. The reaction mixture was quenched with water (10 mL) and extracted with EA (5.0 mL. Times.3). The combined organic phases were washed with brine (5.0 mL), dried over anhydrous Na ₂SO₄, and filtered. The filtrate was concentrated to dryness. The residue was purified by FCC (gradient: 5% EA in PE) to give 279.2 (610 mg,84% yield) as a colorless oil. MS (ESI): for C ₁₄H₂₂O₂ the calculated m/z was 222.16, found to be 223.3[M+H]⁺.¹H NMR(400MHz,CDCl₃)δ5.61(s,1H),4.14(q,J＝7.2Hz,2H),2.87–2.81(m,2H),2.23–2.17(m,2H),1.66–1.58(m,4H),1.54(s,2H),1.51–1.41(m,6H),1.27(t,J＝7.2Hz,3H). step 2.2- (spiro [4.5] decan-8-yl) acetic acid ethyl ester (279.3) synthesis.

Pd/C (61.0 mg,10% w.t%) was added to a solution of 279.2 (610 mg,2.74 mmol) in EtOH (10 mL). The reaction mixture was degassed three times with H ₂ and stirred at 20 ℃ for 16H under H ₂. Complete consumption of 279.2 was detected by TLC. The reaction mixture was filtered, and the filtrate was concentrated to dryness to give 279.3 (313 mg,99% yield) as a colorless oil ).¹H NMR(400MHz,CDCl₃)δ4.12(q,J＝7.2Hz,2H),2.18(d,J＝7.2Hz,1H),1.79–1.68(m,1H),1.63–1.54(m,3H),1.48–1.41(m,1H),1.40–1.22(m,5H),1.15–1.03.(m,1H).

Step 3.2 Synthesis of- (spiro [4.5] decan-8-yl) acetic acid (279.4).

To a solution of 279.3 (313 mg,2.73 mmol) in EtOH (6.0 mL) was added a solution of sodium hydroxide (219 mg,5.47 mmol) in water (6.0 mL). The reaction mixture was stirred under nitrogen at 80 ℃ for 2h. TLC showed complete consumption of 279.3. The reaction mixture was concentrated to remove the organic solvent. The residue was diluted with water (10 mL) and extracted with EA (5.0 mL). The aqueous phase was acidified with HCl (1M) and extracted with EA (5.0 ml×2). The combined organic phases were washed with brine (5.0 mL) and then concentrated to give 279.4 (562 mg, crude) as a white solid ).¹H NMR(400MHz,DMSO)δ11.95(s,1H),2.08(d,J＝6.8Hz,2H),1.65–1.47(m,7H),1.44–1.27(m,6H),1.26–1.15(m,2H),1.09–0.97(m,2H).

Synthesis of((3 aR,4R,6 aR) -6- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) methyl 2- (spiro [4.5] decan-8-yl) acetate (279.5).

A solution of 279.4 (200 mg,1.0 mmol), EDCI (586 mg,3.1 mmol) and DMAP (373 mg,3.1 mmol) in dry THF (20 mL) was stirred at 20deg.C for 30min, then 6.4 (321 mg,0.97 mmol) was added. The reaction mixture was stirred at 20℃for 16h. The mixture was quenched with water (15 mL) and extracted with EA (5.0 mL. Times.2). The combined organic phases were washed with brine (5.0 mL), dried over anhydrous Na ₂SO₄, and filtered. The filtrate was concentrated to dryness. The residue was purified by FCC (gradient: 25% EA in PE) to give 279.5 (450 mg,87% yield) as a colorless oil. MS (ESI): for a calculated m/z of C ₂₇H₃₅N₅O₅ of 509.26, the actual measurement was 510.4[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.91(br s,3H),6.90(d,J＝4.4Hz,1H),6.80(d,J＝4.4Hz,1H),5.39(d,J＝6.4Hz,1H),4.93(dd,J＝6.4,2.8Hz,1H),4.61–4.54(m,1H),4.21(dd,J＝12.0,4.0Hz,1H),4.09(dd,J＝12.0,5.6Hz,1H),2.12–1.99(m,2H),1.64(s,3H),1.56–1.47(m,4H),1.45–1.22(m,12H),1.16–1.05(m,2H),1.01–0.87(m,2H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2- (spiro [4.5] decan-8-yl) acetate (279).

To a solution of 279.5 (100 mg,0.20 mmol) in dry THF (1.0 mL) at 0deg.C was added dropwise concentrated HCl (0.5 mL). The reaction mixture was stirred at 20℃for 30min. LC-MS showed complete consumption of 279.5. The organic solvent was removed with flowing nitrogen and the residue was diluted with ACN. The solution was purified by preparative HPLC to give the title compound as a white solid (33.12 mg,36% yield). MS (ESI): for a calculated m/z of C ₂₄H₃₁N₅O₅ of 469.23, the actual measurement was 470.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92(br s,3H),6.91(d,J＝4.4Hz,1H),6.80(d,J＝4.4Hz,1H),6.32(d,J＝6.0Hz,1H),5.37(d,J＝5.2Hz,1H),4.68(t,J＝5.2Hz,1H),4.30(dd,J＝11.6,2.4Hz,1H),4.24–4.13(m,2H),3.93(dd,J＝11.2,6.0Hz,1H),2.20–2.12(m,2H),1.63–1.44(m,7H),1.40–1.25(m,6H),1.21–1.11(m,2H),1.06–0.94(m,2H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2- (1, 1-tetrahydro-2H-thiopyran-4-yl) acetate (Compound 280).

Step 1.2 Synthesis of Ethyl 2- (tetrahydro-4H-thiopyran-4-ylidene) acetate (280.2).

To a solution of ethyl 2- (diethoxyphosphoryl) acetate (2.12 g,9.40 mmol) and 280.1 (1.00 g,8.6 mmol) in dry DMF (10 mL) was added potassium carbonate (1.78 g,12.9 mmol). The reaction mixture was stirred under nitrogen at 80 ℃ for 16h. The reaction mixture was diluted with water (50 mL) and extracted with EA (15 ml×3). The combined organic phases were washed with brine (20 ml×3), dried over anhydrous Na ₂SO₄, and filtered. The filtrate was concentrated to dryness. The residue was purified by FCC (gradient: 5% EA in PE) to give 280.2 (1.39 g,87% yield) as a white solid. MS (ESI): the calculated mass for C ₉H₁₄O₂ S was 186.07, m/z found 187.0[M+H]⁺.¹H NMR(400MHz,CDCl₃)δ5.67(s,1H),4.15(q,J＝7.2Hz,2H),3.22–3.17(m,2H),2.80–2.73(m,4H),2.56–2.51(m,2H),1.28(t,J＝7.2Hz,4H).

Step 2.2 Synthesis of ethyl 2- (tetrahydro 2H-thiopyran-4-yl) acetate (280.3).

To a solution of 280.2 (1.00 g,5.37 mmol) and nickel (II) chloride hexahydrate (1.28 g,5.37 mmol) in dry THF (10 mL) at 0deg.C was added sodium borohydride (1.02 g,26.8 mmol) in four portions. The reaction mixture was stirred at 0℃for 6h and at 20℃for 10h. TLC showed about half of the consumption of 280.2. The reaction mixture was quenched with EA (10 mL) and saturated aqueous NH ₄ Cl (20 mL). The aqueous phase was filtered and extracted with EA (10 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na ₂SO₄, and filtered. The filtrate was concentrated to dryness. The residue was purified by FCC (gradient: 5% EA in PE) to give 280.3 (399 mg,33% yield) as a colorless oil ).¹H NMR(400MHz,CDCl₃)δ4.13(q,J＝7.2Hz,2H),2.75–2.66(m,2H),2.63–2.55(m,2H),2.21(d,J＝7.2Hz,2H),2.06–1.97(m,2H),1.90–1.78(m,1H),1.46–1.35(m,2H),1.26(t,J＝7.2Hz,3H).

Step 3.synthesis of ethyl 2- (1, 1-tetrahydro-2H-thiopyran-4-yl) acetate (280.4).

To a solution of 280.3 (399 mg,1.75 mmol) in dry DCM (10 mL) was added in portions m-CPBA (754 mg,4.37 mmol) at 0deg.C. The reaction mixture was stirred at 0 ℃ for 6h and at 20 ℃ for another 4h. TLC showed 280.3 complete consumption. The mixture was diluted with DCM (10 mL) and washed with saturated aqueous Na ₂S₂O₃ (10 mL) then saturated aqueous NaHCO ₃ (10 mL), water (10 mL) and brine (5.0 mL). The organic phase was dried over anhydrous Na ₂SO₄ and filtered. The filtrate was concentrated to dryness. The residue was concentrated to dryness to give 280.4 (693 mg, crude product) as a yellow oil ).¹H NMR(400MHz,DMSO)δ4.06(q,J＝7.2Hz,2H),3.15(td,J＝13.2,3.2Hz,2H),3.03–2.94(m,2H),2.34–2.23(m,2H),2.09–1.92(m,3H),1.73–1.57(m,2H),1.18(t,J＝7.2Hz,3H).

Step 4.2 synthesis of (1, 1-tetrahydro-2H-thiopyran-4-yl) acetic acid (280.5).

To a solution of 280.4 (693 mg,3.15 mmol) in EtOH (6.0 mL) was added a solution of sodium hydroxide (251 mg,6.29 mmol) in water (6.0 mL). The reaction mixture was stirred under nitrogen at 80 ℃ for 2h. TLC showed 280.4 complete consumption. The reaction mixture was concentrated to remove the organic solvent. The residue was diluted with water (10 mL) and extracted with EA (5.0 mL). The aqueous phase was acidified with HCl (1M) and extracted with EA (5.0 ml×5). The combined organic phases were washed with brine (5.0 mL) and then concentrated to give 280.5 (501 mg, crude) as a yellow oil.

Synthesis of((3 aR,4R,6 aR) -6- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxan-4-yl) methyl 2- (1, 1-dioxan-2H-thiopyran-4-yl) acetate (280.6).

A solution of 280.5 (155 mg,0.81 mmol), EDCI (460 mg,2.42 mmol) and DMAP (298 mg,2.42 mmol) in dry THF (12 mL) was stirred at 20℃for 30min, then 6.4 (240 mg,0.73 mmol) was added. The reaction mixture was stirred at 20℃for 16h. The mixture was quenched with water (15 mL) and extracted with EA (5.0 mL. Times.2). The combined organic phases were washed with brine (5.0 mL), dried over anhydrous Na ₂SO₄, and filtered. The filtrate was concentrated to dryness. The residue was purified by FCC (gradient: 50% EA in PE) to give 280.6 (208 mg, crude DMAP-containing) as a colorless oil. MS (ESI): the calculated mass for C ₂₂H₂₇N₅O₇ S was 505.16 and the m/z found was 506.3[ M+H ] ⁺.

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2- (1, 1-tetrahydro-2H-thiopyran-4-yl) acetate (280).

To a solution of 280.6 (208 mg,0.41 mmol) in dry THF (2.0 mL) was added dropwise concentrated HCl (1.0 mL) at 0 ℃. The reaction mixture was stirred at 20℃for 30min. The organic solvent was removed with flowing nitrogen and the residue was diluted with ACN. The solution was purified by preparative HPLC to give the title compound as a white solid (64.73 mg,33% yield). MS (ESI): the calculated mass for C ₁₉H₂₃N₅O₇ S was 465.13 and the m/z found was 466.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92(br s,3H),6.92(d,J＝4.4Hz,1H),6.81(d,J＝4.4Hz,1H),6.31(d,J＝6.4Hz,1H),5.39(d,J＝5.6Hz,1H),4.70(t,J＝5.6Hz,1H),4.33(dd,J＝11.4,2.0Hz,1H),4.25–4.14(m,2H),3.94(dd,J＝11.2,5.6Hz,1H),3.12(td,J＝13.6,3.2Hz,2H),3.00–2.91(m,2H),2.39–2.27(m,2H),2.06–1.91(m,3H),1.70–1.58(m,2H).

Example 127: synthesis of (((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl (S) -2-cyclohexylpropionate (Compound 281).

Synthesis of((3 aR,4R,6 aR) -6- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) methyl (S) -2-cyclohexylpropionate (281.1).

Compound 281.1 was prepared according to the procedure of step 1 of example 266 using 6.3 and (S) -2-cyclohexylpropionic acid. MS (ESI): the calculated mass for C ₂₄H₃₁N₅O₅ was 469.23, found m/z was 470.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92-7.90(br,s,3H),6.91(d,J＝4.4Hz,1H),6.81(d,J＝4.4Hz,1H),6.32(d,J＝6.0Hz,1H),5.37(d,J＝5.6Hz,1H),4.71(t,J＝5.6Hz,1H),4.39–4.13(m,3H),4.08–3.83(m,1H),2.24-2.17(m,1H),1.64–1.36(m,6H),1.20–1.00(m,3H),0.98(d,J＝7.2Hz,3H),0.95–0.83(m,2H).

Step 2: synthesis of (((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl (S) -2-cyclohexylpropionate (Compound 281).

The title compound 281 was prepared according to the procedure of step 2 of example 272 using 281.1. MS (ESI): the calculated mass for C ₂₁H₂₇N₅O₅ was 429.20 and the measured m/z was 430.2[M+H]⁺.1H NMR(400MHz,DMSO)δ7.92-7.90(br,s,3H),6.91(d,J＝4.4Hz,1H),6.81(d,J＝4.4Hz,1H),6.32(d,J＝6.0Hz,1H),5.37(d,J＝5.6Hz,1H),4.71(t,J＝5.6Hz,1H),4.39–4.13(m,3H),4.08–3.83(m,1H),2.24-2.17(m,1H),1.64–1.36(m,6H),1.20–1.00(m,3H),0.98(d,J＝7.2Hz,3H),0.95–0.83(m,2H).

Synthesis of (((2R, 3S,4R, 5R) -5-cyano-3, 4-dihydroxy-5- (4-pentanamido pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuranyl) methylpropionate (Compound 282).

The title compound was prepared according to the procedure for step 4 of example 5 using 264 and propionyl chloride. MS (ESI): the calculated mass for C ₂₀H₂₅N₅O₆ was 431.18, the measured m/z was 432.2[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.90(s,1H),8.39(s,1H),7.27(d,J＝4.8Hz,1H),7.04(d,J＝4.8Hz,1H),6.44(d,J＝6.0Hz,1H),5.45(d,J＝6.0Hz,1H),4.67(t,J＝5.2Hz,1H),4.38–4.31(m,1H),4.29–4.24(m,1H),4.19–4.13(m,1H),3.94(dd,J＝11.6,6.0Hz,1H),2.71(t,J＝7.6Hz,2H),2.34–2.27(m,2H),1.67–1.54(m,2H),1.40–1.30(m,2H),0.99(t,J＝7.6Hz,3H),0.91(t,J＝7.2Hz,3H).

Example 129 synthesis of ((2R, 3S,4R, 5R) -5-cyano-3, 4-dihydroxy-5- (4-pentanamido pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuranyl-2-yl) methyl 3-methylbutanoate (compound 283).

The title compound was prepared according to the procedure for step 1 of example 288 using compound 264 and 3-methylbutyryl chloride. MS (ESI): the calculated mass for C ₂₂H₂₉N₅O₆ was 459.21 and the measured m/z was 460.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.89(s,1H),8.39(s,1H),7.29(d,J＝4.8Hz,1H),7.05(d,J＝4.8Hz,1H),6.43(d,J＝6.0Hz,1H),5.44(d,J＝6.0Hz,1H),4.70–4.65(m,1H),4.35–4.23(m,2H),4.17(dd,J＝12.0,5.2Hz,1H),3.94(dd,J＝11.6,6.4Hz,1H),2.75–2.67(m,2H),2.20–2.08(m,2H),1.91(m,1H),1.66–1.54(m,2H),1.40–1.28(m,2H),0.95–0.81(m,9H).

Synthesis of((2R, 3S,4R, 5R) -5-cyano-3, 4-dihydroxy-5- (4-pentanamido pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuranyl-2-yl) methyl 2-cyclohexylacetate (Compound 284).

The title compound was prepared according to the procedure for step 1 of example 288 using compound 264 and 2-cyclohexylacetyl chloride. MS (ESI): the calculated mass for C ₂₅H₃₃N₅O₆ was 499.24 and the measured m/z was 500.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.85(s,1H),8.39(s,1H),7.29(d,J＝4.8Hz,1H),7.05(d,J＝4.8Hz,1H),6.55(s,1H),5.55(s,1H),4.68(d,J＝4.8Hz,1H),4.34–4.22(m,2H),4.16(dd,J＝12.0,5.2Hz,1H),3.99–3.90(m,1H),2.72(t,J＝7.6Hz,2H),2.19–2.05(m,2H),1.65–1.53(m,8H),1.42–1.29(m,2H),1.21–1.04(m,3H),0.94–0.80(m,5H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-benzoylamino pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2-cyclohexylacetate (Compound 285).

The title compound was prepared according to the procedure for step 1 of example 103 using compound 85 and 2-cyclohexylacetyl chloride. MS (ESI): the calculated mass for C ₂₇H₂₉N₅O₆ was 519.21 and the measured m/z was 520.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ11.89(s,1H),8.34(s,1H),8.06(d,J＝8.0Hz,2H),7.64(t,J＝7.6Hz,1H),7.54(t,J＝7.6Hz,2H),7.15(d,J＝3.2Hz,1H),7.03(d,J＝4.8Hz,1H),6.45(s,1H),5.47(s,1H),4.70(s,1H),4.35–4.24(m,2H),4.17(dd,J＝12.0,5.2Hz,1H),3.97(t,J＝5.6Hz,1H),2.20–2.04(m,2H),1.60(d,J＝11.2Hz,6H),1.24–0.99(m,3H),0.96–0.79(m,2H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2- (1-aminocyclohexyl) acetate.

Synthesis of((3 aR,4R,6 aR) -6- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) methyl 2- (1- ((tert-butoxycarbonyl) amino) cyclohexyl) acetate (286.1).

To a mixture of 6.4 (300 mg,0.90 mmol), (1- { [ (tert-butoxy) carbonyl ] amino } cyclohexyl) acetic acid (233 mg,0.90 mmol) and EDCI (520 mg,2.71 mmol) in THF was slowly added DMAP (331 mg,2.71 mmol) at 0deg.C. The mixture was then stirred at 20 ℃ for about 5 hours. After completion, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 ml×3). The organic layer was dried over sodium sulfate and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC to give 286.1 (410 mg,78.5% yield) as a white solid. MS (ESI): for a calculated m/z of C ₂₈H₃₈N₆O₇ of 570.28, the actual measurement was 571.35[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.96(s,3H),6.91(d,J＝4.4Hz,1H),6.83(d,J＝4.4Hz,1H),6.24(s,1H),5.43(d,J＝6.4Hz,1H),4.96(dd,J＝6.4,3.2Hz,1H),4.54(dd,J＝8.4,5.2Hz,1H),4.18(dd,J＝12.0,4.4Hz,1H),4.07(dd,J＝12.0,6.0Hz,1H),1.95(d,J＝10.0Hz,2H),1.64(s,3H),1.55–1.00(m,22H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2- (1-aminocyclohexyl) acetate (286).

To a solution of 286.1 (200 mg,0.37 mmol) in THF (2.0 mL) at 0 ℃ was added 6M HCl (2.0 mL) dropwise, and the mixture was stirred at 20 ℃ for 2 hours. The mixture was quenched with water (2 mL) and dried with a stream of nitrogen to remove the solvent. The residue was purified by prep HPLC to give 286 (113 mg,74.6% yield) as a white solid. MS (ESI): for a calculated m/z of C ₂₀H₂₆N₆O₅ of 430.20, the actual measurement was 431.10[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.93(s,5H),6.93(d,J＝4.4Hz,1H),6.84(d,J＝4.4Hz,1H),6.35(d,J＝4.8Hz,1H),5.46(s,1H),4.74(s,1H),4.41–4.32(m,1H),4.30–4.20(m,2H),3.97(t,J＝5.2Hz,1H),2.68(s,2H),1.71–1.20(m,10H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2- (1-methoxycyclohexyl) acetate (Compound 287).

/>

Synthesis of((3 aR,4R,6 aR) -6- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) methyl 2- (1-methoxycyclohexyl) acetate (287.1).

To a mixture of 6.4 (200 mg,0.60 mmol) and (1-methoxycyclohexyl) acetic acid (103.9 mg,0.60 mmol) and EDCI (347 mg,1.81 mmol) in THF (4 mL) was slowly added DMAP (221 mg,1.81 mmol) at 0deg.C. The mixture was then stirred at 20 ℃ for about 5 hours. After completion, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 ml×3). The organic layer was dried over sodium sulfate and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC to give 287.1 (220 mg,74.3% yield) as a white solid. MS (ESI): for a calculated m/z of C ₂₄H₃₁N₅O₆ of 485.23, the actual measurement was 486.30[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.96(s,3H),6.91(d,J＝4.4Hz,1H),6.85(d,J＝4.4Hz,1H),5.42(d,J＝6.4Hz,1H),4.93(dd,J＝6.4,2.8Hz,1H),4.55(dd,J＝7.6,5.2Hz,1H),4.14(ddd,J＝18.0,12.0,5.2Hz,2H),3.04(s,3H),2.37(s,2H),1.65(d,J＝11.2Hz,5H),1.47–1.28(m,10H),1.14(d,J＝9.6Hz,1H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2- (1-methoxycyclohexyl) acetate (287).

To a solution of 287.1 (150 mg,0.3 mmol) in THF (1.5 mL) at 0deg.C was added dropwise 6M HCl (1.5 mL) and the mixture was stirred at 20deg.C for 2 hours. LCMS (ENB 214167-097-M2) indicated complete consumption of starting material. The mixture was quenched with water (2 mL) and dried with a stream of nitrogen to remove the solvent. The residue was purified by prep HPLC to give 287 (113 mg,74.8% yield) as a white solid. MS (ESI): for a calculated m/z of C ₂₁H₂₇N₅O₆ of 445.20, the actual measurement was 446.25[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92(s,3H),6.91(d,J＝4.4Hz,1H),6.81(d,J＝4.8Hz,1H),6.30(d,J＝6.4Hz,1H),5.38(d,J＝5.6Hz,1H),4.71(t,J＝5.2Hz,1H),4.31–4.18(m,2H),4.18–4.08(m,1H),3.96(q,J＝5.2Hz,1H),3.06(s,3H),2.43(s,2H),1.74–1.61(m,2H),1.48–1.31(m,7H),1.20–1.09(m,1H).

Synthesis of((2R, 3S,4R, 5R) -5-cyano-3, 4-dihydroxy-5- (4-pentanamido pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuranyl) methyl acetate (Compound 288).

To a solution of 264 (80.0 mg,0.21 mmol) in DMPU (0.5 mL) was added HCl/dioxane (0.1 mL, 4M). The mixture solution was stirred at 0 ℃ for 15 minutes. Acetyl chloride (50.2 mg,0.64 mmol) was then added at 0deg.C. The resulting mixture was stirred at 20 ℃ for an additional 2 hours. The reaction was diluted with ACN (2.0 mL) and purified by preparative HPLC to give the title compound as a white solid (19.5 mg,21.5% yield). MS (ESI): for a calculated m/z of C ₁₉H₂₃N₅O₆ of 417.16, the actual measurement was 418.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.89(s,1H),8.40(s,1H),7.29(d,J＝4.8Hz,1H),7.05(d,J＝4.8Hz,1H),6.42(d,J＝6.0Hz,1H),5.44(d,J＝6.0Hz,1H),4.71–4.61(m,1H),4.35–4.23(m,2H),4.15(dd,J＝12.0,5.6Hz,1H),3.93(dd,J＝12.0,5.2Hz,1H),2.73–2.66(m,2H),2.01(s,3H),1.65–1.55(m,2H),1.41–1.29(m,2H),0.91(t,J＝7.2Hz,3H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 1-phenylcyclopropane-1-carboxylate (Compound 289).

Synthesis of((3 aR,4R,6 aR) -6- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) methyl 1-phenylcyclopropane-1-carboxylate (289.1).

The title compound was prepared according to the procedure of step 1 of example 273 using 6.4 and 1-phenylcyclopropane-1-carboxylic acid. MS (ESI): the calculated mass for C ₂₅H₂₅N₅O₅ was 475.19 and the m/z found was 476.1[ M+H ] ⁺.

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 1-phenylcyclopropane-1-carboxylate (289).

The title compound was prepared according to the procedure for step 2 of example 273 using 289.1. MS (ESI): the calculated mass for C ₂₂H₂₁N₅O₅ was 435.15 and the measured m/z was 436.0[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ7.93(br s,3H),7.33–7.19(m,5H),6.92(d,J＝4.4Hz,1H),6.64(d,J＝4.4Hz,1H),6.21(d,J＝6.0Hz,1H),5.36(d,J＝5.2Hz,1H),4.41(t,J＝5.2Hz,1H),4.30–4.23(m,1H),4.20–4.10(m,2H),3.87–3.80(m,1H),1.50–1.41(m,2H),1.23–1.12(m,2H).

Synthesis of (2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-2- (hydroxymethyl) tetrahydrofuran-3-ylbenzoate (Compound 290).

Synthesis of (2R, 3R,4S, 5R) -2- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5- (((tert-butyldiphenylsilyl) oxy) methyl) -3, 4-dihydroxytetrahydrofuran-2-carbonitrile (290.1).

To a solution of 6.3 (1.00 g,3.4 mmol) and pyridine (540 mg,6.8 mmol) in dry DMSO (10 mL) was added TBDPSCl (1.03 g,3.7 mmol) dropwise. The reaction mixture was stirred at 20 ℃ for 16 hours. The reaction mixture was poured into cold water (25 mL) and a white solid precipitated. The filter cake was collected and dried to give 290.1 (1.90 g,94.1% yield) as a white solid. MS (ESI): the calculated m/z for C ₂₈H₃₁N₅O₄ Si was 529.21, found to be 530.2[M+H]⁺.¹H NMR(400MHz,MeOD)δ7.79(s,1H),7.63–7.55(m,4H),7.41–7.35(m,3H),7.30(dd,J＝13.2,7.2Hz,4H),6.86–6.81(m,2H),4.37(t,J＝5.2Hz,1H),4.34–4.27(m,1H),3.93(dd,J＝11.6,2.8Hz,1H),3.83(dd,J＝11.6,3.6Hz,1H),1.00–0.92(m,9H).

Synthesis of (2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -2- (((tert-butyldiphenylsilyl) oxy) methyl) -5-cyano-4-hydroxytetrahydrofuran-3-yl benzoate (290.2).

A solution of benzoic acid (184 mg,1.51 mmol), HOBT (612 mg,4.53 mmol), EDCI (869 mg,4.53 mmol) and DIPEA (586 mg,4.53 mmol) in dry DMF (8.0 mL) was stirred at 25℃for 1h. 290.1 (800 mg,1.51 mmol) was then added to the flask. The reaction mixture was stirred at 25℃for 16h. The reaction mixture was quenched with water (10 mL) and extracted with EA (5.0 mL. Times.2). The combined organic phases were washed with brine (5.0 mL), dried over anhydrous Na ₂SO₄, and filtered. The filtrate was concentrated to dryness. The residue was purified by FCC (gradient: 15% EA in PE) to give 290.2 (552 mg,93% purity, 57% yield) as a white solid. MS (ESI): the calculated m/z for C ₃₅H₃₅N₅O₅ Si was 633.24, found to be 634.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.13(d,J＝7.2Hz,2H),7.91(br s,3H),7.73–7.67(m,1H),7.60–7.51(m,4H),7.48–7.35(m,4H),7.29(t,J＝7.2Hz,2H),7.21(t,J＝7.6Hz,2H),6.86(dd,J＝16.0,4.4Hz,2H),6.73(d,J＝6.4Hz,1H),5.70(dd,J＝5.2,3.2Hz,1H),5.20(t,J＝6.0Hz,1H),4.55(dd,J＝6.0,3.2Hz,1H),3.89–4.77(m,2H),0.94(s,9H).

Synthesis of (2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-2- (hydroxymethyl) tetrahydrofuran-3-yl benzoate (290).

A mixture of 290.2 (80.0 mg,0.126 mmol) in THF (1.0 mL) was added dropwise to TBAF (0.2 mL, 1M). The reaction mixture was stirred at 20℃for 2h. The reaction was diluted with ACN (2.0 mL) and purified by preparative HPLC to give 290 (12.0 mg,24% yield) as a white solid. MS (ESI): for a calculated m/z of C ₁₉H₁₇N₅O₅ of 395.12, the actual measurement was 396.0[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ8.16–8.09(m,2H),7.96(br s,3H),7.69(t,J＝7.2Hz,1H),7.56(t,J＝7.6Hz,2H),6.93(q,J＝4.8Hz,2H),6.56(d,J＝6.4Hz,1H),5.53(dd,J＝5.6,2.8Hz,1H),5.12(q,J＝6.0Hz,2H),4.44(q,J＝3.6Hz,1H),3.73–3.51(m,2H).

Synthesis of((2R, 3R,4R, 5R) -5- (2-amino-6- (2-cyclohexyl-N-methylacetamido) -9H-purin-9-yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methyl 2-cyclohexylacetate (Compound 291).

To a solution of 3.3 (1.00 g,3.2 mmol) in DMPU (4 mL) was added HCl in dioxane (4M, 1.6 mL). The solution was stirred at 20℃for 15min. The reaction mixture was cooled at 0deg.C and 2-cyclohexylacetyl chloride (0.59 mL,3.8 mmol) was added immediately. The reaction was stirred at 0 ℃ for 2 hours. The reaction was diluted with ACN (4.0 mL) and purified by preparative HPLC to give 291 (27.8 mg,1.55% yield) as a white solid. MS (ESI): for a calculated m/z of C ₂₈H₄₁FN₆O₅ of 560.31, the actual measurement was 561.3[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ8.18(s,1H),6.82(s,2H),6.14(d,J＝19.2Hz,1H),5.84(s,1H),4.56–4.25(m,3H),4.16–4.03(m,1H),2.42–2.32(m,2H),2.23(d,J＝6.8Hz,2H),1.58(dd,J＝28.8,10.8Hz,13H),1.25–0.73(m,15H).¹⁹F NMR(376MHz,DMSO)δ-159.44(s,1H).

Synthesis of((2R, 3R,4R, 5R) -5- (2- (2-cyclohexylacetamido) -6- (methylamino) -9H-purin-9-yl) -4-fluoro-3-hydroxy-4-methyltetrahydrof-n-2-yl) methyl 2-cyclohexylacetate (Compound 292).

To a solution of 3.3 (1.00 g,3.2 mmol) in DMPU (4 mL) was added HCl in dioxane (4M, 1.6 mL) and the solution was stirred at 20deg.C for 15min. The reaction mixture was cooled at 0deg.C and 2-cyclohexylacetyl chloride (0.59 mL,3.8 mmol) was added immediately. The reaction was stirred at 0 ℃ for 2 hours. The reaction was diluted with ACN (4.0 mL) and purified by preparative HPLC to give 292 as a white solid (28.0 mg,1.52% yield). MS (ESI): for a calculated m/z of C ₂₈H₄₁FN₆O₅ of 560.31, the actual measurement was 561.3[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ9.93(s,1H),8.12(s,1H),7.83(d,J＝17.6Hz,1H),6.12(d,J＝20.0Hz,1H),5.64(s,1H),4.86(s,1H),4.47(dd,J＝12.4,2.0Hz,1H),4.33(dd,J＝12.4,7.6Hz,1H),4.03(t,J＝8.0Hz,1H),2.93(s,3H),2.38(s,1H),2.17(d,J＝6.8Hz,2H),1.84–1.54(m,13H),1.30–1.05(m,10H),0.93(dt,J＝16.4,10.8Hz,4H).¹⁹F NMR(376MHz,DMSO)δ-159.44.

Synthesis of((2R, 3R,4R, 5R) -4-fluoro-4-methyl-5- (6- (methylamino) -2-propionamido-9H-purin-9-yl) -3- (propionyloxy) tetrahydrofuran-2-yl) methyl isobutyrate (Compound 293).

To a solution of 3 (50 mg,0.13 mmol) in NMP (0.5 mL) was added dropwise 4 MHCl/dioxane (0.05 mL), and the mixture was stirred at 0deg.C for 20 min. Propionyl chloride (0.05 mL) was added dropwise to the mixture at 0 ℃ and the mixture was stirred at 20 ℃ for 16 hours. After completion, the mixture was purified by preparative HPLC to give 293 (20 mg,30.9% yield) as a white solid. MS (ESI): for a calculated m/z of C ₂₂H₃₁FN₆O₆ of 494.23, the actual measurement was 495.20[M+H]⁺.¹H NMR(400MHz,DMSO)δ9.88(s,1H),8.18(s,1H),7.89(s,1H),6.17(dd,J＝55.6,17.6Hz,2H),4.53–4.21(m,3H),2.94(s,3H),2.59–2.52(m,2H),2.48–2.31(m,3H),1.24–0.94(m,15H).¹⁹F NMR(377MHz,DMSO)δ-155.61.

Example 140 synthesis of (2 r,3r,4r,5 r) -4-fluoro-5- (2-isobutyramide-6- (methylamino) -9H-purin-9-yl) -2- ((isobutyryloxy) methyl) -4-methyltetrahydrofuran-3-yl isobutyrate (compound 294).

/>

The title compound was prepared according to the procedure for example 293 using 3 and isobutyryl chloride. MS (ESI): for a calculated m/z of C ₂₄H₃₅FN₆O₆ of 522.26, the actual measurement was 523.25[M+H]⁺.¹H NMR(400MHz,DMSO)δ9.90(s,1H),8.18(s,1H),7.87(s,1H),6.24(d,J＝19.6Hz,2H),4.51–4.27(m,3H),2.94(s,4H),2.71–2.63(m,1H),2.57–2.52(m,1H),1.25–1.03(m,21H).¹⁹F NMR(377MHz,DMSO)δ-156.16.

Example 141 synthesis of (2 r,3r,4r,5 r) -4-fluoro-2- ((isobutyryloxy) methyl) -4-methyl-5- (6- (methylamino) -2- (3-methylbutanamino) -9H-purin-9-yl) tetrahydrofuran-3-yl 3-methylbutanoate (compound 295).

The title compound was prepared according to the procedure for example 293 using 3 and 3-methylbutyryl chloride. MS (ESI): for a calculated m/z of C ₂₆H₃₉FN₆O₆ of 550.29, the actual measurement was 551.25[M+H]⁺.¹H NMR(400MHz,DMSO)δ9.91(s,1H),8.17(s,1H),7.87(s,1H),6.23(d,J＝19.6Hz,2H),4.56–4.25(m,3H),2.95(s,3H),2.57–2.51(m,1H),2.32(dd,J＝17.6,6.8Hz,4H),2.04(tt,J＝15.6,6.8Hz,2H),1.18(d,J＝23.2Hz,3H),1.07(d,J＝7.2Hz,6H),0.99–0.88(m,12H).¹⁹F NMR(377MHz,DMSO)δ-155.59.

Synthesis of((2R, 3R,4R, 5R) -5- (2- (2-cyclohexylacetamido) -6- (methylamino) -9H-purin-9-yl) -3- (2-cyclohexylacetoxy) -4-fluoro-4-methyltetrahydrofuran-2-yl) methylisobutyate (Compound 296).

To a solution of 3 (100 mg,0.26 mmol) in NMP (1 mL) was added HCl in dioxane (4M, 0.3 mL) and the solution was stirred at 20deg.C for 15 min. The reaction mixture was cooled at 0 ℃ and 2-cyclohexylacetyl chloride (0.2 ml,1.3 mmol) was added immediately. The reaction was stirred at 20℃for 16 hours. The reaction was diluted with ACN (2 mL) and purified by preparative HPLC to give 296 (25.5 mg,14.7% yield) as a white solid. MS (ESI): for a calculated m/z of C ₃₂H₄₇FN₆O₆ of 630.35, the actual measurement was 631.4[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ9.91(s,1H),8.16(s,1H),7.86(s,1H),6.23(d,J＝19.6Hz,2H),4.48–4.39(m,2H),4.34–4.27(m,1H),2.94(s,3H),2.56–2.52(m,1H),2.36–2.27(m,4H),1.76–1.60(m,11H),1.25–0.92(m,20H).

Synthesis of((2R, 3R,4R, 5R) -4-fluoro-3-hydroxy-4-methyl-5- (6- (methylamino) -2- (2-phenylacetamido) -9H-purin-9-yl) tetrahydrofurane-2-yl) methylisobutyrate (Compound 297).

To a solution of 3 (100 mg,0.26 mmol) in NMP (1 mL) was added HCl in dioxane (4M, 0.3 mL) and the solution was stirred at 20deg.C for 15 min. The reaction mixture was cooled at 0deg.C, and 2-phenylacetyl chloride (0.17 mL,1.3 mmol) was added immediately. The reaction was stirred at 20℃for 16 hours. The reaction was diluted with ACN (2 mL) and purified by preparative HPLC to give 297 as a white solid (8.72 mg,6.65% yield). MS (ESI): for a calculated m/z of C ₂₄H₂₉FN₆O₅ of 500.22, the actual measurement was 501.3[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.24(s,1H),8.13(s,1H),7.85(s,1H),7.35–7.28(m,4H),7.25–7.19(m,1H),6.12(d,J＝20.0Hz,1H),5.65(d,J＝6.0Hz,1H),4.81(s,1H),4.46(dd,J＝12.4,2.0Hz,1H),4.32(dd,J＝12.4,7.6Hz,1H),4.04(t,J＝8.0Hz,1H),3.82(s,2H),2.93(s,2H),2.57–2.52(m,1H),1.10(t,J＝15.6Hz,10H).¹⁹F NMR(376MHz,DMSO)δ-158.63.

Synthesis of((2R, 3R,4R, 5R) -4-fluoro-4-methyl-5- (6- (methylamino) -2- (2-phenylacetamido) -9H-purin-9-yl) -3- (2-phenylacetoxy) tetrahydrofurane-2-yl) methylisobutyate (Compound 298).

To a solution of 3 (100 mg,0.26 mmol) in NMP (1 mL) was added HCl in dioxane (4M, 0.3 mL) and the solution was stirred at 20deg.C for 15 min. The reaction mixture was cooled at 0deg.C, and 2-phenylacetyl chloride (0.17 mL,1.3 mmol) was added immediately. The reaction was stirred at 20℃for 16 hours. The reaction was diluted with ACN (2 mL) and purified by preparative HPLC to give 298 as a white solid (6.75 mg,4.71% yield). MS (ESI): for a calculated m/z of C ₃₂H₃₅FN₆O₆ of 618.26, the actual measurement was 619.2[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.18(s,1H),8.18(s,1H),7.90(s,1H),7.40–7.15(m,10H),6.23(d,J＝19.6Hz,2H),4.46–4.29(m,3H),3.89–3.71(m,4H),2.92(s,3H),1.23(s,1H),1.13(d,J＝23.2Hz,3H),1.06(dd,J＝7.2,2.0Hz,6H).¹⁹F NMR(376MHz,DMSO)δ-155.52.

Synthesis of((2R, 3R,4R, 5R) -4-fluoro-3-hydroxy-4-methyl-5- (6- (methylamino) -2- (2-phenylacetamido) -9H-purin-9-yl) tetrahydrof-n-2-yl) methyl 2-cyclohexylacetate (Compound 299).

To a solution of 175 (100 mg,0.22 mmol) in NMP (1 mL) was added HCl in dioxane (4M, 0.2 mL) and the solution was stirred at 20deg.C for 15 min. The reaction mixture was cooled at 0deg.C and 2-phenylacetyl chloride (0.21 mL,1.6 mmol) was added immediately. The reaction was stirred at 20℃for 16 hours. The reaction was diluted with ACN (2 mL) and purified by preparative HPLC to give 299 as a white solid (9.27 mg,7.29% yield). MS (ESI): for a calculated m/z of C ₂₈H₃₅FN₆O₅ of 554.27, the actual measurement was 555.2[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.24(s,1H),8.12(s,1H),7.84(s,1H),7.35–7.28(m,4H),7.25–7.20(m,1H),6.12(d,J＝20.0Hz,1H),5.64(d,J＝7.2Hz,1H),4.77(s,1H),4.46(dd,J＝12.4,2.0Hz,1H),4.30(dd,J＝12.4,7.2Hz,1H),4.02(t,J＝7.6Hz,1H),3.82(s,2H),2.93(s,3H),2.17(d,J＝6.8Hz,2H),1.62(d,J＝12.8Hz,6H),1.15(dd,J＝29.6,17.6Hz,6H),0.89(dd,J＝18.8,8.8Hz,2H).

Synthesis of (2R, 3R,4R, 5R) -2- ((2-cyclohexylacetoxy) methyl) -4-fluoro-4-methyl-5- (6- (methylamino) -2-propionamido-9H-purin-9-yl) tetrahydrofuran-3-yl propionate (Compound 300).

The title compound was prepared according to the procedure for example 293 using 175 and propionyl chloride. MS (ESI): for a calculated m/z of C ₂₆H₃₇FN₆O₆ of 548.28, the actual measurement was 549.35[M+H]⁺.¹H NMR(400MHz,DMSO)δ9.85(s,1H),8.17(s,1H),7.89(s,1H),6.23(d,J＝19.6Hz,1H),6.08(d,J＝14.8Hz,1H),4.48–4.25(m,3H),2.94(s,3H),2.54(Q,J＝7.6Hz,2H),2.45(q,J＝7.6Hz,2H),2.17(d,J＝6.8Hz,2H),1.69–1.54(m,6H),1.24–1.02(m,12H),0.97–0.82(m,2H).¹⁹F NMR(377MHz,DMSO)δ-155.53.

Synthesis of (2R, 3R,4R, 5R) -2- ((2-cyclohexylacetoxy) methyl) -4-fluoro-5- (2-isobutyramide-6- (methylamino) -9H-purin-9-yl) -4-methyltetrahydrofuran-3-yl isobutyrate (Compound 301).

/>

The title compound was prepared according to the procedure for example 293 using 175 and isobutyryl chloride. MS (ESI): for a calculated m/z of C ₂₈H₄₁FN₆O₆ of 576.31, the actual measurement was 577.25[M+H]⁺.¹H NMR(400MHz,DMSO)δ9.88(s,1H),8.17(s,1H),7.87(s,1H),6.23(d,J＝19.6Hz,2H),4.48–4.27(m,3H),2.94(s,4H),2.71–2.63(m,1H),2.16(d,J＝6.4Hz,2H),1.71–1.51(m,6H),1.26–1.03(m,18H),0.96–0.83(m,2H).¹⁹F NMR(377MHz,DMSO)δ-156.04.

Synthesis of (2R, 3R,4R, 5R) -4-fluoro-4-methyl-5- (6- (methylamino) -2-propionamido-9H-purin-9-yl) -2- ((2-phenylacetyloxy) methyl) tetrahydrofuran-3-yl propionate (Compound 302).

The title compound was prepared according to the procedure for example 293 using 177 and propionyl chloride. MS (ESI): for a calculated m/z of C ₂₆H₃₁FN₆O₆ of 542.23, the actual measurement was 543.15[M+H]⁺.¹H NMR(400MHz,DMSO)δ9.88(s,1H),8.16(s,1H),7.88(s,1H),7.35–7.19(m,5H),6.24(d,J＝19.6Hz,1H),6.18–5.99(m,1H),4.51–4.41(m,2H),4.37–4.30(m,1H),3.74–3.63(m,2H),2.94(s,3H),2.57–2.52(m,2H),2.44(q,J＝7.2Hz,2H),1.18(d,J＝23.2Hz,3H),1.10–1.00(m,6H).¹⁹F NMR(377MHz,DMSO)δ-155.41.

Synthesis of((2R, 3R,4R, 5R) -4-fluoro-3-hydroxy-4-methyl-5- (6- (methylamino) -2- (3-methylbutanamino) -9H-purin-9-yl) tetrahydrofuran-2-yl) methyl 2-phenylacetate (Compound 303).

The title compound was prepared from example 185. MS (ESI): for a calculated m/z of C ₂₅H₃₁FN₆O₅ of 514.23, the actual measurement was 515.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ9.94(s,1H),8.12(s,1H),7.81(s,1H),7.32–7.21(m,5H),6.13(d,J＝20.0Hz,1H),5.63(s,1H),4.88(s,1H),4.50–4.36(m,2H),4.05(t,J＝8.0Hz,1H),3.68(s,2H),2.94(s,3H),2.43–2.34(m,2H),2.12–2.01(m,1H),1.13(d,J＝22.4Hz,3H),0.91(d,J＝6.4Hz,6H).¹⁹F NMR(377MHz,DMSO)δ-158.33.

Synthesis of (2R, 3R,4R, 5R) -4-fluoro-4-methyl-5- (6- (methylamino) -2- (3-methylbutanamino) -9H-purin-9-yl) -2- ((2-phenylacetyloxy) methyl) tetrahydrofuran-3-yl 3-methylbutanoate (Compound 304).

The title compound was prepared from example 185. MS (ESI): for a calculated m/z of C ₃₀H₃₉FN₆O₆ of 598.29, the actual measurement was 599.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ9.91(s,1H),8.16(s,1H),7.85(s,1H),7.32–7.21(m,5H),6.44–6.16(m,2H),4.53–4.43(m,2H),4.35–4.29(m,1H),3.67(s,2H),2.94(s,3H),2.35–2.27(m,4H),2.07–1.96(m,2H),1.17(d,J＝23.2Hz,3H),0.94(d,J＝6.4Hz,6H),0.90(d,J＝6.8Hz,6H).¹⁹F NMR(377MHz,DMSO)δ-155.42.

Synthesis of((2R, 3R,4R, 5R) -5- (2- (2-cyclohexylacetamido) -6- (methylamino) -9H-purin-9-yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methyl 2-phenylacetate (Compound 305).

To a solution of 177 (100 mg,0.23 mmol) in NMP (1 mL) was added HCl in dioxane (4M, 0.5 mL) and the solution was stirred at 20deg.C for 15 min. The reaction mixture was cooled at 0deg.C and 2-cyclohexylacetyl chloride (0.36 mL,2.32 mmol) was added immediately. The reaction was stirred at 20℃for 16 hours. The reaction was diluted with ACN (2 mL) and purified by preparative HPLC to give 305 (8.40 mg,6.50% yield) as a white solid. MS (ESI): for a calculated m/z of C ₂₈H₃₅FN₆O₅ of 554.27, the actual measurement was 555.3[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ9.93(s,1H),8.12(s,1H),7.80(s,1H),7.36–7.17(m,5H),6.13(d,J＝20.0Hz,1H),5.62(s,1H),4.85(s,1H),4.48(dd,J＝12.4,2.0Hz,1H),4.39(dd,J＝12.4,7.2Hz,1H),4.05(t,J＝7.6Hz,1H),3.68(s,2H),2.93(s,3H),2.36(s,2H),1.79–1.57(m,6H),1.24–1.08(m,6H),0.98–0.90(m,2H).

Synthesis of((2R, 3R,4R, 5R) -5- (2- (2-cyclohexylacetamido) -6- (methylamino) -9H-purin-9-yl) -3- (2-cyclohexylacetoxy) -4-fluoro-4-methyltetrahydrofuran-2-yl) methyl 2-phenylacetate (Compound 306).

/>

To a solution of 177 (100 mg,0.23 mmol) in NMP (1 mL) was added HCl in dioxane (4M, 0.5 mL) and the solution was stirred at 20deg.C for 15 min. The reaction mixture was cooled at 0deg.C and 2-cyclohexylacetyl chloride (0.36 mL,2.32 mmol) was added immediately. The reaction was stirred at 20℃for 16 hours. The reaction was diluted with ACN (2 mL) and purified by preparative HPLC to give 306 (12.0 mg,7.62% yield) as a white solid. MS (ESI): for a calculated m/z of C ₃₆H₄₇FN₆O₆ of 678.35, the actual measurement was 679.43[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ9.91(s,1H),8.15(s,1H),7.85(s,1H),7.40–7.09(m,5H),6.23(d,J＝20.0Hz,2H),4.47(d,J＝5.2Hz,2H),4.31(dt,J＝9.6,5.2Hz,1H),3.67(s,2H),2.94(s,3H),2.28(d,J＝6.8Hz,2H),1.75–1.57(m,12H),0.99–0.83(m,11H),1.01–0.86(m,4H).¹⁹F NMR(376MHz,DMSO)δ-155.45.

Synthesis of((2R, 3R,4R, 5R) -4-fluoro-3-hydroxy-4-methyl-5- (6- (methylamino) -2- (2-phenylacetamido) -9H-purin-9-yl) tetrahydrofurane-2-yl) methyl 2-phenylacetate (Compound 307).

To a solution of 177 (100 mg,0.23 mmol) in NMP (1 mL) was added HCl in dioxane (4M, 0.5 mL) and the solution was stirred at 20deg.C for 15 min. The reaction mixture was cooled at 0deg.C and 2-phenylacetyl chloride (0.25 mL,1.85 mmol) was added immediately. The reaction was stirred at 20℃for 16 hours. The reaction was diluted with ACN (2 mL) and purified by preparative HPLC to give 307 (13.6 mg,10.3% yield) as a white solid. MS (ESI): for a calculated m/z of C ₂₈H₂₉FN₆O₅ of 548.22, the actual measurement was 549.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.24(s,1H),8.13(s,1H),7.84(s,1H),7.35–7.17(m,10H),6.13(d,J＝20.0Hz,1H),5.64(s,1H),4.85(s,1H),4.52–4.43(m,1H),4.37(dd,J＝12.4,7.6Hz,1H),4.04(t,J＝7.6Hz,1H),3.81(s,2H),3.68(s,2H),2.93(s,3H),1.11(d,J＝22.8Hz,3H).

Synthesis of (2R, 3R,4R, 5R) -4-fluoro-4-methyl-5- (6- (methylamino) -2- (2-phenylacetamido) -9H-purin-9-yl) -2- ((2-phenylacetoxy) methyl) tetrahydrofuran-3-yl 2-phenylacetate (Compound 308).

To a solution of 177 (100 mg,0.23 mmol) in NMP (1 mL) was added HCl in dioxane (4M, 0.5 mL) and the solution was stirred at 20deg.C for 15 min. The reaction mixture was cooled at 0deg.C and 2-phenylacetyl chloride (0.25 mL,1.85 mmol) was added immediately. The reaction was stirred at 20℃for 16 hours. The reaction was diluted with ACN (2 mL) and purified by preparative HPLC to give 308 (22.1 mg,13.9% yield) as a white solid. MS (ESI): for a calculated m/z of C ₃₆H₃₅FN₆O₆ of 666.26, the actual measurement was 667.2[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.18(s,1H),8.16(s,1H),7.89(s,1H),7.33–7.17(m,15H),6.24(m,2H),4.49–4.39(m,2H),4.34(dt,J＝9.6,4.8Hz,1H),3.86–3.74(m,4H),3.69–3.61(m,2H),2.93(s,3H),1.14(d,J＝23.2Hz,3H).

Synthesis of (2R, 3R,4R, 5R) -4-fluoro-4-methyl-5- (6- (methylamino) -2-propionamido-9H-purin-9-yl) -2- ((propionyloxy) methyl) tetrahydrofuran-3-yl propionate (Compound 309).

The title compound was prepared according to the procedure for example 293 using 180 and propionyl chloride. MS (ESI): for a calculated m/z of C ₂₁H₂₉FN₆O₆ of 480.21, the actual measurement was 481.10[M+H]⁺.¹H NMR(400MHz,DMSO)δ9.87(s,1H),8.19(s,1H),7.89(s,1H),6.23(d,J＝19.6Hz,1H),6.09(d,J＝15.2Hz,1H),4.51–4.24(m,3H),2.95(s,3H),2.59–2.51(m,2H),2.45(q,J＝7.2Hz,2H),2.32(q,J＝7.2Hz,2H),1.26–0.96(m,12H).¹⁹F NMR(377MHz,DMSO)δ-155.56.

Synthesis of (2R, 3R,4R, 5R) -5- (2-amino-6- (methylamino) -9H-purin-9-yl) -4-fluoro-4-methyl-2- (((3-methylbutanoyl) oxy) methyl) tetrahydrofuran-3-yl 3-methylbutanoate (Compound 312).

The title compound was prepared according to the procedure for example 183 using 174 and 3-methylbutyryl chloride. MS (ESI): for a calculated m/z of C ₂₂H₃₃FN₆O₅ of 480.25, the actual measurement was 481.25[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.89(s,1H),7.39(s,1H),6.13(d,J＝19.6Hz,1H),6.04–5.76(m,3H),4.50–4.40(m,1H),4.40–4.26(m,2H),2.87(s,3H),2.33(dd,J＝7.6,1.2Hz,2H),2.26–2.19(m,2H),2.08–1.92(m,2H),1.14(d,J＝22.8Hz,3H),0.99–0.85(m,12H).¹⁹F NMR(377MHz,DMSO)δ-156.35.

Example 157 Synthesis of (2R, 3R,4R, 5R) -4-fluoro-4-methyl-5- (6- (methylamino) -2- (3-methylbutanamino) -9H-purin-9-yl) -2- (((3-methylbutananyl) oxy) methyl) tetrahydrofuran-3-yl 3-methylbutanoate (Compound 313).

/>

The title compound was prepared according to the procedure for example 293 using 174 and 3-methylbutyryl chloride. MS (ESI): for a calculated m/z of C ₂₇H₄₁FN₆O₆ of 564.31, the actual measurement was 565.40[M+H]⁺.¹H NMR(400MHz,DMSO)δ9.90(s,1H),8.17(s,1H),7.86(s,1H),6.40–6.10(m,2H),4.45(d,J＝5.2Hz,2H),4.35–4.25(m,1H),2.94(s,3H),2.40–2.27(m,4H),2.17(d,J＝7.2Hz,2H),2.10–1.89(m,3H),1.18(d,J＝23.2Hz,3H),0.98–0.85(m,18H).¹⁹F NMR(377MHz,DMSO)δ-155.56.

Synthesis of((2R, 3R,4R, 5R) -5- (2- (2-cyclohexylacetamido) -6- (methylamino) -9H-purin-9-yl) -4-fluoro-3-hydroxy-4-methyltetrahydrof-n-2-yl) methyl 3-methylbutanoate (Compound 314).

To a solution of 174 (100 mg,0.25 mmol) in NMP (1 mL) was added HCl in dioxane (4M, 0.5 mL) and the solution was stirred at 20deg.C for 15 min. The reaction mixture was cooled at 0deg.C, and 2-cyclohexylacetyl chloride (0.39 mL,2.52 mmol) was added immediately. The reaction was stirred at 20℃for 48 hours. The reaction was diluted with ACN (2 mL) and purified by preparative HPLC to give 314 as a white solid (7.30 mg,5.55% yield). MS (ESI): for a calculated m/z of C ₂₅H₃₇FN₆O₅ of 520.28, the actual measurement was 521.3[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ9.93(s,1H),8.12(s,1H),7.81(s,1H),6.12(d,J＝20.0Hz,1H),5.62(s,1H),4.82(s,1H),4.55–4.41(m,1H),4.35(dd,J＝12.4,7.6Hz,1H),4.04(t,J＝8.0Hz,1H),2.93(s,3H),2.38–2.33(m,2H),2.18(d,J＝7.2Hz,2H),1.96–1.91(m,1H),1.84–1.59(m,6H),1.23–1.10(m,6H),1.00–0.91(m,2H),0.88(dd,J＝6.8,1.2Hz,6H).

Synthesis of((2R, 3R,4R, 5R) -5- (2- (2-cyclohexylacetamido) -6- (methylamino) -9H-purin-9-yl) -3- (2-cyclohexylacetoxy) -4-fluoro-4-methyltetrahydrofuran-2-yl) methyl 3-methylbutanoate (Compound 315).

To a solution of 174 (100 mg,0.25 mmol) in NMP (1 mL) was added HCl in dioxane (4M, 0.5 mL) and the solution was stirred at 20deg.C for 15 min. The reaction mixture was cooled at 0deg.C, and 2-cyclohexylacetyl chloride (0.39 mL,2.52 mmol) was added immediately. The reaction was stirred at 20℃for 48 hours. The reaction was diluted with ACN (2 mL) and purified by preparative HPLC to give 315 (35.4 mg,21.4% yield) as a white solid. MS (ESI): for a calculated m/z of C ₃₃H₄₉FN₆O₆ of 644.37, the actual measurement was 645.4[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ9.90(s,1H),8.16(s,1H),7.85(s,1H),6.22(d,J＝19.6Hz,2H),4.51–4.37(m,2H),4.35–4.26(m,1H),2.94(s,3H),2.30(d,J＝6.8Hz,2H),2.17(d,J＝7.2Hz,2H),1.95(dt,J＝14.0,6.8Hz,1H),1.77–1.57(m,12H),1.20–1.14(m,10H),1.05–0.91(m,4H),0.88(dd,J＝6.8,0.8Hz,6H).

Synthesis of (+) - (2R, 3R,4R, 5R) -5- (2-acetamido-6- (methylamino) -9H-purin-9-yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methylpropionate (Compound 317).

The title compound was prepared from example 220. MS (ESI): for a calculated m/z of C ₁₇H₂₃FN₆O₅ of 410.17, the actual measurement was 411.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.01(s,1H),8.12(s,1H),7.84(s,1H),6.12(d,J＝19.6Hz,1H),5.70–5.60(m,1H),4.91–4.70(br,1H),4.49–4.43(m,1H),4.39–4.32(m,1H),4.07–4.01(m,1H),2.93(s,3H),2.35–2.29(m,2H),2.19(s,3H),1.13(d,J＝22.8Hz,3H),1.01(t,J＝7.6Hz,3H).¹⁹F NMR(377MHz,DMSO)δ-158.46.

Synthesis of((2R, 3R,4R, 5R) -5- (2-acetamido-6- (methylamino) -9H-purin-9-yl) -3-acetoxy-4-fluoro-4-methyltetrahydrofuran-2-yl) methylpropionate (Compound 318).

The title compound was prepared from example 220. MS (ESI): for a calculated m/z of C ₁₉H₂₅FN₆O₆ of 452.18, the actual measurement was 453.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ9.93(s,1H),8.18(s,1H),7.90(s,1H),6.23(d,J＝20.0Hz,1H),6.17–5.98(m,1H),4.47–4.38(m,2H),4.35–4.29(m,1H),2.93(s,3H),2.35–2.28(m,2H),2.20(s,3H),2.14(s,3H),1.17(d,J＝23.2Hz,3H),1.01(t,J＝7.6Hz,3H).¹⁹F NMR(377MHz,DMSO)δ-155.35.

Synthesis of (2R, 3R,4R, 5R) -4-fluoro-4-methyl-5- (6- (methylamino) -2- (3-methylbutanamino) -9H-purin-9-yl) -2- ((propionyloxy) methyl) tetrahydrofuran-3-yl 3-methylbutanoate (Compound 320).

The title compound was prepared according to the procedure for example 293 using 180 and 3-methylbutyryl chloride. MS (ESI): for a calculated m/z of C ₂₅H₃₇FN₆O₆ of 536.28, the actual measurement was 537.15[M+H]⁺.¹H NMR(400MHz,DMSO)δ9.90(s,1H),8.18(s,1H),7.86(s,1H),6.23(d,J＝19.6Hz,2H),4.44(d,J＝4.8Hz,2H),4.36–4.27(m,1H),2.94(s,3H),2.39–2.25(m,6H),2.11–1.96(m,2H),1.18(d,J＝23.2Hz,3H),1.00(t,J＝7.2Hz,3H),0.95(dd,J＝6.8,1.6Hz,6H),0.91(dd,J＝6.4,0.4Hz,6H).¹⁹F NMR(377MHz,DMSO)δ-155.51.

Synthesis of (+) -2R, 3R,4R, 5R) -5- (2- (2-cyclohexylacetamido) -6- (methylamino) -9H-purin-9-yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methylpropionate (Compound 321).

To a solution of 180 (100 mg,0.27 mmol) in NMP (1 mL) was added HCl in dioxane (4M, 0.5 mL) and the solution was stirred at 20deg.C for 15 min. The reaction mixture was cooled at 0deg.C and 2-cyclohexylacetyl chloride (0.33 mL,2.17 mmol) was added immediately. The reaction was stirred at 20℃for 16 hours. The reaction was diluted with ACN (2 mL) and purified by preparative HPLC to give 321 (12.0 mg,8.99% yield) as a white solid. MS (ESI): for a calculated m/z of C ₂₃H₃₃FN₆O₅ of 492.25, the actual measurement was 493.2[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ9.92(s,1H),8.12(s,1H),7.81(s,1H),6.12(d,J＝20.0Hz,1H),5.63(d,J＝6.4Hz,1H),4.82(s,1H),4.45(dd,J＝12.4,2.0Hz,1H),4.36(dd,J＝12.4,7.2Hz,1H),4.05(t,J＝7.6Hz,1H),2.93(s,3H),2.32(d,J＝7.6Hz,2H),1.81–1.59(m,7H),1.32–1.07(m,7H),1.03–0.92(m,5H).

Synthesis of (((2R, 3R,4R, 5R) -5- (2- (2-cyclohexylacetamido) -6- (methylamino) -9H-purin-9-yl) -3- (2-cyclohexylacetoxy) -4-fluoro-4-methyltetrahydrofuran-2-yl) methylpropionate (Compound 322).

/>

To a solution of 180 (100 mg,0.27 mmol) in NMP (1 mL) was added HCl in dioxane (4M, 0.5 mL) and the solution was stirred at 20deg.C for 15 min. The reaction mixture was cooled at 0deg.C and 2-cyclohexylacetyl chloride (0.33 mL,2.17 mmol) was added immediately. The reaction was stirred at 20℃for 16 hours. The reaction was diluted with ACN (2 mL) and purified by preparative HPLC to give 322 (31.8 mg,19.0% yield) as a white solid. MS (ESI): for a calculated m/z of C ₃₁H₄₅FN₆O₆ of 616.34, the actual measurement was 617.3[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ9.90(s,1H),8.17(s,1H),7.85(s,1H),6.35–6.20(m,2H),4.47–4.40(m,2H),4.31(dt,J＝9.6,5.2Hz,1H),2.94(s,3H),2.35–2.26(m,5H),1.80–1.58(m,12H),1.30–1.09(m,10H),1.02–0.92(m,7H).¹⁹F NMR(376MHz,DMSO)δ-155.52.

Synthesis of((2R, 3R,4R, 5R) -5- (2-acetamido-6- (methylamino) -9H-purin-9-yl) -3-acetoxy-4-fluoro-4-methyltetrahydrofuran-2-yl) methyl 3-methylbutanoate (Compound 324).

The title compound was prepared from example 214. MS (ESI): for a calculated m/z of C ₂₁H₂₉FN₆O₆ of 480.21, the actual measurement was 481.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ9.92(s,1H),8.17(s,1H),7.90(s,1H),6.23(d,J＝20.0Hz,1H),6.17–5.99(m,1H),4.48–4.38(m,2H),4.34–4.28(m,1H),2.94(s,3H),2.22–2.13(m,8H),2.00–1.92(m,1H),1.17(d,J＝22.8Hz,3H),0.89(dd,J＝6.4,1.2Hz,6H).¹⁹F NMR(377MHz,DMSO)δ-155.37.

Synthesis of((2R, 3R,4R, 5R) -4-fluoro-5- (2-isobutyramide-6- (methylamino) -9H-purin-9-yl) -3- (isobutyryloxy) -4-methyltetrahydrofuran-2-yl) methyl 3-methylbutanoate (Compound 325).

The title compound was prepared from example 222. MS (ESI): for a calculated m/z of C ₂₅H₃₇FN₆O₆ of 536.28, the actual measurement was 537.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ9.89(s,1H),8.17(s,1H),7.86(s,1H),6.34–5.96(m,2H),4.47–4.36(m,2H),4.35–4.29(m,1H),2.94(s,3H),2.71–2.63(m,1H),2.18(d,J＝7.2Hz,2H),2.01–1.90(m,1H),1.21–1.12(m,9H),1.06(dd,J＝6.8,4.0Hz,6H),0.88(dd,J＝6.8,2.0Hz,6H).¹⁹F NMR(377MHz,DMSO)δ-156.11.

Synthesis of((2R, 3R,4R, 5R) -5- (2-acetamido-6- (methylamino) -9H-purin-9-yl) -3-acetoxy-4-fluoro-4-methyltetrahydrofuran-2-yl) methyl 2-cyclohexylacetate (Compound 326).

The title compound was prepared from example 215. MS (ESI): for a calculated m/z of C ₂₄H₃₃FN₆O₆ of 520.24, the actual measurement was 521.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ9.90(s,1H),8.17(s,1H),7.91(s,1H),6.23(d,J＝19.6Hz,1H),6.08(d,J＝18.4Hz,1H),4.47–4.35(m,2H),4.33–4.27(m,1H),2.94(s,3H),2.26–2.08(m,8H),1.68–1.53(m,6H),1.25–1.03(m,6H),0.96–0.83(m,2H).¹⁹F NMR(377MHz,DMSO)δ-155.31.

Synthesis of((2R, 3R,4R, 5R) -5- (2-acetamido-6- (methylamino) -9H-purin-9-yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methylacetate (Compound 328).

To a solution of 3 (700 mg,2.24 mmol) in DMA (3 mL) was added HCl/dioxane (1.1 mL, 4M). The mixture solution was stirred at 20℃for 15 minutes. The reaction mixture was cooled at 0deg.C and acetyl chloride (1.27 mL,17.9 mmol) was added immediately. The reaction was stirred at 0 ℃ for 1 hour. The reaction was diluted with ACN (4.0 mL) and purified by preparative HPLC to give 328 (12.6 mg,1.35% yield) as a white solid. MS (ESI): for a calculated m/z of C ₁₆H₂₁FN₆O₅ of 396.16, the actual measurement was 397.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.01(s,1H),8.13(s,1H),7.83(d,J＝10.4Hz,1H),6.12(d,J＝20.0Hz,1H),5.65(d,J＝7.2Hz,1H),4.82(s,1H),4.45(dd,J＝12.4,2.0Hz,1H),4.34(dd,J＝12.4,7.6Hz,1H),4.05(t,J＝7.6Hz,1H),2.93(s,3H),2.19(s,3H),2.01(s,3H),1.17–1.09(m,3H).¹⁹F NMR(376MHz,DMSO)δ-158.32(s,1H).

Synthesis of (2R, 3R,4R, 5R) -2- (acetoxymethyl) -5- (2-amino-6- (methylamino) -9H-purin-9-yl) -4-fluoro-4-methyltetrahydrof-n-3-ylpropionate (Compound 329), ((2R, 3R,4R, 5R) -4-fluoro-3-hydroxy-4-methyl-5- (6- (methylamino) -2-propionamido-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate (Compound 330) and (2R, 3R,4R, 5R) -2- (acetoxymethyl) -4-fluoro-4-methyl-5- (6- (methylamino) -2-propionamido-9H-purin-9-yl) tetrahydrofuran-3-yl propionate (Compound 331).

The title compounds 329, 330 and 331 were prepared according to the procedure of step 1 of example 65 using 178 and propionyl chloride.

For compound 329: MS (ESI): the calculated mass for C ₁₇H₂₃FN₆O₅ was 410.17 and the measured m/z was 411.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.90(s,1H),7.38(s,1H),6.13(d,J＝19.6Hz,1H),5.97(d,J＝29.2Hz,3H),4.53–4.39(m,1H),4.38–4.25(m,2H),2.88(s,3H),2.48–2.43(m,2H),2.06–2.00(m,3H),1.15(d,J＝22.8Hz,6H),1.08(t,J＝7.6Hz,3H).¹⁹F NMR(376MHz,DMSO)δ-156.37.

For compound 330: MS (ESI): the calculated mass for C ₁₇H₂₃FN₆O₅ was 410.17 and the measured m/z was 411.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ9.94(s,1H),8.12(s,1H),7.81(s,1H),6.12(d,J＝20.0Hz,1H),5.65(d,J＝6.4Hz,1H),4.78(s,1H),4.44(dd,J＝12.4,2.0Hz,1H),4.35(dd,J＝12.4,7.2Hz,1H),4.06(d,J＝7.6Hz,1H),2.93(s,3H),2.52(s,2H),2.01(s,3H),1.16–1.03(m,6H).

For compound 331: MS (ESI): the calculated mass for C ₂₀H₂₇FN₆O₆ was 466.20 and the m/z found was 467.1[ M+H ] ⁺.¹⁹ F NMR (376 MHz, DMSO) delta-155.50.

Synthesis of (2R, 3R,4R, 5R) -2- (acetoxymethyl) -4-fluoro-4-methyl-5- (6- (methylamino) -2- (3-methylbutanamino) -9H-purin-9-yl) tetrahydrofuran-3-yl 3-methylbutanoate (Compound 332).

The title compound was prepared according to the procedure for example 293 using 178 and 3-methylbutyryl chloride. MS (ESI): for a calculated m/z of C ₂₄H₃₅FN₆O₆ of 522.26, the actual measurement was 523.15[M+H]⁺.¹H NMR(400MHz,DMSO)δ9.90(s,1H),8.18(s,1H),7.86(s,1H),6.23(d,J＝19.6Hz,2H),4.49–4.38(m,2H),4.36–4.28(m,1H),2.94(s,3H),2.40–2.26(m,4H),2.11–1.96(m,5H),1.18(d,J＝23.2Hz,3H),0.98–0.83(m,12H).¹⁹F NMR(377MHz,DMSO)δ-155.47.

Synthesis of (2R, 3R,4R, 5R) -2- (acetoxymethyl) -5- (2- (2-cyclohexylacetamido) -6- (methylamino) -9H-purin-9-yl) -4-fluoro-4-methyltetrahydrofuran-3-yl 2-cyclohexylacetate (Compound 333).

To a solution of 178 (100 mg,0.28 mmol) in NMP (1 mL) was added HCl in dioxane (4M, 0.5 mL) and the solution was stirred at 20deg.C for 15min. The reaction mixture was cooled at 0deg.C and 2-cyclohexylacetyl chloride (0.35 mL,2.25 mmol) was added immediately. The reaction was stirred at 20℃for 16 hours. The reaction was diluted with ACN (2 mL) and purified by preparative HPLC to give 333 (35.5 mg,20.6% yield) as a white solid. MS (ESI): for a calculated m/z of C ₃₀H₄₃FN₆O₆ of 602.32, the actual measurement was 603.4[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ9.90(s,1H),8.17(s,1H),7.85(s,1H),6.25–6.19(m,2H),4.41(d,J＝5.2Hz,2H),4.33–4.28(m,1H),2.94(s,3H),2.38–2.26(m,4H),2.00(s,3H),1.74–1.60(m,11H),1.32–1.05(m,10H),1.05–0.87(m,4H).¹⁹F NMR(376MHz,DMSO)δ-155.48.

Synthesis of((2R, 3R,4R, 5R) -4-fluoro-3-hydroxy-4-methyl-5- (6- (methylamino) -2- (2-phenylacetamido) -9H-purin-9-yl) tetrahydrofurane-2-yl) methylacetate (Compound 334).

The title compound was prepared from example 210. MS (ESI): for a calculated m/z of C ₂₂H₂₅FN₆O₅ of 472.19, the actual measurement was 473.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.23(s,1H),8.13(s,1H),7.84(s,1H),7.35–7.28(m,4H),7.25–7.20(m,1H),6.12(d,J＝20.0Hz,1H),5.64(s,1H),4.80(s,1H),4.45–4.38(m,1H),4.35–4.29(m,1H),4.07–4.01(m,1H),3.82(s,2H),2.93(s,3H),2.01(s,3H),1.11(d,J＝22.4Hz,3H).¹⁹F NMR(377MHz,DMSO)δ-158.02.

Example 173 synthesis of ((2 r,3r,4r,5 r) -4-fluoro-3-hydroxy-4-methyl-5- (6- (methylamino) -2- (2-phenylacetamido) -9H-purin-9-yl) tetrahydrofurane-2-yl) methylpropionate (compound 336).

The title compound was prepared from example 212. MS (ESI): for a calculated m/z of C ₂₃H₂₇FN₆O₅ of 486.20, the actual measurement was 487.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.23(s,1H),8.13(s,1H),7.84(s,1H),7.35–7.20(m,5H),6.12(d,J＝20.0Hz,1H),5.64(d,J＝6.0Hz,1H),4.79(s,1H),4.47–4.30(m,2H),4.07–4.00(m,1H),3.82(s,2H),2.93(s,3H),2.32(q,J＝7.6Hz,2H),1.11(d,J＝22.4Hz,3H),1.01(t,J＝7.6Hz,3H).¹⁹F NMR(377MHz,DMSO)δ-158.58.

Synthesis of (((2R, 3R,4R, 5R) -4-fluoro-4-methyl-5- (6- (methylamino) -2- (2-phenylacetamido) -9H-purin-9-yl) -3- (2-phenylacetoxy) tetrahydrofuran-2-yl) methylpropionate (Compound 337).

The title compound was prepared from example 212. MS (ESI): for a calculated m/z of C ₃₁H₃₃FN₆O₆ of 604.24, the actual measurement was 605.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.17(s,1H),8.18(s,1H),7.89(s,1H),7.36–7.18(m,10H),6.23(d,J＝19.6Hz,2H),4.42–4.30(m,3H),3.82(s,4H),2.92(s,3H),2.28(q,J＝7.6Hz,2H),1.14(d,J＝23.2Hz,3H),0.99(t,J＝7.6Hz,3H).¹⁹F NMR(377MHz,DMSO)δ-155.42.

Synthesis of((2R, 3R,4R, 5R) -5- (2-acetamido-6- (methylamino) -9H-purin-9-yl) -3-acetoxy-4-fluoro-4-methyltetrahydrofuran-2-yl) methyl 2-phenylacetate (Compound 338).

The title compound was prepared from compound 217. MS (ESI): for a calculated m/z of C ₂₄H₂₇FN₆O₆ of 514.20, the actual measurement was 515.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ9.93(s,1H),8.16(s,1H),7.89(s,1H),7.33–7.22(m,5H),6.24(d,J＝20.0Hz,1H),6.11(s,1H),4.50–4.41(m,2H),4.35–4.29(m,1H),3.68(s,2H),2.93(s,3H),2.19(s,3H),2.13(s,3H),1.17(d,J＝23.2Hz,3H).¹⁹F NMR(377MHz,DMSO)δ-155.20.

Synthesis of (((2R, 3S,4R, 5R) -5-cyano-3, 4-dihydroxy-5- (4- (((pentoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuranyl) methyl L-valine ester (Compound 86).

Synthesis of (7- ((3 aR,4R,6 aR) -4-cyano-6- (hydroxymethyl) -2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) carbamic acid pentyl ester (86.1).

The title compound 86.1 was prepared according to the procedure for step 1 of example 58 using 81.1. MS (ESI): for a calculated mass of C ₂₁H₂₇N₅O₆ of 445.20m/z, the actual measurement was 446.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.97(s,1H),8.39(s,1H),7.30(d,J＝4.4Hz,1H),7.11(d,J＝4.8Hz,1H),5.35(d,J＝6.4Hz,1H),5.03(t,J＝5.6Hz,1H),4.90(dd,J＝6.4,2.8Hz,1H),4.36(dd,J＝8.0,5.2Hz,1H),4.18(t,J＝6.8Hz,2H),3.59–3.45(m,2H),1.72–1.63(m,5H),1.35(dd,J＝14.0,10.8Hz,7H),0.90(t,J＝7.2Hz,3H).

Synthesis of (((3 aR,4R,6 aR) -6-cyano-2, 2-dimethyl-6- (4- (((pentoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) methyl (tert-butoxycarbonyl) -L-valine ester (86.2).

The title compound 86.2 was prepared according to the procedure for step 1 of example 19 using 86.1 and (tert-butoxycarbonyl) -L-valine. MS (ESI): the calculated mass for C ₃₁H₄₄N₆O₉ was 644.32 and the measured m/z was 645.5[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.93(s,1H),8.42(s,1H),7.32(d,J＝4.8Hz,1H),7.14(d,J＝8.0Hz,1H),7.06(d,J＝4.8Hz,1H),5.42(d,J＝6.4Hz,1H),4.93(dd,J＝6.4,2.8Hz,1H),4.61(s,1H),4.29–4.10(m,4H),3.76(s,1H),1.82(dd,J＝13.2,6.8Hz,1H),1.76–1.60(m,5H),1.41–1.22(m,16H),0.90(t,J＝7.2Hz,3H),0.77(dd,J＝13.2,6.8Hz,6H).

Synthesis of (((2R, 3S,4R, 5R) -5-cyano-3, 4-dihydroxy-5- (4- (((pentoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuranyl) 2-methyl L-valine ester (86).

The title compound 86 was prepared according to the procedure of step 2 of example 19 using 86.2. MS (ESI): the calculated mass for C ₂₃H₃₂N₆O₇ was 504.23, the measured m/z was 505.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.35(s,1H),7.31(d,J＝4.8Hz,1H),7.04(d,J＝4.8Hz,1H),6.45(s,1H),5.46(s,1H),4.69(s,1H),4.33–4.25(m,3H),4.18(t,J＝6.8Hz,2H),3.95(s,1H),3.21(d,J＝5.2Hz,1H),1.84–1.75(m,1H),1.71–1.64(m,2H),1.41–1.31(m,4H),0.90(t,J＝7.2Hz,3H),0.82(d,J＝6.8Hz,3H),0.78(d,J＝6.8Hz,3H).

EXAMPLE 177((2R, 3S,4R, 5R) -5- (4- ((S) -2-amino-3- (4-fluorophenyl) propanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl L-valine ester (compound 94).

Synthesis of((3 aR,4R,6 aR) -6- (4- ((S) -2- ((tert-butoxycarbonyl) amino) -3- (4-fluorophenyl) propanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) methyl (tert-butoxycarbonyl) -L-valine ester (94.1).

A solution of (tert-butoxycarbonyl) -L-valine (37 mg,0.17 mmol), EDCI (48 mg,0.25 mmol), HOBT (34 mg,0.25 mmol) and DIEA (65 mg,0.50 mmol) in dry DMF (1.0 mL) was stirred at 20℃for 1h. 97.1 (100 mg,0.17 mmol) was then added to the flask. The reaction mixture was stirred at 20℃for 16h. The reaction mixture was purified by preparative HPLC (0.1% FA) to give 94.1 (71 mg,53% yield) as a white solid. MS (ESI): the calculated mass for C ₃₉H₅₀FN₇O₁₀ was 795.36 and the measured m/z was 796.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ11.21(s,1H),8.52(s,1H),7.42(dd,J＝7.2,5.2Hz,2H),7.33–7.20(m,2H),7.16–7.07(m,4H),5.43(d,J＝6.4Hz,1H),4.96–4.77(m,2H),4.67–4.60(m,1H),4.30–4.11(m,2H),3.76(t,J＝7.2Hz,1H),3.13–3.01(m,1H),2.81(dd,J＝13.2,11.2Hz,1H),1.86–1.75(m,1H),1.66(s,3H),1.38(s,3H),1.36–1.22(m,18H),0.77(dd,J＝14.4,6.8Hz,6H).¹⁹F NMR(377MHz,DMSO)δ-116.72(s,1F).

Synthesis of (((2R, 3S,4R, 5R) -5- (4- ((S) -2-amino-3- (4-fluorophenyl) propanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl L-valine ester (94).

To a solution of 94.1 (71 mg,0.089 mmol) in THF (0.8 mL) was added dropwise concentrated HCl (0.4 mL, 12M) at 0deg.C. The reaction mixture was stirred at 0 ℃ for 2h. The organic solvent was removed with flowing nitrogen. The residue was purified by preparative HPLC (0.1% FA) to give the crude product. The crude product was dissolved with THF and the pH was adjusted to 8 with saturated aqueous NaHCO ₃. The organic solvent was removed with flowing nitrogen and the residue was purified by preparative HPLC (0.1% FA) to give compound 94 (8.69 mg,18% yield) as a white solid. MS (ESI): the calculated mass for C ₂₆H₃₀FN₇O₆ was 555.22 and the measured m/z was 556.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.58(d,J＝8.0Hz,1H),7.91(s,1H),7.39(dd,J＝8.4,5.6Hz,2H),7.09–7.02(m,3H),6.81(d,J＝4.4Hz,1H),6.36(s,1H),5.39(s,1H),4.97–4.89(m,1H),4.64(d,J＝4.8Hz,1H),4.32–4.18(m,3H),3.92(t,J＝5.2Hz,1H),3.20–3.12(m,2H),3.02(dd,J＝13.6,11.6Hz,2H),1.82–1.71(m,1H),0.79(dd,J＝20.8,6.4Hz,6H).¹⁹F NMR(377MHz,DMSO)δ-116.75(s,1F).

Synthesis of((2R, 3S,4R, 5R) -5- (4- ((S) -2-amino-3- (4-fluorophenyl) propanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl acetate (Compound 95).

Synthesis of((3 aR,4R,6 aR) -6- (4- ((S) -2- ((tert-butoxycarbonyl) amino) -3- (4-fluorophenyl) propanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) methyl acetate (95.1).

To a solution of 97.1 (100 mg,0.17 mmol) in DMPU (1.0 mL) was added HCl/1, 4-dioxane (0.1 mL, 4M) at 0deg.C under nitrogen. The reaction mixture was stirred at 0deg.C for 30min, then acetyl chloride (105 mg,1.33 mmol) was added dropwise. The reaction mixture was stirred at 20℃for 3h. The reaction mixture was purified by preparative HPLC (0.1% FA) to give 95.1 (58 mg,54% yield) as a white solid. MS (ESI): the calculated mass for C ₃₁H₃₅FN₆O₈ was 638.25 and the m/z found was 639.2[ M+H ] ⁺.

Synthesis of((2R, 3S,4R, 5R) -5- (4- ((S) -2-amino-3- (4-fluorophenyl) propanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl acetate (95).

To a solution of 95.1 (58 mg,0.09 mmol) in THF (0.6 mL) was added dropwise concentrated HCl (0.3 mL, 12M) at 0deg.C. The reaction mixture was stirred at 0 ℃ for 2h. The organic solvent was removed with flowing nitrogen. The residue was purified by preparative HPLC (0.1% FA) to give the crude product. The crude product was dissolved with THF and the pH was adjusted to 8 with saturated aqueous NaHCO ₃. The organic solvent was removed with flowing nitrogen and the residue was purified by preparative HPLC (0.1% FA) to give compound 95 (9.32 mg,21% yield) as a white solid. MS (ESI): for a calculated m/z of C ₂₃H₂₃FN₆O₆ of 498.17, the actual measurement was 499.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.56(d,J＝8.4Hz,1H),7.91(s,1H),7.69(s,1H),7.39(dd,J＝8.4,5.6Hz,2H),7.18(s,1H),7.10–7.03(m,3H),6.80(d,J＝4.8Hz,1H),6.31(d,J＝6.0Hz,1H),5.38(d,J＝6.0Hz,1H),4.97–4.89(m,1H),4.66(t,J＝5.6Hz,1H),4.30(dd,J＝11.6,2.4Hz,1H),4.23–4.17(m,1H),4.12(dd,J＝12.0,6.0Hz,1H),3.91(dd,J＝11.6,6.4Hz,1H),3.18(dd,J＝14.0,3.6Hz,1H),3.07–2.98(dd,J＝13.6,11.2Hz,1H),1.99(s,3H).¹⁹F NMR(377MHz,DMSO)δ-116.75(s,1F).

Example 179((2R, 3S,4R, 5R) -5- (4- ((S) -2-amino-3- (4-fluorophenyl) propanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2-cyclohexylacetate (compound 96).

Synthesis of((3 aR,4R,6 aR) -6- (4- ((S) -2- ((tert-butoxycarbonyl) amino) -3- (4-fluorophenyl) propanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) methyl 2-cyclohexyl acetate (96.1).

The title compound was prepared according to the procedure for step 2 of example 58 using 97.1 and 2-cyclohexylacetyl chloride. MS (ESI): the calculated mass for C ₃₇H₄₅FN₆O₈ was 720.33 and the m/z found was 721.2[ M+H ] ⁺.

Synthesis of((2R, 3S,4R, 5R) -5- (4- ((S) -2-amino-3- (4-fluorophenyl) propanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2-cyclohexylacetate (96).

The title compound was prepared according to the procedure for step 2 of example 178 using 96.1. MS (ESI): the calculated mass for C ₂₉H₃₃FN₆O₆ was 580.24 and the measured m/z was 581.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.55(d,J＝8.4Hz,1H),7.91(s,1H),7.67(s,1H),7.39(dd,J＝8.4,5.6Hz,2H),7.17(s,1H),7.09–7.02(m,3H),6.79(d,J＝4.4Hz,1H),6.30(d,J＝6.0Hz,1H),5.36(d,J＝6.0Hz,1H),4.97–4.90(m,1H),4.66–4.61(m,1H),4.29(dd,J＝11.6,2.4Hz,1H),4.23–4.12(m,2H),3.91(dd,J＝11.2,6.4Hz,1H),3.17(dd,J＝14.0,3.6Hz,1H),3.03(dd,J＝13.6,11.2Hz,1H),2.16(d,J＝6.4Hz,2H),1.67–1.52(m,6H),1.24–0.99(m,3H),0.90(dd,J＝22.8,12.0Hz,2H).¹⁹F NMR(377MHz,DMSO)δ-116.77(s,1F).

EXAMPLE 180 (((2R, 3S,4R, 5R) -5- (4- ((S) -2-amino-3- (4-fluorophenyl) propanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methylpropionate (Compound 99).

Synthesis of (((3 aR,4R,6 aR) -6- (4- ((S) -2- ((tert-butoxycarbonyl) amino) -3- (4-fluorophenyl) propanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) methylpropionate (95.1).

The title compound was prepared according to the procedure for step 1 of example 178 using 97.1 and propionyl chloride. MS (ESI): the calculated mass for C ₃₂H₃₇FN₆O₈ was 652.27 and the measured m/z was 653.4[M+H]⁺.¹H NMR(400MHz,DMSO)δ11.32(s,1H),8.50(s,1H),7.49–7.36(dd,J＝7.6,6.0Hz,1H),7.32–7.05(m,5H),5.41(d,J＝6.0Hz,1H),4.98(dd,J＝6.0,2.4Hz,1H),4.91–4.76(m,1H),4.68–4.62(m,1H),4.23(dd,J＝12.0,4.0Hz,1H),4.10(dd,J＝12.0,5.6Hz,1H),3.09(dd,J＝14.4,3.2Hz,1H),2.87–2.74(m,1H),2.27–2.03(m,2H),1.66(s,3H),1.39(s,3H),1.37–1.13(m,11H),0.90(t,J＝7.6Hz,3H).¹⁹F NMR(377MHz,DMSO)δ-116.75(s,1F).

Synthesis of (((2R, 3S,4R, 5R) -5- (4- ((S) -2-amino-3- (4-fluorophenyl) propanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methylpropionate (99).

The title compound was prepared according to the procedure for step 2 of example 178 using 99.1. MS (ESI): the calculated mass for C ₂₄H₂₅FN₆O₆ was 512.18, the measured m/z was 513.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.55(d,J＝8.4Hz,1H),7.91(s,1H),7.39(dd,J＝7.2,6.0Hz,2H),7.10–7.01(m,3H),6.79(d,J＝4.4Hz,1H),6.32(d,J＝5.2Hz,1H),5.39(d,J＝4.4Hz,1H),4.97–4.88(m,1H),4.65(t,J＝4.8Hz,1H),4.35–4.28(m,1H),4.23–4.18(m,1H),4.13(dd,J＝12.0,5.2Hz,1H),3.95–3.89(m,1H),3.21–3.14(m,1H),3.07–2.98(m,1H),2.34–2.21(m,2H),0.97(t,J＝7.6Hz,3H).¹⁹F NMR(377MHz,DMSO)δ-116.75(s,1F).

Example 181 (((2 r,3S,4r,5 r) -5- (4- ((S) -2-amino-3- (4-fluorophenyl) propanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl isobutyrate (compound 100).

Synthesis of((3 aR,4R,6 aR) -6- (4- ((S) -2- ((tert-butoxycarbonyl) amino) -3- (4-fluorophenyl) propanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) methyl isobutyrate (100.1).

The title compound was prepared according to the procedure for step 1 of example 178 using 97.1 and isobutyryl chloride. MS (ESI): the calculated mass for C ₃₃H₃₉FN₆O₈ was 666.28 and the measured m/z was 667.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ11.20(s,1H),8.52(s,1H),7.42(dd,J＝8.0,6.0Hz,2H),7.30(d,J＝8.0Hz,1H),7.23(d,J＝4.4Hz,1H),7.15–7.06(m,3H),5.40(d,J＝6.0Hz,1H),4.98(dd,J＝6.4,2.8Hz,1H),4.85(br,1H),4.68–4.62(m,1H),4.22(dd,J＝12.0,4.0Hz,1H),4.10(dd,J＝12.0,5.6Hz,1H),3.08(dd,J＝13.6,3.6Hz,1H),2.81(dd,J＝13.2,10.8Hz,1H),2.43–2.34(m,1H),1.66(s,3H),1.39(s,3H),1.34–1.21(m,9H),0.96(dd,J＝18.0,7.2Hz,6H).

Synthesis of((2R, 3S,4R, 5R) -5- (4- ((S) -2-amino-3- (4-fluorophenyl) propanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl isobutyrate (100).

The title compound was prepared according to the procedure for step 2 of example 178 using 100.1. MS (ESI): the calculated mass for C ₂₅H₂₇FN₆O₆ was 526.20, the measured m/z was 527.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.58(d,J＝8.4Hz,1H),8.49(s,1H),7.91(s,1H),7.69(s,1H),7.39(dd,J＝8.4,6.0Hz,2H),7.16(s,1H),7.09–7.03(m,3H),6.79(d,J＝4.4Hz,1H),6.39(d,J＝4.4Hz,1H),5.43(d,J＝4.0Hz,1H),4.96–4.88(m,1H),4.65(t,J＝5.2Hz,1H),4.29(dd,J＝12.0,2.8Hz,1H),4.24–4.19(m,1H),4.13(dd,J＝12.0,4.8Hz,1H),3.97–3.91(m,1H),3.17(dd,J＝13.6,3.6Hz,1H),3.06–2.98(m,1H),2.48–2.42(m,1H),1.00(dd,J＝11.6,7.2Hz,6H).¹⁹F NMR(377MHz,DMSO)δ-116.79(s,1F).

Synthesis of (((2R, 3S,4R, 5R) -5- (4-benzoylamino pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl L-valine ester (Compound 102).

Synthesis of N- (7- ((3 aR,4R,6 aR) -4-cyano-6- (hydroxymethyl) -2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) benzamide (102.1).

Compound 102.1 was prepared according to the procedure of step 1 of example 58 using 85.1. MS (ESI): the calculated mass for C ₂₂H₂₁N₅O₅ was 435.15 and the m/z found was 436.1[ M+H ] ⁺.

((3 AR,4R,6 aR) -6- (4-benzoylamino pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) methyl (tert-butoxycarbonyl) -L-valine ester (102.2).

Compound 102.2 was prepared according to the procedure of step 1 of example 266 using 102.1 and (tert-butoxycarbonyl) -L-valine. MS (ESI): the calculated mass for C ₃₂H₃₈N₆O₈ was 634.69 and the m/z found was 635.2[ M+H ] ⁺.

Synthesis of((2R, 3S,4R, 5R) -5- (4-benzoylamino pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl L-valine ester (Compound 102).

Compound 102 was prepared according to the procedure of step 3 of example 112 using 102.2. MS (ESI): synthesis of (((2R, 3S,4R, 5R) -5- (4- ((S) -2-amino-3-methylbutanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methylpropionate (compound 115) with calculated mass of C ₂₄H₂₆N₆O₆ of 494.51, m/z found 495.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.39(s,1H),8.06(d,J＝7.2Hz,2H),7.67(t,J＝7.2Hz,1H),7.56(t,J＝7.6Hz,2H),7.18(d,J＝4.8Hz,1H),7.09(d,J＝4.0Hz,1H),6.52(d,J＝6.0Hz,1H),5.54(d,J＝5.6Hz,1H),4.74(t,J＝5.2Hz,1H),4.42(d,J＝4.4Hz,2H),4.34-4.32(m,1H),4.03–3.95(m,1H),3.80(d,J＝4.0Hz,1H),2.05-2.03(m,1H),0.90(t,J＝6.8Hz,6H)..

Synthesis of (((3 aR,4R,6 aR) -6- (4- ((S) -2- ((tert-butoxycarbonyl) amino) -3-methylbutanamide) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) methylpropionate (115.1).

Compound 115.1 was prepared according to the procedure of step 4 of example 1 using 112.1 and propionyl chloride. MS (ESI): the calculated mass for C ₂₈H₃₈N₆O₈ was 586.65 and the m/z found was 587.3[ M+H ] ⁺.

Synthesis of (((2R, 3S,4R, 5R) -5- (4- ((S) -2-amino-3-methylbutanamide) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methylpropionate (Compound 115).

Compound 115 was prepared according to the procedure of step 3 of example 66 using 112.2. MS (ESI): the calculated mass for C ₂₀H₂₆N₆O₆ was 446.46, m/z found to be 447.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.22(d,J＝8.4Hz,1H),7.98(s,1H),7.56(s,1H),7.24(d,J＝4.4Hz,1H),7.12(s,1H),6.80(d,J＝4.8Hz,1H),6.34(d,J＝6.0Hz,1H),5.40(d,J＝6.0Hz,1H),4.70–4.61(m,2H),4.33(dd,J＝12.0,2.4Hz,1H),4.24-4.20(m,1H),4.15(dd,J＝12.0,5.6Hz,1H),3.93-3.90(m,1H),2.33–2.27(m,2H),2.23–2.14(m,1H),1.00(t,J＝7.6Hz,3H),0.96(dd,J＝6.8,3.6Hz,6H).

Synthesis of (2R, 3S,4R, 5R) -5- (4-benzoylamino pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-2- (hydroxymethyl) tetrahydrofuran-3-yl L-valine ester (Compound 128).

Synthesis of (2R, 3S,4R, 5R) -5- (4-benzoylamino pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-2- (hydroxymethyl) tetrahydrofuran-3-yl (t-butoxycarbonyl) -L-valine ester (128.1).

A mixture of (2S) -2- { [ tert-butyl (formyl) - $l {3} -oxyalkyl ] amino } -3-methylbutanoic acid 85 (55.2 mg, 0.255 mmol), EDCI (72.7 mg,0.379 mmol) and 1-hydroxybenzotriazole (51.3 mg,0.379 mmol) in DMF (1 mL) under nitrogen. DIEA (98.1 mg,0.379 mmol) was added to the mixture, the reaction mixture was stirred for 30min, and N- {7- [ (2R, 3R,4S, 5R) -2-cyano-3, 4-dihydroxy-5- (hydroxymethyl) oxacyclopent-2-yl ] pyrrolo [2,1-f ] [1,2,4] triazin-4-yl } benzamide (100 mg, 0.255 mmol) was added dropwise. The reaction mixture was stirred at 25℃for 16h. The residue was quenched with water and extracted with EtOAc. The organic phase was washed with brine, dried over Na ₂SO₄, and evaporated in vacuo to give the crude product. The crude product was purified by preparative HPLC to give product 128.1 (41.7 mg,23.8% yield) as a white solid. MS (ESI): for a calculated m/z of C ₂₉H₃₄N₆O₈ of 594.6, the actual measurement was 595.4[M+H]⁺.¹H NMR(400MHz,DMSO)δ11.41(s,1H),8.46(s,1H),8.05(s,2H),7.66(t,J＝7.2Hz,1H),7.56(t,J＝7.6Hz,2H),7.18(s,2H),7.08(d,J＝8.8Hz,1H),6.64(d,J＝6.8Hz,1H),5.20–5.16(m,1H),5.08(t,J＝5.6Hz,1H),4.99(s,1H),4.27(s,1H),4.15–4.07(m,1H),3.66–3.53(m,2H),1.41(s,9H),0.91(dd,J＝12.4,6.8Hz,6H).

To a solution of compound 128.1 (40 mg,0.0672 mmol) in THF (1 mL) at 0deg.C was then added HCl/1, 4-dioxane (0.5 mL, 4M). The mixture was stirred at 20℃for 2h. The residue was quenched with water and extracted with EtOAc. The organic phase was washed with brine, dried over Na ₂SO₄, and evaporated in vacuo to give the crude product. The crude product was purified by preparative HPLC to give product 128 (4.52 mg,12.8% yield) as a white solid. MS (ESI): for a calculated m/z of C ₂₄H₂₆N₆O₆ of 494.5, the actual measurement was 495.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.39(s,1H),8.22(s,1H),8.06(d,J＝8.0Hz,2H),7.65(t,J＝7.2Hz,1H),7.55(t,J＝7.6Hz,2H),7.15(d,J＝12.8Hz,2H),6.62(s,1H),5.21(dd,J＝5.6,3.6Hz,1H),5.09(s,1H),5.01(d,J＝5.2Hz,1H),4.29(d,J＝3.6Hz,1H),3.62 -3.54(m,2H),3.25(d,J＝5.2Hz,1H),2.09 -1.98(m,1H),0.94(d,J＝6.8Hz,3H),0.88(d,J＝6.8Hz,3H).

Synthesis of (2R, 3S,4R, 5R) -5- (4- ((S) -2-amino-3- (4-fluorophenyl) propanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-2- (hydroxymethyl) tetrahydrofuran-3-yl 2-cyclohexylacetate (Compound 137).

Synthesis of tert-butyl (S) -1- ((7- ((2R, 3R,4S, 5R) -5- (((tert-butyldiphenylsilyl) oxy) methyl) -2-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) amino) -3- (4-fluorophenyl) -1-oxopropan-2-yl) carbamate (137.1).

To a solution of (S) -2- ((tert-butoxycarbonyl) amino) -3- (4-fluorophenyl) propionic acid (1.71 g, 0.006mmol) in THF (20 mL) was added HATU (3.42 g,0.009 mmol) and the solution stirred at 25℃for 1h. 129.1 (1.6 g, 0.003mmol) and DIEA (2.34 mg,0.018 mmol) were added to the above solution, and the mixture was stirred at 25℃for 16h. The reaction was washed with EtOAc (10 mL. Times.3). The combined organics were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography eluting with 0% to 50% EA in PE to give 137.1 (0.85 g,0.001mol,33% yield) as a white solid. MS (ESI): the calculated m/z for C ₄₂H₄₇FN₆O₇ Si was 794.96, found to be 795.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ11.15(s,1H),8.45(s,1H),7.55(dd,J＝18.0,7.2Hz,4H),7.48–7.40(m,4H),7.33-7.07(m,4H),7.18–7.03(m,4H),6.41(d,J＝6.0Hz,1H),5.33(d,J＝5.6Hz,1H),4.86-4.80(m,1H),4.79–4.68(m,1H),4.21-4.18(m,2H),3.86(d,J＝10.0Hz,1H),3.74(dd,J＝11.6,3.6Hz,1H),3.10(d,J＝10.0Hz,1H),2.90–2.76(m,1H),1.32(s,9H),0.90(s,9H).

Synthesis of (2R, 3S,4R, 5R) -5- (4- ((S) -2- ((tert-Butoxycarbonyl) amino) -3- (4-fluorophenyl) propanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -2- (((tert-butyldiphenylsilyl) oxy) methyl) -5-cyano-4-hydroxytetrahydrofuran-3-yl 2-cyclohexylacetate (137.2).

Compound 137.2 is prepared according to the procedure of step 1 of example 19 using 137.1 and 2-cyclohexylacetic acid. MS (ESI): the calculated mass for C ₅₀H₅₉FN₆O₈ Si is 919.14 and the m/z found is 919.4[ M+H ] ⁺.

Synthesis of (2R, 3S,4R, 5R) -5- (4- ((S) -2- ((tert-butoxycarbonyl) amino) -3- (4-fluorophenyl) propanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-2- (hydroxymethyl) tetrahydrofuran-3-yl 2-cyclohexylacetate (137.3).

Compound 137.3 was prepared according to the procedure of step 1 of example 97 using 137.2. MS (ESI): calculated mass for C ₃₄H₄₁FN₆O₈ Si is 680.73, m/z found is 681.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ11.29(s,1H),8.46(s,1H),7.50–7.37(m,2H),7.24–7.22(m,2H),7.16–7.09(m,3H),6.60(d,J＝5.6Hz,1H),5.24–5.16(m,1H),5.06-5.05(m,1H),4.98(t,J＝5.6Hz,1H),4.85-4.80(m,1H),4.29(d,J＝3.6Hz,1H),3.58-3.56(m,2H),3.12(d,J＝10.4Hz,1H),2.81(t,J＝12.4Hz,1H),2.27(d,J＝6.8Hz,2H),1.81–1.72(m,3H),1.64–1.58(m,3H),1.32(s,9H),1.17–1.10(m,3H),1.03–0.91(m,2H).

Compound 137 was prepared according to the procedure of step 2 of example 19 using 137.3. MS (ESI): the calculated mass for C ₂₉H₃₃FN₆O₆ was 580.62 and the measured m/z was 581.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.60(d,J＝8.4Hz,1H),7.92(s,1H),7.68(s,1H),7.38(dd,J＝8.4,5.6Hz,2H),7.19(s,1H),7.06(dd,J＝10.0,7.6Hz,3H),6.87(d,J＝4.4Hz,1H),6.43(d,J＝6.6Hz,1H),5.20–5.12(m,1H),5.00(t,J＝5.6Hz,1H),4.95–4.92(m,2H),4.29–4.20(m,1H),3.64–3.45(m,2H),3.22–3.15(m,1H),3.09–2.97(m,1H),2.25(d,J＝6.8Hz,2H),1.90–1.69(m,3H),1.65–1.58(m,3H),1.29–1.05(m,3H),0.99–0.93(m,2H).^19F NMR(377MHz,DMSO)δ-116.77(s,1H).

Synthesis of (2R, 3S,4R, 5R) -5- (4- ((S) -2-amino-3-methylbutanamide) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-2- (hydroxymethyl) tetrahydrofuran-3-yl 2-cyclohexylacetate (Compound 139).

Synthesis of (2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -2- (((tert-butyldiphenylsilyl) oxy) methyl) -5-cyano-4-hydroxytetrahydrofuran-3-yl 2-cyclohexylacetate (139.1).

Compound 139.1 was prepared according to the procedure of step 1 of example 19 using 129.1 and 2-cyclohexylacetic acid. MS (ESI): calculated mass for C ₃₆H₄₃N₅O₅ Si as 653.86, measured m/z as 654.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.89-7.80(m,3H),7.53(d,J＝6.8Hz,2H),7.49–7.31(m,6H),7.24(t,J＝7.6Hz,2H),6.85(d,J＝4.4Hz,1H),6.80(d,J＝4.4Hz,1H),6.63(d,J＝6.4Hz,1H),5.36(t,J＝4.8Hz,1H),5.05(t,J＝6.0Hz,1H),4.36(d,J＝3.6Hz,1H),3.77-3.75(m,2H),2.26(d,J＝6.8Hz,2H),1.87–1.53(m,6H),1.32–0.95(m,5H),0.92(s,9H).

Synthesis of (2R, 3S,4R, 5R) -5- (4- ((S) -2- ((tert-butoxycarbonyl) amino) -3-methylbutanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -2- (((tert-butyldiphenylsilyl) oxy) methyl) -5-cyano-4-hydroxytetrahydrofuran-3-yl 2-cyclohexylacetate (139.2).

Compound 139.2 was prepared according to the procedure of step 1 of example 129 using 139.1 and (tert-butoxycarbonyl) -L-valine. MS (ESI): the calculated mass for C ₄₆H₆₀N₆O₈ Si was 853.11 and the m/z found was 853.4[ M+H ] ⁺.

Synthesis of (2R, 3S,4R, 5R) -5- (4- ((S) -2- ((tert-butoxycarbonyl) amino) -3-methylbutanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-2- (hydroxymethyl) tetrahydrofuran-3-yl 2-cyclohexylacetate (139.3).

Compound 139.3 was prepared according to the procedure of step 1 of example 97 using 139.2. MS (ESI): the calculated mass for C ₃₀H₄₂N₆O₈ was 614.70 and the m/z found was 615.2[ M+H ] ⁺.

Compound 139 was prepared according to the procedure of step 2 of example 19 using 139.3. MS (ESI): the calculated mass for C ₂₅H₃₄N₆O₆ was 514.58, the measured m/z was 515.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.26(d,J＝8.4Hz,1H),7.99(s,1H),7.57(s,1H),7.25(d,J＝4.4Hz,1H),7.14(s,1H),6.89(d,J＝4.8Hz,1H),6.46(d,J＝6.4Hz,1H),5.17(dd,J＝5.2,3.6Hz,1H),5.03(t,J＝5.6Hz,1H),4.97(t,J＝6.4Hz,1H),4.66(t,J＝8.0Hz,1H),4.25-4.24(m,1H),3.68–3.46(m,2H),2.26(d,J＝7.2Hz,2H),2.18-2.15(m,1H),1.90–1.53(m,7H),1.22-1.10(m,4H),0.95(dd,J＝6.8,4.4Hz,6H).

Example 187 synthesis of (2 r,3s,4r,5 r) -5-cyano-4-hydroxy-2- (hydroxymethyl) -5- (4- (((pentoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuran-3-yl 2-phenylacetate (compound 141).

Synthesis of (3 aR,4R,6 aR) -4- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6- (((tert-butyldiphenylsilyl) oxy) methyl) -2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxole-4-carbonitrile (141.1).

The title compound 141.1 was prepared according to the procedure for step 2 of example 6 using 290.1. MS (ESI): calculated mass for C ₃₁H₃₅N₅O₄ Si was 569.25, m/z found 570.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.89(br s,3H),7.52(t,J＝8.4Hz,4H),7.43(t,J＝7.6Hz,2H),7.34(t,J＝7.6Hz,4H),6.88(dd,J＝10.8,4.4Hz,2H),5.36(d,J＝6.4Hz,1H),4.91(dd,J＝6.4,2.8Hz,1H),4.45(d,J＝3.2Hz,1H),3.77(d,J＝4.8Hz,2H),1.64(s,3H),1.36(s,3H),0.92(s,9H).

Synthesis of (7- ((3 aR,4R,6 aR) -6- (((tert-butyldiphenylsilyl) oxy) methyl) -4-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) carbamic acid pentyl ester (141.2).

The title compound 141.2 was prepared according to the procedure for step 2 of example 48 using 141.1 and pentylcarbonyl chloride (pentyl carbonochloridate). MS (ESI): the calculated mass for C ₃₇H₄₅N₅O₆ Si was 683.31 and the measured m/z was 684.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.92(s,1H),8.35(s,1H),7.54–7.48(m,4H),7.45–7.40(m,2H),7.36–7.32(m,4H),7.30–7.28(m,1H),7.08(d,J＝4.4Hz,1H),5.34(d,J＝6.0Hz,1H),4.91(dd,J＝6.2,2.8Hz,1H),4.50(d,J＝2.8Hz,1H),4.19(t,J＝6.8Hz,2H),3.76(t,J＝8.0Hz,2H),1.72–1.60(m,5H),1.40–1.34(m,7H),0.92–0.88(m,12H).

Synthesis of (7- ((2R, 3R,4S, 5R) -5- (((tert-butyldiphenylsilyl) oxy) methyl) -2-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) carbamic acid pentyl ester (141.3).

To a solution of amyl 141.2 (500 mg,0.73 mmol) in THF (5 mL) at 0deg.C was added HCl (2 mL,12 mol) and the reaction was stirred at 20deg.C for 1h. The mixture was adjusted to pH 8 with aqueous NaHCO ₃ and extracted with EtOAc (50 mL. Times.3). The organic phase was washed with brine (50 ml×3), then dried over anhydrous sodium sulfate, filtered and concentrated to remove the solvent. The residue was purified by flash column chromatography (0% to 30% petroleum ether/ethyl acetate) to give 141.3 (250 mg,50.5% yield) as a pale yellow solid. MS (ESI): the calculated mass for C ₃₄H₄₁N₅O₆ Si was 643.28, measured m/z 644.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.86(s,1H),8.35(s,1H),7.57(d,J＝7.2Hz,2H),7.52(d,J＝7.2Hz,2H),7.43(q,J＝7.2Hz,2H),7.38–7.28(m,4H),7.23(d,J＝4.8Hz,1H),7.00(d,J＝4.8Hz,1H),6.38(d,J＝6.4Hz,1H),5.32(d,J＝5.2Hz,1H),4.82–4.64(m,1H),4.18(t,J＝5.6Hz,4H),3.84(d,J＝10.0Hz,1H),3.72(dd,J＝11.6,3.2Hz,1H),1.72–1.62(m,2H),1.40–1.32(m,4H),0.94–0.99(m,12H).

Synthesis of (2R, 3S,4R, 5R) -2- (((tert-butyldiphenylsilyl) oxy) methyl) -5-cyano-4-hydroxy-5- (4- (((pentyloxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuran-3-yl 2-phenylacetate (141.4).

The title compound 141.4 was prepared according to the procedure for step 2 of example 17 using 141.3 and 2-phenylacetyl chloride. MS (ESI): the calculated mass for C ₄₂H₄₇N₅O₇ Si was 761.32, the measured m/z was 762.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.91(s,1H),8.33(s,1H),7.49(d,J＝7.6Hz,2H),7.46–7.26(m,11H),7.21(t,J＝7.6Hz,3H),6.99(d,J＝4.0Hz,1H),6.80(d,J＝6.4Hz,1H),5.54–5.34(m,1H),5.07(t,J＝6.0Hz,1H),4.42(d,J＝3.2Hz,1H),4.17(t,J＝6.4Hz,2H),3.83–3.72(m,4H),1.76–1.60(m,2H),1.40–1.30(m,4H),0.94–0.85(m,12H).

Synthesis of (2R, 3S,4R, 5R) -5-cyano-4-hydroxy-2- (hydroxymethyl) -5- (4- (((pentoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuran-3-yl 2-phenylacetate (141).

The title compound 141 was prepared according to the procedure for step 1 of example 58 using 141.4. MS (ESI): the calculated mass for C ₂₆H₂₉N₅O₇ was 523.21, the measured m/z was 524.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.97(s,1H),8.36(s,1H),7.38–7.22(m,6H),7.09(d,J＝4.4Hz,1H),6.64(d,J＝6.4Hz,1H),5.28–5.14(m,1H),5.05(t,J＝5.6Hz,1H),4.98(t,J＝6.0Hz,1H),4.32–4.27(m,1H),4.17(t,J＝6.8Hz,2H),3.86–3.71(m,2H),3.64–3.50(m,2H),1.69–1.63(m,2H),1.36–1.31(m,4H),0.90(t,J＝7.2Hz,3H).

Synthesis of (2R, 3S,4R, 5R) -5- (4-benzoylamino pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-2- (hydroxymethyl) tetrahydrofuran-3-yl 2-phenylacetate (Compound 143).

Synthesis of N- (7- ((3 aR,4R,6 aR) -6- (((tert-butyldiphenylsilyl) oxy) methyl) -4-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) benzamide (143.1).

The title compound 143.1 was prepared according to the procedure for step 1 of example 51 using 141.1 and benzoyl chloride. MS (ESI): calculated mass for C ₃₈H₃₉N₅O₅ Si was 673.27, measured m/z was 674.2[M+H]⁺.¹H NMR(400MHz,DMSO)11.40(s,1H),8.20–7.90(m,3H),7.71–7.32(m,15H),7.15(s,2H),5.37(d,J＝6.4Hz,1H),4.93(dd,J＝6.4,2.8Hz,1H),4.51(d,J＝2.8Hz,1H),1.66(s,3H),1.37(s,3H),0.92(s,9H).

Synthesis of N- (7- ((2R, 3R,4S, 5R) -5- (((tert-butyldiphenylsilyl) oxy) methyl) -2-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) benzamide (143.2).

The title compound 143.2 was prepared according to the procedure for step 3 of example 187 using 143.1. MS (ESI): calculated mass for C ₃₅H₃₅N₅O₅ Si was 633.24, m/z found 634.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ11.35(s,1H),8.46(s,1H),7.99(d,J＝7.6Hz,2H),7.67(t,J＝7.2Hz,1H),7.63–7.49(m,6H),7.46–7.29(m,6H),7.08(d,J＝4.4Hz,2H),6.39(d,J＝6.0Hz,1H),5.34(d,J＝5.2Hz,1H),4.71–4.76(m,1H),4.26–4.12(m,2H),3.88–3.85(m,1H),3.77–3.73(m,1H),0.92(s,9H).

Synthesis of (2R, 3S,4R, 5R) -5- (4-benzoylamino pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -2- (((tert-butyldiphenylsilyl) oxy) methyl) -5-cyano-4-hydroxytetrahydrofuran-3-yl 2-phenylacetate (143.3).

The title compound 143.3 was prepared according to the procedure for step 2 of example 17 using 141.2 and 2-phenylacetyl chloride. MS (ESI): calculated mass for C ₄₃H₄₁N₅O₆ Si was 751.28, m/z found to be 752.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ11.40(s,1H),8.42–8.01(m,2H),7.76–6.95(m,20H),6.82(d,J＝6.8Hz,1H),5.45–5.42(m,1H),5.08(s,1H),4.43(d,J＝3.6Hz,1H),3.78(d,J＝3.2Hz,3H),1.36–1.17(m,2H),0.90(s,9H).

Synthesis of (2R, 3S,4R, 5R) -5- (4-benzoylamino pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-2- (hydroxymethyl) tetrahydrofuran-3-yl 2-phenylacetate (143).

The title compound 143 was prepared according to the procedure for step 1 of example 58 using 143.3. MS (ESI): the calculated mass for C ₂₇H₂₃N₅O₆ was 513.16, the measured m/z was 514.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ11.91(s,1H),8.33(s,1H),8.06(d,J＝7.6Hz,2H),7.63(t,J＝7.2Hz,1H),7.54(t,J＝7.6Hz,2H),7.37–7.23(m,5H),7.13–7.09(m,2H),6.66(d,J＝6.4Hz,1H),5.27–5.17(m,1H),5.11–5.06(m,1H),5.00(t,J＝6.0Hz,1H),4.28–4.34(m,1H),3.87–3.67(m,2H),3.64–3.51(m,2H).

Synthesis of (2R, 3S,4R, 5R) -5- (4- ((S) -2-amino-3-methylbutanamide) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-2- (hydroxymethyl) tetrahydrofuran-3-yl 2-phenylacetate (Compound 144).

Synthesis of (2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -2- (((tert-butyldiphenylsilyl) oxy) methyl) -5-cyano-4-hydroxytetrahydrofuran-3-yl 2-phenylacetate (144.1).

Compound 144.1 was prepared according to the procedure of step 1 of example 19 using 129.1 and 2-phenylacetic acid. MS (ESI): the calculated mass for C ₃₆H₃₇N₅O₅ Si was 647.81 and the M/z found was 648.2.[ M+H ] ⁺.

Synthesis of (2R, 3S,4R, 5R) -5- (4- ((S) -2- ((tert-butoxycarbonyl) amino) -3-methylbutanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -2- (((tert-butyldiphenylsilyl) oxy) methyl) -5-cyano-4-hydroxytetrahydrofuran-3-yl 2-phenylacetate (144.2).

Compound 144.2 was prepared according to the procedure of step 1 of example 129 using 139.1 and (tert-butoxycarbonyl) -L-valine. MS (ESI): the calculated mass for C ₄₆H₅₄N₆O₈ Si was 847.06, the m/z found was 847.3[ M+H ] ⁺.

Synthesis of (2R, 3S,4R, 5R) -5- (4- ((S) -2- ((tert-butoxycarbonyl) amino) -3-methylbutanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-2- (hydroxymethyl) tetrahydrofuran-3-yl 2-phenylacetate (144.3).

Compound 144.3 was prepared according to the procedure of step 1 of example 97 using 144.2. MS (ESI): the calculated mass for C ₃₀H₃₆N₆O₈ was 608.65 and the m/z found was 609.2[ M+H ] ⁺.

Compound 144 was prepared according to the procedure of step 2 of example 19 using 144.3. MS (ESI): the calculated mass for C ₂₅H₂₈N₆O₆ was 508.54, m/z found to be 509.2[M+H]⁺.1H NMR(400MHz,DMSO)δ8.27(d,J＝8.8Hz,1H),7.99(s,1H),7.57(s,1H),7.37–7.26(m,5H),7.25(d,J＝4.8Hz,1H),7.15(s,1H),6.90(d,J＝4.8Hz,1H),6.54(d,J＝6.4Hz,1H),5.25–5.16(m,1H),5.04(t,J＝5.6Hz,1H),5.00(t,J＝6.0Hz,1H),4.66(t,J＝8.4Hz,1H),4.27-4.25(m,1H),3.76(d,J＝11.2Hz,2H),3.57-3.52(m,2H),2.18-2.15(m,1H),0.95(dd,J＝6.4,4.4Hz,6H).

Synthesis of((2R, 3S,4R, 5R) -5- (4- ((S) -2-amino-3-methylbutanamide) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl acetate (Compound 339).

Synthesis of (((3 aR,4R,6 aR) -6- (4- ((S) -2- ((tert-butoxycarbonyl) amino) -3-methylbutanamide) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) methyl acetate (339.1).

Compound 339.1 was prepared according to the procedure of step 4 of example 1 using 112.1 and AcCl. MS (ESI): the calculated mass for C ₂₇H₃₆N₆O₈ was 572.62 and the m/z found was 573.2[ M+H ] ⁺.

Synthesis of (((2R, 3S,4R, 5R) -5- (4- ((S) -2-amino-3-methylbutanamide) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl acetate (Compound 339).

Compound 339 was prepared according to the procedure of step 3 of example 112 using 112.1. MS (ESI): the calculated mass for C ₁₉H₂₆N₆O₆ was 432.44, the measured m/z was 433.1[M+H]⁺.1H NMR(400MHz,DMSO)δ8.21(d,J＝8.4Hz,1H),7.98(s,1H),7.55(s,1H),7.24(d,J＝4.4Hz,1H),7.13(s,1H),6.81(d,J＝4.8Hz,1H),6.32(d,J＝6.0Hz,1H),5.39(d,J＝6.0Hz,1H),4.73–4.61(m,2H),4.32(dd,J＝12.0,2.4Hz,1H),4.22-4.20(m,1H),4.14(dd,J＝12.0,6.0Hz,1H),3.92-3.90(m,1H),2.18-2.15(m,1H),2.01(s,3H),0.96(dd,J＝6.8,3.6Hz,6H).

Synthesis of (2R, 3S,4R, 5R) -5-cyano-4-hydroxy-2- (hydroxymethyl) -5- (4-pentanamidopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuranyl 2-phenylacetate (Compound 340).

Synthesis of (2R, 3S,4R, 5R) -2- (((tert-butyldiphenylsilyl) oxy) methyl) -5-cyano-4-hydroxy-5- (4-pentanamido pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuran-3-yl 2-phenylacetate (340.2).

The title compound was prepared according to the procedure for step 2 of example 17 using 340.1 and 2-phenylacetyl chloride. MS (ESI): the calculated m/z for C ₄₁H₄₅N₅O₆ Si was 731.1, found to be 732.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.89(s,1H),8.37(s,1H),7.49(d,J＝7.6Hz,2H),7.42(d,J＝7.2Hz,3H),7.37–7.27(m,7H),7.23–7.19(m,3H),7.03(d,J＝4.8Hz,1H),6.80(d,J＝6.8Hz,1H),5.46–5.37(m,1H),5.07(t,J＝6.0Hz,1H),4.42(d,J＝3.2Hz,1H),3.77(s,3H),2.72(t,J＝7.2Hz,2H),1.67–1.54(m,2H),1.35(dd,J＝14.8,7.2Hz,2H),1.23(s,2H),0.93–0.85(m,12H).

Synthesis of (2R, 3S,4R, 5R) -5-cyano-4-hydroxy-2- (hydroxymethyl) -5- (4-pentanamido pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuranyl-3-2-phenylacetate (Compound 340).

To a solution of compound 340.2 (40 mg,0.0547 mmol) in THF (1 mL) at 0deg.C was added HF/pyridine (27.1 mg,0.274 mmol). The reaction mixture was stirred at 20℃for 1h. The residue was quenched with water and extracted with EtOAc. The organic phase was washed with brine, dried over Na ₂SO₄, and evaporated in vacuo to give the crude product. The crude product was purified by preparative HPLC to give product 340 as a white solid (4.89 mg,15.9% yield). MS (ESI): for a calculated m/z of C ₂₅H₂₇N₅O₆ of 493.5, the actual measurement was 494.1[M+H].¹H NMR(400MHz,DMSO)δ10.91(s,1H),8.42(s,1H),7.36–7.24(m,6H),7.13(d,J＝4.8Hz,1H),6.65(d,J＝6.4Hz,1H),5.24–5.17(m,1H),4.98(s,2H),4.30(d,J＝4.0Hz,1H),3.82–3.72(m,2H),3.62–3.52(m,2H),2.72(t,J＝7.6Hz,2H),1.66–1.54(m,2H),1.42–1.30(m,2H),0.91(t,J＝7.6Hz,3H).

Synthesis of (((2R, 3S,4R, 5R) -5-cyano-3, 4-dihydroxy-5- (4-pentanamido pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuranyl) 2-methyl L-valine ester (Compound 341).

Synthesis of N- (7- ((3 aR,4R,6 aR) -4-cyano-6- (hydroxymethyl) -2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) pentanamide (341.1).

The title compound 341.1 was prepared according to the procedure for step 1 of example 58 using 264.1. MS (ESI): the calculated mass for C ₂₀H₂₅N₅O₅ was 415.19, the measured m/z was 416.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.92(s,1H),8.43(s,1H),7.27(d,J＝4.8Hz,1H),7.14(d,J＝4.8Hz,1H),5.35(d,J＝6.4Hz,1H),5.03(t,J＝5.6Hz,1H),4.90(dd,J＝6.4,2.8Hz,1H),4.36(dd,J＝8.0,5.2Hz,1H),3.61–3.45(m,2H),2.72(dd,J＝9.2,5.2Hz,2H),1.66–1.57(m,5H),1.39–1.33(m,5H),0.91(t,J＝7.2Hz,3H).

Synthesis of (((3 aR,4R,6 aR) -6-cyano-2, 2-dimethyl-6- (4-pentanamidopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) methyl (tert-butoxycarbonyl) -L-valine ester (341.2).

The title compound 341.2 was prepared according to the procedure of step 1 of example 19 using 341.1 and (tert-butoxycarbonyl) -L-valine. MS (ESI): the calculated mass for C ₃₀H₄₂N₆O₈ was 614.31, the measured m/z was 615.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.93(s,1H),8.44(s,1H),7.28(d,J＝4.8Hz,1H),7.15(d,J＝8.1Hz,1H),7.08(d,J＝4.8Hz,1H),5.42(d,J＝6.4Hz,1H),4.93(dd,J＝6.4,2.8Hz,1H),4.62(s,1H),4.24(dd,J＝12.0,4.0Hz,1H),4.14(dd,J＝12.0,6.4Hz,1H),3.82–3.69(m,1H),2.72(t,J＝7.2Hz,2H),1.82(d,J＝6.8Hz,1H),1.65(d,J＝6.0Hz,3H),1.60(dd,J＝15.2,7.6Hz,2H),1.40–1.33(m,14H),0.91(t,J＝7.2Hz,3H),0.77(dd,J＝13.6,6.8Hz,6H).

Synthesis of (((2R, 3S,4R, 5R) -5-cyano-3, 4-dihydroxy-5- (4-pentanamido pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuranyl) methyl L-valine ester (341).

The title compound 341 was prepared according to the procedure of step 2 of example 19 using 341.2. MS (ESI): the calculated mass for C ₂₂H₃₀N₆O₆ was 474.22 and the measured m/z was 475.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.92(s,1H),8.39(s,1H),7.29(d,J＝4.8Hz,1H),7.07(d,J＝4.8Hz,1H),6.47(d,J＝6.0Hz,1H),5.47(s,1H),4.69(t,J＝5.2Hz,1H),4.36–4.26(m,3H),3.97–3.92(m,1H),3.30(s,1H),2.72(t,J＝7.2Hz,2H),1.88–1.79(m,1H),1.67–1.55(m,2H),1.40–1.30(m,2H),0.91(t,J＝7.2Hz,3H),0.82(dd,J＝14.4,6.8Hz,6H).

Synthesis of (2R, 3S,4R, 5R) -5- (4-benzoylamino pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-2- (hydroxymethyl) tetrahydrofuran-3-yl 2-cyclohexylacetate (Compound 342).

Synthesis of (2R, 3S,4R, 5R) -5- (4-benzoylamino pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -2- (((tert-butyldiphenylsilyl) oxy) methyl) -5-cyano-4-hydroxytetrahydrofuran-3-yl 2-cyclohexylacetate (342.1).

The title compound 342.1 was prepared according to the procedure for step 2 of example 17 using 143.2 and 2-cyclohexylacetyl chloride. MS (ESI): the calculated mass for C ₄₃H₄₇N₅O₆ Si was 757.33, the measured m/z was 758.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ11.40(s,1H),8.42(s,1H),8.04(s,2H),7.70–7.62(m,1H),7.58–7.51(m,4H),7.47–7.44(m,3H),7.41–7.33(m,3H),7.24(t,J＝7.6Hz,2H),7.13(d,J＝4.4Hz,1H),7.04(s,1H),6.75(d,J＝6.4Hz,1H),5.47–5.35(m,1H),5.06(t,J＝6.0Hz,1H),4.42(d,J＝3.6Hz,1H),3.79(d,J＝2.8Hz,2H),2.28(d,J＝6.8Hz,2H),1.85–1.70(m,3H),1.68–1.56(m,3H),1.28–1.20(m,5H),0.92(s,9H).

Synthesis of (2R, 3S,4R, 5R) -5- (4-benzoylamino pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-2- (hydroxymethyl) tetrahydrofuran-3-yl 2-cyclohexylacetate (342).

The title compound 342 was prepared according to the procedure of step 2 of example 19 using 342.1. MS (ESI): the calculated mass for C ₂₇H₂₉N₅O₆ was 519.21 and the measured m/z was 520.0[M+H]⁺.¹H NMR(400MHz,DMSO)δ11.85(s,1H),8.37(s,1H),8.06(d,J＝7.6Hz,2H),7.65(t,J＝7.2Hz,1H),7.55(t,J＝7.6Hz,2H),7.16–7.06(m,2H),6.59(d,J＝6.8Hz,1H),5.25–5.16(m,1H),5.07(t,J＝5.6Hz,1H),4.97(t,J＝6.0Hz,1H),4.34–4.22(m,1H),3.64–3.51(m,2H),2.27(d,J＝6.8Hz,2H),1.82–1.72(m,3H),1.69–1.56(m,3H),1.32–1.07(m,3H),1.05–0.90(m,2H).

EXAMPLE 194 Synthesis of (2R, 3R,4R, 5R) -4-acetoxy-5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-2- ((2-phenylacetyloxy) methyl) tetrahydrofuran-3-yl L-valine ester (Compound 343).

Synthesis of (2R, 3R,4R, 5R) -4-acetoxy-5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-2- ((2-phenylacetyloxy) methyl) tetrahydrofuran-3-yl (tert-butoxycarbonyl) -L-valine ester (343.1).

To a solution of 43.1 (DMAP-containing 80mg,0.131 mmol) in DMF (3 mL) was added 2, 5-dioxopyrrolidin-1-ylacetate (61.94 mg, 0.390 mmol) and the mixture was stirred at 20℃for 16h. The reaction was washed with EtOAc (5 mL. Times.3). The combined organics were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by preparative HPLC to give 343 as a white solid (40 mg,42% yield). MS (ESI): the calculated m/z for C ₃₂H₃₈N₆O₉ was 650.69, found 651.2[ M+H ] ⁺.

Synthesis of (2R, 3R,4R, 5R) -4-acetoxy-5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-2- ((2-phenylacetyloxy) methyl) tetrahydrofuran-3-yl L-valine ester (Compound 343).

Compound 343 was prepared according to the procedure of step 2 of example 19 using 343.1. MS (ESI): the calculated mass for C ₂₇H₃₀N₆O₇ was 550.57 and the measured m/z was 551.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.02(d,J＝22.0Hz,2H),7.94(s,1H),7.49–7.13(m,5H),6.94(d,J＝4.4Hz,1H),6.79(d,J＝4.8Hz,1H),6.09(d,J＝6.0Hz,1H),5.45(dd,J＝5.6,3.6Hz,1H),4.61-4.58(m,1H),4.40(dd,J＝12.4,3.6Hz,1H),4.30(dd,J＝12.0,4.8Hz,1H),3.66(d,J＝4.4Hz,2H),3.21(d,J＝5.6Hz,1H),2.11(s,3H),1.95 -1.92(m,1H),0.90(dd,J＝14.4,6.8Hz,6H).

Synthesis of (2R, 3S,4R, 5R) -5- (4-acetamidopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-2- ((2-phenylacetyloxy) methyl) tetrahydrofuran-3-yl L-valine ester (Compound 344).

Synthesis of (2R, 3S,4R, 5R) -5- (4-acetamidopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-2- ((2-phenylacetyloxy) methyl) tetrahydrofuran-3-yl (tert-butoxycarbonyl) -L-valine ester (344.1).

To a solution of 43.1 (60 mg,0.098 mmol) in DMA (2 mL) was added HCl in dioxane (4M, 0.1 mL) and the reaction was stirred at 20deg.C for 15min. Acetyl chloride (387.00 mg,4.93 mmol) was then added to the above solution at 0deg.C and the resulting mixture was stirred at 20deg.C for 16h. The crude product was purified by prep HPLC to give 344 as a white solid (30 mg,42% yield). MS (ESI): the calculated m/z for C ₃₂H₃₈N₆O₉ was 650.69, found 651.2[ M+H ] ⁺.

Compound 344 was prepared according to the procedure of step 2 of example 19 using 344.1. MS (ESI): the calculated mass for C ₂₇H₃₀N₆O₇ was 550.57 and the measured m/z was 551.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ11.00(s,1H),8.39(s,1H),7.33(d,J＝4.8Hz,1H),7.29–7.23(m,3H),7.20–7.18(m,2H),7.07(d,J＝4.8Hz,1H),6.69(d,J＝6.4Hz,1H),5.15(t,J＝5.2Hz,1H),5.04(t,J＝5.6Hz,1H),4.52–4.49(m,1H),4.32(dd,J＝12.4,3.6Hz,1H),4.26(dd,J＝12.4,4.8Hz,1H),3.66(s,2H),3.25(d,J＝5.2Hz,1H),2.40(s,3H),2.01–1.97(m,1H),0.90(dd,J＝20.0,6.8Hz,6H).

Synthesis of (2R, 3S,4R, 5R) -5- (4- ((S) -2-amino-3- (4-fluorophenyl) propanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-2- (hydroxymethyl) tetrahydrofuran-3-yl 2- (1-aminocyclohexyl) acetate (Compound 345).

Synthesis of (2R, 3S,4R, 5R) -5- (4- ((S) -2- ((tert-butoxycarbonyl) amino) -3- (4-fluorophenyl) propanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -2- (((tert-butyldiphenylsilyl) oxy) methyl) -5-cyano-4-hydroxytetrahydrofuran-3-yl 2- (1- ((tert-butoxycarbonyl) amino) cyclohexyl) acetate (345.1).

Compound 345.1 was prepared according to the procedure of step 1 of example 19 using 137.1 and 2- (1- ((tert-butoxycarbonyl) amino) cyclohexyl) acetic acid. MS (ESI): the calculated mass for C ₅₅H₆₈FN₇O₁₀ Si is 1034.27 and the measured m/z is 1034.5[ M+H ] ⁺.

Synthesis of (2R, 3S,4R, 5R) -5- (4- ((S) -2- ((tert-butoxycarbonyl) amino) -3- (4-fluorophenyl) propanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-2- (hydroxymethyl) tetrahydrofuran-3-yl 2- (1- ((tert-butoxycarbonyl) amino) cyclohexyl) acetate (345.2).

Compound 345.2 was prepared according to the procedure of step 1 of example 97 using 345.1. MS (ESI): the calculated mass for C ₃₉H₅₀FN₇O₁₀ was 795.87 and the measured m/z was 796.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ11.22(s,1H),8.48(s,1H),7.45–7.40(m,2H),7.27–7.22(m,2H),7.17–7.10(m,3H),6.58(d,J＝6.4Hz,1H),6.27–6.25(m,1H),5.06-5.02(m,2H),4.94(t,J＝6.0Hz,1H),4.87–4.85(m,1H),4.37–4.27(m,1H),3.71–3.51(m,2H),3.11–3.09(m,1H),2.86–2.77(m,1H),2.70–2.66(m,2H),1.45-1.22(m,28H).

Compound 345 was prepared according to the procedure of step 2 of example 19 using 345.2. MS (ESI): the calculated mass for C ₂₉H₃₄FN₇O₆ was 595.63, the measured m/z was 596.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.60(d,J＝8.0Hz,1H),8.32(s,1H),7.93(s,1H),7.69(s,1H),7.38(dd,J＝8.4,5.6Hz,2H),7.18(s,1H),7.06(dd,J＝10.4,7.2Hz,3H),6.87(d,J＝4.4Hz,1H),5.33–5.22(m,1H),4.97–4.95(m,1H),4.90(d,J＝5.6Hz,1H),4.28-4.27(m,1H),3.56–3.50(m,2H),3.23–3.16(m,1H),3.06–2.98(m,1H),2.42(d,J＝12.8Hz,2H),1.59–1.30(m,10H).¹⁹F NMR(376MHz,DMSO)δ-116.76(s,1F).

Example 197 synthesis of (2 r,3s,4r,5 r) -5- (4-butyrylaminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-2- ((2-phenylacetyloxy) methyl) tetrahydrofuran-3-yl L-valine ester (compound 346).

Synthesis of (2R, 3S,4R, 5R) -5- (4-butyrylaminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-2- ((2-phenylacetyloxy) methyl) tetrahydrofuran-3-yl (tert-butoxycarbonyl) -L-valine ester (346.1).

Compound 346.1 was prepared according to the procedure of step 1 of example 195 using 43.1 and butyryl chloride. MS (ESI): the calculated mass for C ₃₄H₄₂N₆O₉ was 678.74 and the m/z found was 679.3[ M+H ] ⁺.

Synthesis of (2R, 3S,4R, 5R) -5- (4-butyrylaminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-2- ((2-phenylacetyloxy) methyl) tetrahydrofuran-3-yl L-valine ester (Compound 346).

Compound 346 was prepared according to the procedure of step 2 of example 19 using 346.1. MS (ESI): the calculated mass for C ₂₉H₃₄N₆O₇ was 578.63 and the measured m/z was 579.3[M+H]⁺.1H NMR(400MHz,DMSO)δ10.94(s,1H),8.40(s,1H),7.32–7.18(m,6H),7.07(d,J＝4.8Hz,1H),6.69(d,J＝6.0Hz,1H),5.20–5.09(m,1H),5.05(t,J＝4.8Hz,1H),4.50(dd,J＝8.0,4.4Hz,1H),4.32(dd,J＝12.4,3.6Hz,1H),4.26(dd,J＝12.4,4.8Hz,1H),3.66(s,2H),3.25(d,J＝5.2Hz,1H),2.71(t,J＝7.2Hz,2H),2.07–1.97(m,1H),1.65-1.60(m,2H),0.94(dd,J＝14.0,6.8Hz,6H),0.86(t,J＝6.0Hz,3H).

Example 198 synthesis of (2 r,3s,4r,5 r) -5-cyano-4-hydroxy-5- (4-isobutyramidopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -2- ((2-phenylacetyloxy) methyl) tetrahydrofuran-3-yl L-valine ester (compound 347).

Synthesis of (2R, 3S,4R, 5R) -5-cyano-4-hydroxy-5- (4-isobutyrylaminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -2- ((2-phenylacetyloxy) methyl) tetrahydrofuran-3-yl (tert-butoxycarbonyl) -L-valine ester (347.1).

Compound 347.1 was prepared according to the procedure of step 1 of example 195 using 43.1 and isobutyryl chloride. MS (ESI): the calculated mass for C ₃₄H₄₂N₆O₉ was 678.74 and the m/z found was 679.3[ M+H ] ⁺.

Synthesis of (2R, 3S,4R, 5R) -5-cyano-4-hydroxy-5- (4-isobutyramidopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -2- ((2-phenylacetyloxy) methyl) tetrahydrofuran-3-yl L-valine ester (Compound 347).

Compound 347 was prepared according to the procedure of step 2 of example 19 using 347.1. MS (ESI): the calculated mass for C ₂₉H₃₄N₆O₇ was 578.63 and the measured m/z was 579.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.91(s,1H),8.41(s,1H),7.28–7.18(m,6H),7.08(d,J＝4.8Hz,1H),6.70–6.68(m,1H),5.19–5.12(m,1H),5.04(d,J＝5.6Hz,1H),4.51(dd,J＝8.0,4.0Hz,1H),4.33(dd,J＝12.4,3.6Hz,1H),4.26(dd,J＝12.4,4.8Hz,1H),3.66(s,2H),3.28(d,J＝5.2Hz,1H),3.11–3.07(m,1H),2.09–1.98(m,1H),1.16(d,J＝6.8Hz,6H),0.95–0.85(m,6H).

Synthesis of (2R, 3S,4R, 5R) -5- (4-acetamidopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-2- ((2-cyclohexylacetoxy) methyl) -4-hydroxytetrahydrofuran-3-yl L-valine ester (Compound 348).

Synthesis of (2R, 3S,4R, 5R) -5- (4-acetamidopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-2- ((2-cyclohexylacetoxy) methyl) -4-hydroxytetrahydrofuran-3-yl (tert-butoxycarbonyl) -L-valine ester (348.1).

To a solution of 27.1 (200 mg,0.325 mmol) in DMA (1.0 mL) was added a solution of HCl in 1-4 dioxane (0.2 mL, 4M) and the mixture was stirred at 20deg.C for 15 min. The reaction mixture was then cooled at 0deg.C and acetyl chloride (0.46 mL,6.5 mmol) was added immediately. The reaction was stirred at 20℃for 12h. The reaction was diluted with ACN (1 mL) and purified by preparative HPLC (column: gemini-C18.times.21.2 mm,5 μm; mobile phase: ACN-H ₂ O (0.1% FA; gradient: 40% -70%) to give 348.1 (40 mg,17.8% yield) as a white solid. MS (ESI): the calculated mass for C ₃₂H₄₄N₆O₉ was 656.30 and the measured m/z was 657.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.99(s,1H),8.40(s,1H),7.33(d,J＝4.8Hz,1H),7.11(t,J＝8.0Hz,2H),6.76(d,J＝6.4Hz,1H),5.13(t,J＝5.2Hz,1H),5.10–5.03(m,1H),4.46(d,J＝3.6Hz,1H),4.29(dd,J＝12.4,3.2Hz,1H),4.18(dd,J＝12.4,4.8Hz,1H),4.06(dd,J＝8.0,6.0Hz,1H),2.40(s,3H),2.26–2.16(m,1H),2.15–2.06(m,2H),1.56(s,6H),1.40(s,9H),1.11(d,J＝10.4Hz,3H),0.94–0.80(m,8H).

Synthesis of (2R, 3S,4R, 5R) -5- (4-acetamidopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-2- ((2-cyclohexylacetoxy) methyl) -4-hydroxytetrahydrofuran-3-yl L-valine ester (348).

To a solution of 348.1 (40 mg,0.061 mmol) in THF (1.0 mL) at 0deg.C was added HCl in dioxane (2.0 mL, 4M) and the reaction was stirred at 20deg.C for 2h. After completion, the mixture was concentrated in vacuo to give a residue, which was purified by preparative HPLC (mobile phase: ACN-H ₂ O (0.1% FA), 20% -45%) to give 348 (14.61 mg, 38.9%) as a white solid. MS (ESI): the calculated mass for C ₂₇H₃₆N₆O₇ was 556.26 and the measured m/z was 557.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ11.00(s,1H),8.40(s,1H),7.34(d,J＝4.8Hz,1H),7.10(d,J＝4.8Hz,1H),6.72(d,J＝6.0Hz,1H),5.17–5.12(m,1H),5.10–5.06(m,1H),4.49(d,J＝4.0Hz,1H),4.31–4.26(m,1H),4.24–4.19(m,1H),3.24(d,J＝5.2Hz,1H),2.40(s,3H),2.16–2.09(m,2H),2.03–1.96(m,1H),1.60–1.50(m,6H),1.18–1.05(m,3H),0.92(d,J＝6.8Hz,3H),0.87–0.82(m,5H).

EXAMPLE 200 Synthesis of (2R, 3S,4R, 5R) -5-cyano-2- ((2-cyclohexylacetoxy) methyl) -4-hydroxy-5- (4-isobutyramidopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuran-3-yl L-valine ester (Compound 349).

Synthesis of (2R, 3S,4R, 5R) -5-cyano-2- ((2-cyclohexylacetoxy) methyl) -4-hydroxy-5- (4-isobutyrylaminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuranyl (t-butoxycarbonyl) -L-valine ester (349.1).

Title compound 349.1 was prepared according to the procedure of step 1 of example 199 using 27.1 and isobutyryl chloride. MS (ESI): the calculated mass for C ₃₄H₄₈N₆O₉ was 684.35 and the measured m/z was 685.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.91(s,1H),8.41(s,1H),7.28(d,J＝4.8Hz,1H),7.17–7.04(m,2H),6.77(d,J＝6.4Hz,1H),5.18–5.12(m,1H),5.11–5.07(m,1H),4.53–4.41(m,1H),4.29(dd,J＝12.4,3.6Hz,1H),4.18(dd,J＝12.4,4.8Hz,1H),4.07(dd,J＝8.0,5.6Hz,1H),3.12(dt,J＝13.6,6.8Hz,1H),2.27–2.16(m,1H),2.15–2.06(m,2H),1.62–1.50(m,6H),1.41–1.36(m,9H),1.17–1.04(m,9H),0.95–0.77(m,8H).

Synthesis of (2R, 3S,4R, 5R) -5-cyano-2- ((2-cyclohexylacetoxy) methyl) -4-hydroxy-5- (4-isobutyramidopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuran-3-yl L-valine ester (349).

The title compound 349 was prepared according to the procedure of step 2 of example 199 using 349.1. MS (ESI): the calculated mass for C ₂₉H₄₀N₆O₇ was 584.30 and the measured m/z was 585.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.90(s,1H),8.41(s,1H),7.28(d,J＝4.8Hz,1H),7.11(d,J＝4.8Hz,1H),6.72(d,J＝6.0Hz,1H),5.18–5.12(m,1H),5.11–5.07(m,1H),4.50(q,J＝4.0Hz,1H),4.28(dd,J＝12.4,3.6Hz,1H),4.21(dd,J＝12.4,4.8Hz,1H),3.24(d,J＝5.2Hz,1H),3.16–3.08(m,1H),2.18–2.10(m,2H),2.03–1.95(m,1H),1.61–1.50(m,6H),1.18–1.05(m,9H),0.96–0.80(m,8H).

Example 201 synthesis of (2 r,3s,4r,5 r) -5- (4-butyrylaminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-2- ((2-cyclohexylacetoxy) methyl) -4-hydroxytetrahydrofuran-3-yl L-valine ester (compound 350).

/>

Synthesis of (2R, 3S,4R, 5R) -5- (4-butyrylaminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-2- ((2-cyclohexylacetoxy) methyl) -4-hydroxytetrahydrofuran-3-yl (tert-butoxycarbonyl) -L-valine ester (350.1).

The title compound 350.1 was prepared according to the procedure for step 1 of example 199 using 27.1 and butyryl chloride. MS (ESI): the calculated mass for C ₃₄H₄₈N₆O₉ was 684.35 and the measured m/z was 685.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.94(s,1H),8.40(s,1H),7.32(d,J＝4.8Hz,1H),7.11(t,J＝7.6Hz,2H),6.76(d,J＝6.4Hz,1H),5.13(t,J＝5.2Hz,1H),5.10–5.04(m,1H),4.46(d,J＝4.0Hz,1H),4.29(dd,J＝12.4,3.2Hz,1H),4.22–4.14(m,1H),4.12–4.04(m,1H),2.70(t,J＝7.2Hz,2H),2.26–2.06(m,3H),1.69–1.52(m,8H),1.40(s,9H),1.15–0.81(m,14H).

Synthesis of (2R, 3S,4R, 5R) -5- (4-butyrylaminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-2- ((2-cyclohexylacetoxy) methyl) -4-hydroxytetrahydrofuran-3-yl L-valine ester (350).

Title compound 350 was prepared according to the procedure for step 2 of example 199 using 350.1. MS (ESI): the calculated mass for C ₂₉H₄₀N₆O₇ was 584.30 and the measured m/z was 585.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.94(s,1H),8.40(s,1H),7.32(d,J＝4.8Hz,1H),7.08(d,J＝4.8Hz,1H),6.75–6.70(m,1H),5.16–5.11(m,1H),5.10–5.06(m,1H),4.51–4.47(m,1H),4.31–4.16(m,2H),3.24(d,J＝5.2Hz,1H),2.73–2.66(m,2H),2.19–2.07(m,2H),2.04–1.95(m,1H),1.69–1.51(m,8H),1.19–0.99(m,3H),0.97–0.90(m,6H),0.88–0.82(m,5H).

EXAMPLE 202 Synthesis of (2R, 3R,4R, 5R) -2- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -2-cyano-5- ((2-phenylacetyloxy) methyl) tetrahydrofuran-3, 4-diyl (2S, 2' S) -bis (2-amino-3-methylbutanoate) (Compound 351).

Synthesis of (2R, 3R,4R, 5R) -2- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -2-cyano-5- ((2-phenylacetyloxy) methyl) tetrahydrofuran-3, 4-diyl (2S, 2' S) -bis (2-amino-3-methylbutanoate) (Compound 351).

Compound 351 was prepared according to the procedure of step 2 of example 19 using 351.1. MS (ESI): the calculated mass for C ₃₀H₃₇N₇O₇ was 607.67, the measured m/z was 608.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.02(d,J＝24.0Hz,2H),7.95(s,1H),7.25 -7.20(m,5H),6.95(d,J＝4.4Hz,1H),6.81(d,J＝4.8Hz,1H),6.13(d,J＝6.0Hz,1H),5.46(dd,J＝5.6,4.0Hz,1H),4.57 -4.55(m,1H),4.42(dd,J＝12.4,3.2Hz,1H),4.31(dd,J＝12.4,4.8Hz,1H),3.67(d,J＝2.8Hz,2H),3.30(d,J＝5.2Hz,1H),3.27(d,J＝4.8Hz,1H),2.04 -2.00(m,1H),1.93 -1.90(m,1H),0.90(dd,J＝13.2,6.8Hz,6H),0.85(d,J＝6.8Hz,6H).

Example 203 synthesis of ((2 r,3S,4r,5 r) -5- (4- ((S) -2-amino-3- (4-fluorophenyl) propanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2- (1-aminocyclohexyl) acetate (compound 352).

Synthesis of((3 aR,4R,6 aR) -6- (4- ((S) -2- ((tert-butoxycarbonyl) amino) -3- (4-fluorophenyl) propanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) methyl 2- (1- ((tert-butoxycarbonyl) amino) cyclohexyl) acetate (Compound 352.1).

Compound 352.1 was prepared according to the procedure of step 1 of example 185 using 286.1 and (S) -2- ((tert-butoxycarbonyl) amino) -3- (4-fluorophenyl) propionic acid. MS (ESI): the calculated mass for C ₄₂H₅₄FN₇O₁₀ is 835.93 and the m/z found is 836.2[ M+H ] ⁺.

Synthesis of((2R, 3S,4R, 5R) -5- (4- ((S) -2-amino-3- (4-fluorophenyl) propanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2- (1-aminocyclohexyl) acetate (Compound 352).

Compound 352 was prepared according to the procedure of step 2 of example 49 using 352.1. MS (ESI): the calculated mass for C ₂₉H₃₄FN₇O₆ was 595.63, the measured m/z was 596.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.57(d,J＝8.4Hz,1H),7.91(s,1H),7.69(s,1H),7.39(dd,J＝8.4,5.6Hz,2H),7.17(s,1H),7.09–7.03(m,3H),6.81(d,J＝4.4Hz,1H),6.33–6.30(m,1H),5.50–5.45(m,1H),4.93(dd,J＝13.2,5.6Hz,1H),4.66(d,J＝4.4Hz,1H),4.30(d,J＝10.8Hz,1H),4.24–4.16(m,2H),3.94–3.90(m,1H),3.17(d,J＝10.4Hz,1H),3.01(d,J＝13.6Hz,1H),2.40(s,2H),1.43–1.31(m,10H).¹⁹F NMR(376MHz,DMSO)δ-116.76(s,1F).

Synthesis of((2R, 3S,4R, 5R) -5- (4-acetamidopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-3- (propionyloxy) tetrahydrofuran-2-yl) methyl L-valine ester (Compound 353).

Synthesis of (((2R, 3S,4R, 5R) -5- (4-acetamidopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-3- (propionyloxy) tetrahydrofuran-2-yl) methyl (tert-butoxycarbonyl) -L-valine ester (353.1).

Compound 353.1 was prepared according to the procedure of step 1 of example 195 using 39.1 and AcCl. MS (ESI): the calculated mass for C ₂₇H₃₆N₆O₉ was 588.62 and the m/z found was 589.2[ M+H ] ⁺.

Synthesis of (((2R, 3S,4R, 5R) -5- (4-acetamidopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-3- (propionyloxy) tetrahydrofuran-2-yl) methyl L-valine ester (Compound 353).

Compound 353 was prepared according to the procedure of step 2 of example 19 using 347.1. MS (ESI): the calculated mass for C ₂₂H₂₈N₆O₇ was 488.50 and the measured m/z was 489.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.97(s,1H),8.40(s,1H),7.32(d,J＝4.4Hz,1H),7.10(d,J＝4.8Hz,1H),6.71(d,J＝6.0Hz,1H),5.15(t,J＝5.2Hz,1H),5.05(t,J＝6.0Hz,1H),4.53–4.50(m,1H),4.29–4.24(m,2H),3.09(d,J＝5.2Hz,1H),2.41–2.38(m,5H),1.78–1.73(m,1H),1.09(t,J＝7.2Hz,3H),0.77(dd,J＝22.4,6.8Hz,6H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-butyrylaminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2- (1-aminocyclohexyl) acetate (Compound 354).

Synthesis of((3 aR,4R,6 aR) -6- (4-butyrylaminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) methyl 2- (1- ((tert-butoxycarbonyl) amino) cyclohexyl) acetate (354.1).

Compound 354.1 was prepared according to the procedure of step 1 of example 195 using 286.1 and butyryl chloride. MS (ESI): the calculated mass for C ₃₂H₄₄N₆O₈ was 640.74 and the m/z found was 641.2[ M+H ] ⁺.

Compound 354 was prepared according to the procedure of step 2 of example 49 using 354.1. MS (ESI): the calculated mass for C ₂₄H₃₂N₆O₆ was 500.56, the measured m/z was 501.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.40(s,1H),7.30(d,J＝4.8Hz,1H),7.07(d,J＝4.8Hz,1H),6.46(d,J＝6.0Hz,1H),5.49–5.48(m,1H),4.71(t,J＝4.4Hz,1H),4.38–4.28(m,2H),4.23(dd,J＝11.6,5.6Hz,1H),3.96(t,J＝5.6Hz,1H),2.70(t,J＝7.2Hz,2H),2.55(s,2H),1.68–1.61(m,2H),1.54–1.31(m,10H),0.94(t,J＝7.2Hz,3H).

Synthesis of (2R, 3S,4R, 5R) -5- (4- (((acetoxymethoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-2- ((2-phenylacetyloxy) methyl) tetrahydrofuran-3-yl L-valine ester (Compound 355).

Synthesis of (2R, 3R,4R, 5R) -5- (4- (((acetoxymethoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-2- ((2-phenylacetyloxy) methyl) -4- ((trimethylsilyl) oxy) tetrahydrofuran-3-yl (tert-butoxycarbonyl) -L-valine ester (355.1).

To a solution of 43.1 (80 mg,0.131 mmol) in DCM (5 mL) at 0deg.C was added TMSCL (42.83 mg, 0.390 mmol) and stirred at 20deg.C for 2h. Methyl [ (chlorocarbonyl) oxy ] acetate (60.13 mg, 0.390 mmol) was added to the above solution at 0℃and stirred at 0℃for 2h. The reaction was washed with DCM (5 mL. Times.3). The combined organics were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by preparative HPLC to give 355.1 (25 mg,21% yield) as a white solid. MS (ESI): the calculated m/z for C ₃₇H₄₈N₆O₁₂ Si was 796.91, found to be 797.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ11.52(s,1H),8.29(s,1H),7.30–7.21(m,6H),7.14(d,J＝8.4Hz,1H),6.99–6.95(m,1H),5.79(s,2H),5.26(d,J＝5.2Hz,1H),5.16(t,J＝5.2Hz,1H),4.60–4.48(m,1H),4.40(dd,J＝12.4,3.2Hz,1H),4.30(dd,J＝12.0,5.2Hz,1H),4.04(dd,J＝8.0,6.0Hz,1H),3.69(s,2H),2.20–2.12(m,1H),2.11(s,3H),1.38(s,9H),0.88(t,J＝6.8Hz,6H),0.00(s,9H).

Compound 355 was prepared according to the procedure of step 2 of example 19 using 355.1. MS (ESI): the calculated mass for C ₂₉H₃₂N₆O₁₀ was 624.61, the measured m/z was 625.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.35(s,1H),7.24–7.18(m,6H),7.02(d,J＝4.4Hz,1H),6.69(d,J＝6.0Hz,1H),5.81(s,2H),5.15(t,J＝4.8Hz,1H),5.04–5.02(m,1H),4.50–4.49(m,1H),4.33(dd,J＝12.4,3.2Hz,1H),4.26(dd,J＝12.4,4.8Hz,1H),3.66(s,2H),3.25(d,J＝5.2Hz,1H),2.12(s,3H),2.06–1.97(m,1H),0.89(dd,J＝26.4,6.4Hz,6H).

EXAMPLE 207 (2R, 3R,4R, 5R) -2- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -2-cyano-5- ((2-cyclohexylacetoxy) methyl) tetrahydrofuran-3, 4-diyl (2S, 2' S) -bis (2-amino-3-methylbutanoate) (compound 356.1).

Synthesis of (2R, 3R,4R, 5R) -2- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -2-cyano-5- ((2-cyclohexylacetoxy) methyl) tetrahydrofuran-3, 4-diyl (2S, 2' S) -bis (2- ((tert-butoxycarbonyl) amino) -3-methylbutanoate) (356.1).

To a solution of compound 10 (6.0 g,14.4 mmol) in THF (200 mL) were added (tert-butoxycarbonyl) -L-valine (3.14 g,14.4 mmol), EDCI (8.28 g,43.2 mmol) and DMAP (5.28 g,43.2 mmol), and the mixture was stirred at 25℃for 16h. The organic phase was washed with brine (100 ml×3), then dried over anhydrous sodium sulfate, filtered and concentrated to remove the solvent. The residue was purified by preparative HPLC [ gradient: 70% -95% ACN in water (0.1% FA) ] to obtain 356.1 (3.0 g,26% yield) as a white solid. MS (ESI): the calculated mass for C ₄₀H₅₉N₇O₁₁ was 813.43 and the measured m/z was 814.7[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.95(br s,3H),7.22(d,J＝8.4Hz,1H),7.17(d,J＝8.4Hz,1H),6.93(d,J＝4.4Hz,1H),6.82(d,J＝4.4Hz,1H),6.04(d,J＝6.0Hz,1H),5.46(dd,J＝5.2,3.2Hz,1H),4.52(d,J＝3.2Hz,1H),4.44–4.33(m,1H),4.30–4.23(m,1H),4.12–4.07(m,1H),4.06–3.98(m,1H),2.35–2.25(m,1H),2.20–2.05(m,3H),1.56(s,6H),1.39(d,J＝5.2Hz,16H),1.25–0.99(m,5H),0.98–0.75(m,14H).

Synthesis of (2R, 3R,4R, 5R) -2- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -2-cyano-5- ((2-cyclohexylacetoxy) methyl) tetrahydrofuran-3, 4-diyl (2S, 2' S) -bis (2-amino-3-methylbutanoate) (356).

The title compound 356 was prepared according to the procedure for step 2 of example 199 using 356.1. MS (ESI): the calculated mass for C ₃₀H₄₃N₇O₇ was 613.32 and the measured m/z was 614.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.11–7.90(m,3H),6.95(d,J＝4.8Hz,1H),6.85(d,J＝4.8Hz,1H),6.18(d,J＝6.0Hz,1H),5.51–5.40(m,1H),4.57(dd,J＝7.6,4.0Hz,1H),4.40–4.35(m,1H),4.32–4.25(m,1H),3.38(d,J＝4.8Hz,1H),3.34(d,J＝4.8Hz,1H),2.21–1.92(m,4H),1.65–1.50(m,6H),1.20–1.00(m,3H),0.98–0.80(m,14H).

Synthesis of (+) -5- (4-butyrylaminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-3- (propionyloxy) tetrahydrofuran-2-yl) methyl L-valine ester (Compound 357).

Synthesis of (((2R, 3S,4R, 5R) -5- (4-butyrylaminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-3- (propionyloxy) tetrahydrofuran-2-yl) methyl (tert-butoxycarbonyl) -L-valine ester (357.1).

The title compound 357.1 was prepared according to the procedure of step 1 of example 199 using 39.1 and butyryl chloride. MS (ESI): the calculated mass for C ₂₉H₄₀N₆O₉ was 616.29 and the measured m/z was 617.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.92(s,1H),8.40(s,1H),7.30(d,J＝4.8Hz,1H),7.17(d,J＝8.0Hz,1H),7.10(d,J＝4.8Hz,1H),6.71(d,J＝6.4Hz,1H),5.12(d,J＝5.2Hz,1H),5.05(d,J＝6.0Hz,1H),4.56–4.50(m,1H),4.32–4.24(m,2H),3.88–3.80(m,1H),2.70(t,J＝7.2Hz,2H),2.41(q,J＝7.6Hz,2H),1.99–1.83(m,1H),1.67–1.59(m,2H),1.36(s,8H),1.20(s,1H),1.08(t,J＝7.6Hz,3H),0.94(t,J＝7.6Hz,3H),0.80–0.74(m,6H).

Synthesis of (((2R, 3S,4R, 5R) -5- (4-butyrylaminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-3- (propionyloxy) tetrahydrofuran-2-yl) methyl L-valine ester (357).

The title compound 357 was prepared according to the procedure of step 2 of example 199 using 357.1. MS (ESI): the calculated mass for C ₂₄H₃₂N₆O₇ was 516.23, the measured m/z was 517.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.93(s,1H),8.40(s,1H),7.31(d,J＝4.8Hz,1H),7.10(d,J＝4.8Hz,1H),6.71(d,J＝6.4Hz,1H),5.15(t,J＝5.2Hz,1H),5.06(t,J＝6.0Hz,1H),4.53(q,J＝4.4Hz,1H),4.33–4.24(m,2H),3.09(d,J＝5.2Hz,1H),2.70(t,J＝7.2Hz,2H),2.44–2.38(m,2H),1.78–1.73(m,1H),1.69–1.60(m,2H),1.08(t,J＝7.6Hz,3H),0.94(t,J＝7.2Hz,3H),0.79(d,J＝6.8Hz,3H),0.74(d,J＝6.8Hz,3H).

Example 209 synthesis of (2 r,3s,4r,5 r) -5- (4- (((acetoxymethoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-2- ((2-cyclohexylacetoxy) methyl) -4-hydroxytetrahydrofuran-3-yl L-valine ester (compound 358).

Synthesis of (2R, 3R,4R, 5R) -5- (4- (((acetoxymethoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-2- ((2-cyclohexylacetoxy) methyl) -4- ((trimethylsilyl) oxy) tetrahydrofuran-3-yl (tert-butoxycarbonyl) -L-valine ester (358.1).

To a solution of 27.1 (80.0 mg,0.13 mmol) and pyridine (0.13 mL,1.56 mmol) in DCM (1.0 mL) at 0deg.C was added TMSCl (42.4 mg,0.39 mmol) and the mixture was stirred at 20deg.C for 1h. And methyl [ (chlorocarbonyl) oxy ] acetate (29.8 mg,0.195 mmol) was then added to the reaction at 0℃and the mixture was stirred at 0℃for 1h. The reaction was then diluted with water (50 mL) and extracted with DCM (50 ml×3). The organic phase was washed with brine (50 ml×3), then dried over anhydrous sodium sulfate, filtered and concentrated to remove the solvent. The residue was diluted with ACN (2 mL) and purified by preparative HPLC (mobile phase: ACN-H ₂ O (0.1% FA), 50% -80%) to give 358.1 (25.0 mg,22.8% yield) as a white solid. MS (ESI): the calculated mass for C ₃₇H₅₄N₆O₁₂ Si was 802.36, the measured m/z was 803.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ11.45(s,1H),8.32(s,1H),7.27(s,1H),7.17–7.11(m,1H),7.05(s,1H),5.79(s,2H),5.28(d,J＝5.2Hz,1H),5.16(t,J＝5.2Hz,1H),4.49(dd,J＝8.8,5.2Hz,1H),4.34(dd,J＝12.0,3.2Hz,1H),4.26(dd,J＝12.4,5.2Hz,1H),4.04(dd,J＝8.4,6.0Hz,1H),2.22–2.15(m,2H),2.11(s,3H),1.60(d,J＝13.2Hz,6H),1.38(s,9H),1.26–0.81(m,12H),0.00(s,9H).

Synthesis of (2R, 3S,4R, 5R) -5- (4- (((acetoxymethoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-2- ((2-cyclohexylacetoxy) methyl) -4-hydroxytetrahydrofuran-3-yl L-valine ester (358).

Title compound 358 was prepared according to the procedure of step 2 of example 199 using 358.1. MS (ESI): the calculated mass for C ₂₉H₃₈N₆O₁₀ was 630.26, the measured m/z was 631.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.34(s,1H),7.28–7.25(m,1H),7.08–7.02(m,1H),6.70(d,J＝6.4Hz,1H),5.80(s,2H),5.17–5.13(m,1H),5.11–5.07(m,1H),4.51–4.46(m,1H),4.31–4.26(m,1H),4.24–4.19(m,1H),3.25(d,J＝5.2Hz,1H),2.17–2.09(m,5H),2.04–1.97(m,1H),1.65–1.50(m,7H),1.20–1.05(m,3H),0.95–0.84(m,7H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-acetamidopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2- (1-aminocyclohexyl) acetate (Compound 359).

Synthesis of((3 aR,4R,6 aR) -6- (4-acetamidopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) methyl 2- (1- ((tert-butoxycarbonyl) amino) cyclohexyl) acetate (359.1).

To a solution of 286.1 (250 mg,0.438 mmol) and pyridine (416 mg,5.26 mmol) in DCM (1.0 mL) at 0deg.C was added acetyl chloride (68.8 mg,0.88 mmol), and the reaction was stirred at 0deg.C for 2h. After completion, the mixture was concentrated in vacuo to give a residue, which was purified by preparative HPLC (mobile phase: ACN-H ₂ O (0.1% FA), 40% -70%) to give 359.1 (180 mg,63.7% yield) as a white solid. MS (ESI): the calculated mass for C ₃₀H₄₀N₆O₈ was 612.29, the measured m/z was 613.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.99(s,1H),8.43(s,1H),7.31(d,J＝4.8Hz,1H),7.07(d,J＝4.8Hz,1H),6.26(s,1H),5.41(d,J＝6.2Hz,1H),4.96(dd,J＝6.4,2.8Hz,1H),4.62(s,1H),4.21–4.15(m,1H),4.10–4.05(m,1H),2.48(s,2H),2.39(s,3H),1.96–1.88(m,2H),1.65(s,3H),1.43–1.15(m,20H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-acetamidopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2- (1-aminocyclohexyl) acetate (359).

To a solution of 359.1 (100 mg,0.163 mmol) in THF (1.0 mL) at 0deg.C was added HCl (0.8 mL, 4M), and the reaction was stirred at 0deg.C for 0.5h. After completion, the mixture was concentrated in vacuo to give a residue, which was purified by preparative HPLC [ gradient: 5-35% ACN in water (0.1% FA) ] to give 359 as a white solid (39.5 mg,49.0% yield). MS (ESI): the calculated mass for C ₂₂H₂₈N₆O₆ was 472.21 and the measured m/z was 473.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.41–8.38(m,1H),7.32(d,J＝4.8Hz,1H),7.07(d,J＝4.8Hz,1H),6.60–6.40(m,1H),4.71(d,J＝4.8Hz,1H),4.35–4.25(m,2H),4.23–4.18(m,1H),3.96(t,J＝5.6Hz,1H),2.44(s,2H),2.39(s,3H),1.53–1.29(m,10H).

Example 211 synthesis of (2 r,3s,4r,5 r) -5-cyano-4-hydroxy-2- ((2-phenylacetyloxy) methyl) -5- (4- ((((pivaloyloxy) methoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuran-3-yl L-valine ester (compound 360).

Synthesis of (2R, 3R,4R, 5R) -5-cyano-2- ((2-phenylacetyloxy) methyl) -5- (4- (((((pivaloyloxy) methoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -4- ((trimethylsilyl) oxy) tetrahydrofuran-3-yl (tert-butoxycarbonyl) -L-valine ester (360.1).

Compound 360.1 was prepared according to the procedure of step 1 of example 206 using 43.1 and ((chlorocarbonyl) oxy) methyl pivalate. MS (ESI): the calculated mass for C ₄₀H₅₄N₆O₁₂ Si was 838.99 and the m/z found was 839.3[ M+H ] ⁺.

Synthesis of (2R, 3S,4R, 5R) -5-cyano-4-hydroxy-2- ((2-phenylacetyloxy) methyl) -5- (4- ((((pivaloyloxy) methoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuranyl L-valine ester (Compound 360).

Compound 360 was prepared according to the procedure of step 2 of example 19 using 360.1. MS (ESI): the calculated mass for C ₃₂H₃₈N₆O₁₀ was 666.69 and the measured m/z was 667.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.39(s,1H),7.33–7.17(m,6H),7.06(d,J＝4.4Hz,1H),6.76(d,J＝6.4Hz,1H),5.85(s,2H),5.25–5.15(m,1H),5.05(t,J＝6.0Hz,1H),4.53(d,J＝4.0Hz,1H),4.34–4.24(m,2H),3.66(s,2H),3.50–3.47(m,1H)2.10–2.09(m,1H),1.18(s,9H),0.93(dd,J＝16.0,6.8Hz,6H).

Example 212 synthesis of (2 r,3s,4r,5 r) -5-cyano-2- ((2-cyclohexylacetoxy) methyl) -4-hydroxy-5- (4- ((((pivaloyloxy) methoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuran-3-yl L-valine ester (compound 361).

Synthesis of (2R, 3R,4R, 5R) -5-cyano-2- ((2-cyclohexylacetoxy) methyl) -5- (4- (((((pivaloyloxy) methoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -4- ((trimethylsilyl) oxy) tetrahydrofuran-3-yl (tert-butoxycarbonyl) -L-valine ester (358.1).

The title compound 361.1 was prepared according to the procedure for step 1 of example 209 using 27.1 and (chlorocarbonyl) oxy) methyl pivalate. MS (ESI): calculated mass for C ₄₀H₆₀N₆O₁₂ Si as 844.40, m/z found 845.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ11.31(s,1H),8.41(s,1H),7.36(s,1H),7.15(d,J＝8.4Hz,1H),7.09(s,1H),5.84(s,2H),5.25(s,1H),5.15(t,J＝5.2Hz,1H),4.50(d,J＝4.0Hz,1H),4.34(d,J＝9.6Hz,1H),4.25(dd,J＝12.4,5.2Hz,1H),4.06–4.01(m,1H),2.18–2.08(m,3H),1.59(d,J＝12.0Hz,6H),1.38(s,9H),1.17(s,11H),0.94–0.83(m,9H),0.02(s,9H).

Synthesis of (2R, 3S,4R, 5R) -5-cyano-2- ((2-cyclohexylacetoxy) methyl) -4-hydroxy-5- (4- ((((pivaloyloxy) methoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuranyl-3-L-valine ester (361).

The title compound 361 was prepared according to the procedure of step 2 of example 209 using 361.1. MS (ESI): the calculated mass for C ₃₂H₄₄N₆O₁₀ was 672.31 and the measured m/z was 673.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.34(s,1H),7.26(s,1H),7.06(d,J＝4.8Hz,1H),6.70(d,J＝6.0Hz,1H),5.83(s,2H),5.18–5.12(m,1H),5.10–5.06(m,1H),4.53–4.45(m,1H),4.30–4.26(m,1H),4.24–4.19(m,1H),3.25(d,J＝5.2Hz,1H),2.20–2.06(m,2H),2.03–1.96(m,1H),1.62–1.50(m,6H),1.17(s,9H),1.12–0.98(m,3H),0.96–0.80(m,8H).

EXAMPLE 213 Synthesis of (((2R, 3S,4R, 5R) -5-cyano-4-hydroxy-5- (4-isobutyrylaminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3- (propionyloxy) tetrahydrofuran-2-yl) methyl L-valine ester (Compound 362).

Synthesis of (((2R, 3S,4R, 5R) -5-cyano-4-hydroxy-5- (4-isobutyrylaminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3- (propionyloxy) tetrahydrofuran-2-yl) methyl (t-butoxycarbonyl) -L-valine ester (362.1).

Compound 362.1 was prepared according to the procedure of step 1 of example 195 using 39.1 and isobutyryl chloride. MS (ESI): the calculated mass for C ₂₉H₄₀N₆O₉ was 616.67 and the m/z found was 617.2[ M+H ] ⁺.

Synthesis of (((2R, 3S,4R, 5R) -5-cyano-4-hydroxy-5- (4-isobutyramidopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3- (propionyloxy) tetrahydrofuranyl-2-yl) methyl L-valine ester (Compound 362).

Compound 362 is prepared according to the procedure of step 2 of example 19 using 362.1. MS (ESI): the calculated mass for C ₂₄H₃₂N₆O₇ was 516.56, the measured m/z was 517.1[M+H]⁺.1H NMR(400MHz,DMSO)δ10.90(s,1H),8.41(s,1H),7.27(d,J＝4.8Hz,1H),7.11(d,J＝4.8Hz,1H),6.71(d,J＝6.4Hz,1H),5.15(t,J＝5.2Hz,1H),5.06(t,J＝6.0Hz,1H),4.58–4.50(m,1H),4.33–4.25(m,2H),3.12–3.08(m,2H),2.44–2.38(m,2H),1.77–1.75(m,1H),1.15(d,J＝6.8Hz,6H),1.08(t,J＝7.6Hz,3H),0.77(dd,J＝16.0,9.2Hz,6H).

Synthesis of((2R, 3S,4R, 5R) -5- (4- (((acetoxymethoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2- (1-aminocyclohexyl) acetate (Compound 363).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2- (1- ((tert-butoxycarbonyl) amino) cyclohexyl) acetate (363.1).

Compound 363.1 was prepared according to the procedure of step 1 of example 17 using 363.1.MS (ESI): the calculated mass for C ₂₅H₃₄N₆O₇ was 530.58 and the m/z found was 531.2[ M+H ] ⁺.

Compound 363.2 was prepared according to the procedure of step 1 of example 206 using 363.1 and ((chlorocarbonyl) oxy) methyl acetate. MS (ESI): the calculated mass for C ₃₅H₅₄N₆O₁₁Si₂ was 791.02 and the m/z found was 791.3[ M+H ] ⁺.

Compound 363 was prepared according to the procedure of step 2 of example 19 using 363.2. MS (ESI): synthesis of (((2R, 3S,4R, 5R) -5- (4- (((acetoxymethoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-3- (propionyloxy) tetrahydrofuran-2-yl) methyl L-valine ester (compound 364) with calculated mass of C ₂₄H₃₀N₆O₉ of 546.54, found m/z of 547.1[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.28(s,1H),8.23(s,1H),7.16(d,J＝4.4Hz,1H),6.99(d,J＝4.8Hz,1H),6.43-6.40(m,1H),5.78(s,2H),4.72(d,J＝4.4Hz,1H),4.36–4.24(m,2H),4.20(dd,J＝11.6,5.8Hz,1H),3.96(t,J＝5.8Hz,1H),2.44(s,2H),2.11(s,3H),1.61–1.22(m,10H)..

Synthesis of (((2R, 3R,4R, 5R) -5- (4- (((acetoxymethoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3- (propionyloxy) -4- ((trimethylsilyl) oxy) tetrahydrofuran-2-yl) methyl (tert-butoxycarbonyl) -L-valine ester (364.1).

The title compound 364.1 was prepared according to the procedure of step 1 of example 209 using 39.1 and ((chlorocarbonyl) oxy) methyl acetate. MS (ESI): the calculated mass for C ₃₂H₄₆N₆O₁₂ Si was 734.29 and the measured m/z was 735.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ12.55–10.65(m,1H),8.32(s,1H),7.27(s,1H),7.18(d,J＝8.0Hz,1H),7.07(s,1H),5.79(s,2H),5.27(d,J＝4.4Hz,1H),5.15(t,J＝5.2Hz,1H),4.54(d,J＝4.0Hz,1H),4.36(s,2H),3.90(t,J＝6.8Hz,1H),2.45–2.35(m,2H),2.11(s,3H),2.02–1.94(m,1H),1.37(s,9H),1.07(t,J＝7.6Hz,3H),0.81(d,J＝6.8Hz,6H),-0.01(d,J＝4.4Hz,9H).

Synthesis of (((2R, 3S,4R, 5R) -5- (4- (((acetoxymethoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-3- (propionyloxy) tetrahydrofuran-2-yl) methyl L-valine ester (364).

The title compound 364 was prepared according to the procedure of step 2 of example 209 using 364.1. MS (ESI): the calculated mass for C ₂₄H₃₀N₆O₁₀ was 562.20 and the measured m/z was 563.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.36(s,1H),7.30–7.26(m,1H),7.07(d,J＝4.4Hz,1H),6.70(d,J＝6.4Hz,1H),5.80(s,2H),5.16(t,J＝5.2Hz,1H),5.06(t,J＝6.0Hz,1H),4.55–4.50(m,1H),4.34–4.24(m,2H),3.14(d,J＝5.2Hz,1H),2.41(q,J＝7.6Hz,2H),2.12(s,3H),1.82–1.72(m,1H),1.08(t,J＝7.6Hz,3H),0.80(d,J＝6.8Hz,3H),0.75(d,J＝6.8Hz,3H).

Synthesis of (((2R, 3S,4R, 5R) -5-cyano-4-hydroxy-5- (4- ((((pivaloyloxy) methoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3- (propionyloxy) tetrahydrofuran-2-yl) methyl L-valine ester (Compound 365).

Synthesis of (((2R, 3R,4R, 5R) -5-cyano-5- (4- ((((pivaloyloxy) methoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3- (propionyloxy) -4- ((trimethylsilyl) oxy) tetrahydrofuran-2-yl) methyl (tert-butoxycarbonyl) -L-valine ester (365.1).

The title compound 365.1 was prepared according to the procedure for step 1 of example 209 using 39.1 and ((chlorocarbonyl) oxy) methyl pivalate. MS (ESI): calculated mass for C ₃₅H₅₂N₆O₁₂ Si as 776.34, measured m/z 777.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ11.39(s,1H),8.36(s,1H),7.31(s,1H),7.18(d,J＝8.0Hz,1H),7.09(s,1H),5.83(s,2H),5.25(d,J＝4.8Hz,1H),5.14(t,J＝5.2Hz,1H),4.54(dd,J＝9.2,4.8Hz,1H),4.38–4.34(m,2H),3.98–3.83(m,1H),2.45–2.31(m,2H),2.03–1.90(m,1H),1.40–1.25(m,9H),1.17(s,9H),1.06(t,J＝7.6Hz,3H),0.81(d,J＝6.8Hz,6H),0.00(s,9H).

Synthesis of (((2R, 3S,4R, 5R) -5-cyano-4-hydroxy-5- (4- ((((pivaloyloxy) methoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3- (propionyloxy) tetrahydrofuran-2-yl) methyl L-valine ester (365).

The title compound 365 was prepared according to the procedure for step 2 of example 209 using 365.1. MS (ESI): for a calculated mass of C ₂₇H₃₆N₆O₁₀, 604.25, m/z found is the synthesis of 605.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.35(s,1H),7.27(d,J＝4.4Hz,1H),7.07(d,J＝4.8Hz,1H),6.70(d,J＝6.4Hz,1H),5.83(s,2H),5.15(t,J＝5.2Hz,1H),5.06(t,J＝6.0Hz,1H),4.55–4.49(m,1H),4.34–4.24(m,2H),3.13(d,J＝5.2Hz,1H),2.44–2.36(m,2H),1.81–1.70(m,1H),1.17(s,9H),1.12–1.06(m,3H),0.83–0.78(m,3H),0.77–0.72(m,3H). example 217 ((((2 r,3S,4r,5 r) -5- (4- ((S) -2-amino-3- (4-fluorophenyl) propanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) carbonyl) oxy) methyl acetate (compound 366).

Synthesis of tert-butyl (S) -1- ((7- ((2R, 3R,4S, 5R) -2-cyano-3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) amino) -3- (4-fluorophenyl) -1-oxopropan-2-yl) carbamate (366.1).

Compound 366.1 was prepared according to the procedure of step 1 of example 97 using 137.1. MS (ESI): the calculated mass for C ₂₆H₂₉FN₆O₇ was 556.55 and the m/z found was 557.1[ M+H ] ⁺.

Synthesis of (((((2R, 3S,4R, 5R) -5- (4- ((S) -2- ((tert-butoxycarbonyl) amino) -3- (4-fluorophenyl) propanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) carbonyl) oxy) methyl acetate (366.2).

Pyridine (142.06 mg,1.796 mmol) and [ (chlorocarbonyl) oxy ] methyl acetate (20.55 mg,0.134 mmol) were added to a solution of 366.1 (50 mg,0.089 mmol) in DCM (2 mL) at 0deg.C and the mixture stirred at 25deg.C for 4h. The reaction was washed with DCM (5 mL. Times.3). The combined organics were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by preparative HPLC to give 366.2 (6 mg,9% yield) as a white solid. MS (ESI): the calculated mass for C ₃₀H₃₃FN₆O₁₁ was 672.62 and the measured m/z was 673.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ11.23(s,1H),8.44(s,1H),7.42(t,J＝5.6Hz,2H),7.19–7.15(m,2H),7.12(t,J＝8.4Hz,2H),7.03–7.01(m,1H),6.51(d,J＝5.2Hz,1H),5.67(s,2H),5.55–5.50(m,1H),4.83–4.80(m,1H),4.69(t,J＝4.4Hz,1H),4.49(d,J＝9.2Hz,1H),4.33–4.27(m,2H),3.96–3.92(m,1H),3.11(d,J＝11.4Hz,1H),2.86–2.77(m,1H),1.32(s,9H).

Synthesis of (((((2R, 3S,4R, 5R) -5- (4- ((S) -2-amino-3- (4-fluorophenyl) propanamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) carbonyl) oxy) methyl acetate (Compound 366).

Compound 366 was prepared according to the procedure of step 2 of example 19 using 366.2. MS (ESI): the calculated mass for C ₂₅H₂₅FN₆O₉ was 572.51 and the measured m/z was 573.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.59(d,J＝8.0Hz,1H),7.90(s,1H),7.69(s,1H),7.38(dd,J＝8.0,6.0Hz,2H),7.17(s,1H),7.06–7.03(m,3H),6.77(d,J＝4.4Hz,1H),6.38(d,J＝6.0Hz,1H),5.67(s,2H),5.50(d,J＝5.6Hz,1H),4.93–4.90(m,1H),4.65(t,J＝5.2Hz,1H),4.44–4.42(m,1H),4.35–4.20(m,2H),3.93–3.92(m,1H),3.18(dd,J＝14.0,3.6Hz,1H),3.07–2.98(m,1H),2.08(s,3H).¹⁹F NMR(377MHz,DMSO)δ-116.75(s,1F).

Synthesis of (((7- ((2R, 3R,4S, 5R) -5- ((2- (1-aminocyclohexyl) acetoxy) methyl) -2-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) carbamoyl) oxy) methyl pivalate (Compound 367).

Synthesis of(((7- ((2R, 3R,4R, 5R) -5- ((2- (1- ((tert-butoxycarbonyl) amino) cyclohexyl) acetoxy) methyl) -2-cyano-3, 4-bis ((trimethylsilyl) oxy) tetrahydrofuran-2-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) carbamoyl) oxy) methyl pivalate (367.1).

Compound 367.1 was prepared according to the procedure of step 1 of example 206 using 363.1 and ((chlorocarbonyl) oxy) methyl pivalate. MS (ESI): the calculated mass for C ₃₈H₆₀N₆O₁₁Si₂ was 833.10 and the m/z found was 833.3[ M+H ] ⁺.

The title compound 367 was prepared according to the procedure of step 2 of example 19 using 367.1. MS (ESI): calculated mass for C ₂₇H₃₆N₆O₉ was 588.62, measured m/z 589.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.27(s,1H),7.12(d,J＝4.4Hz,1H),6.97(d,J＝4.8Hz,1H),6.43–6.40(m,1H),5.80(s,2H),4.71(d,J＝4.4Hz,1H),4.35–4.14(m,3H),3.96(t,J＝5.2Hz,1H),2.40(s,2H),1.66–1.21(m,10H),1.17(s,9H).

Synthesis of (2R, 3S,4R, 5R) -2- ((2- (1-aminocyclohexyl) acetoxy) methyl) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxytetrahydrofuran-3-yl 2-cyclohexylacetate (Compound 368).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2- (1- ((tert-butoxycarbonyl) amino) cyclohexyl) acetate (368.1).

The title compound 368.1 was prepared according to the procedure for step 1 of example 17 using 288.1 and tsoh·h ₂ O. MS (ESI): the calculated mass for C ₂₅H₃₄N₆O₇ was 530.25 and the measured m/z was 531.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92(br s,3H),6.91(d,J＝4.8Hz,1H),6.81(d,J＝4.8Hz,1H),6.32–6.26(m,2H),5.35(d,J＝6.0Hz,1H),4.71(t,J＝5.6Hz,1H),4.29–4.21(m,2H),4.16–4.10(m,1H),3.96–3.90(m,1H),2.60(s,2H),2.02–1.96(m,2H),1.49–1.16(m,17H).

Synthesis of (2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -2- ((2- (1- ((tert-butoxycarbonyl) amino) cyclohexyl) acetoxy) methyl) -5-cyano-4-hydroxytetrahydrofuran-3-yl 2-cyclohexylacetate (368.2).

To a solution of 368.1 (250 mg,0.471 mmol) in THF (10 mL) were added cyclohexylacetic acid (70.4 mg,0.494 mmol), EDCI (271mg, 1.414 mmol) and DMAP (172.7 mg,1.414 mmol), and the mixture was stirred at 25℃for 16h. After completion, the mixture was concentrated in vacuo to give a residue. The reaction residue was then diluted with water (50 mL) and extracted with EtOAc (50 ml×3). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The residue was purified by preparative HPLC [ gradient: 40-70% ACN in water (0.1% FA) ] to give 368.2 (65 mg,20% yield) as a white solid. MS (ESI): the calculated mass for C ₃₃H₄₆N₆O₈ was 654.34 and the measured m/z was 655.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92(br s,3H),6.93(d,J＝4.4Hz,1H),6.86(d,J＝4.4Hz,1H),6.59(d,J＝5.6Hz,1H),6.27(s,1H),5.11(d,J＝4.4Hz,2H),4.44(d,J＝3.6Hz,1H),4.26(dd,J＝12.0,3.6Hz,1H),4.19(dd,J＝12.0,5.6Hz,1H),2.62–2.54(m,2H),2.26(d,J＝6.8Hz,2H),1.95(s,2H),1.77(dd,J＝11.6,8.0Hz,3H),1.62(t,J＝14.8Hz,3H),1.40–1.06(m,20H),1.01–0.88(m,2H).

Synthesis of (2R, 3S,4R, 5R) -2- ((2- (1-aminocyclohexyl) acetoxy) methyl) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxytetrahydrofuran-3-yl 2-cyclohexylacetate (368).

The title compound 368 was prepared according to the procedure for step 2 of example 209 using 368.2. MS (ESI): synthesis of (2R, 3S,4R, 5R) -5- (4- (((acetoxymethoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-2- (hydroxymethyl) tetrahydrofuran-3-yl 2-cyclohexylacetate (compound 369) having a calculated mass of 554.29 for C ₂₈H₃₈N₆O₆, m/z found 555.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92(br s,3H),6.93(d,J＝4.4Hz,1H),6.87(d,J＝4.8Hz,1H),6.68–6.56(m,1H),5.21–5.01(m,2H),4.50–4.41(m,1H),4.32–4.22(m,2H),2.39–2.37(m,2H),2.26(d,J＝6.8Hz,2H),1.78–1.46(m,8H),1.46–1.06(m,11H),1.03–0.89(m,2H)..

Synthesis of (6 aR,8R,9 aS) -8- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -9-hydroxy-2, 4-tetraisopropyltetrahydro-6H-furo [3,2-f ] [1,3,5,2,4] trioxadisilacyclooctane-8-carbonitrile (369.1).

To a solution of 6.3 (4 g,0.013 mol) and imidazole (5.6 g,0.082 mol) in DMF (40 mL) was added chloro [ (chlorodiisopropylsilyl) oxy ] diisopropylsilane (5.19 g,0.016 mmol) at 0deg.C and the mixture was stirred at 25deg.C for 4h. The reaction was extracted with EA (10 mL. Times.3). The combined organics were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (0% to 30% EA/PE) to give 369.1 (5.00 g,65% yield) as a white solid. MS (ESI): the calculated mass for C ₂₄H₃₉N₅O₅Si₂ was 533.78 and the m/z found was 534.2[ M+H ] ⁺.

Synthesis of (6 aR,8R,9 aR) -8- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -8-cyano-2, 4-tetraisopropyltetrahydro-6H-furo [3,2-f ] [1,3,5,2,4] trioxadisilacyclooctane-9-yl 2-cyclohexylacetate (369.2).

Compound 369.2 was prepared according to the procedure of step 1 of example 19 using 369.1 and 2-cyclohexylacetic acid. MS (ESI): the calculated mass for C ₃₂H₅₁N₅O₆Si₂ was 657.96 and the measured m/z was 658.3[M+H]⁺.1H NMR(400MHz,DMSO)δ8.01(d,J＝18.8Hz,2H),7.89(s,1H),6.93(d,J＝4.4Hz,1H),6.82(d,J＝4.4Hz,1H),5.87(d,J＝5.2Hz,1H),4.54(dd,J＝8.8,5.2Hz,1H),4.14(t,J＝10.4Hz,2H),4.01–3.91(m,1H),2.35(d,J＝6.4Hz,2H),1.88–1.72(m,3H),1.62–1.60(m,3H),1.23–1.09(m,3H),1.08–0.84(m,30H).

Synthesis of (6 aR,8R,9 aR) -8- (4- (((acetoxymethoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -8-cyano-2, 4-tetraisopropyltetrahydro-6H-furo [3,2-f ] [1,3,5,2,4] trioxadisilacyclooctane-9-yl 2-cyclohexyl acetate (369.3).

Compound 369.3 was prepared according to the procedure of step 1 of example 206 using 369.2 and ((chlorocarbonyl) oxy) methyl acetate. MS (ESI): the calculated mass for C ₃₆H₅₅N₅O₁₀Si₂ was 774.03 and the m/z found was 774.3[ M+H ] ⁺.

Synthesis of (2R, 3S,4R, 5R) -5- (4- (((acetoxymethoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-2- (hydroxymethyl) tetrahydrofuran-3-yl 2-cyclohexylacetate (Compound 369).

Compound 369 was prepared according to the procedure of step 1 of example 97 using 369.3. MS (ESI): the calculated mass for C ₂₄H₂₉N₅O₉ was 531.52 and the measured m/z was 532.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ11.28(s,1H),8.43(s,1H),7.31–7.30(m,1H),7.11–7.10(m,1H),6.58(d,J＝6.8Hz,1H),5.81(s,2H),5.26–5.14(m,1H),5.04(t,J＝5.6Hz,1H),4.95(t,J＝6.0Hz,1H),4.28–4.26(m,1H),3.75–3.43(m,2H),2.27(d,J＝6.8Hz,2H),2.12(s,3H),1.85–1.58(m,6H),1.28–1.09(m,3H),0.96–0.90(m,2H).

Synthesis of (((7- ((2R, 3R,4S, 5R) -2-cyano-4- (2-cyclohexylacetoxy) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) carbamoyl) oxy) methyl pivalate (Compound 370).

Synthesis of (((7- ((6 aR,8R,9 aR) -8-cyano-9- (2-cyclohexylacetoxy) -2, 4-tetraisopropyltetrahydro-6H-furo [3,2-f ] [1,3,5,2,4] trioxadisilacyclooctane-8-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) carbamoyl) oxy) methyl pivalate (370.1).

Compound 370.1 was prepared according to the procedure of step 1 of example 206 using 369.2 and ((chlorocarbonyl) oxy) methyl pivalate. MS (ESI): the calculated mass for C ₃₉H₆₁N₅O₁₀Si₂ was 816.11 and the m/z found was 816.3[ M+H ] ⁺.

The title compound 370 was prepared according to the procedure for step 1 of example 97 using 370.1. MS (ESI): synthesis of (((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3- (2-cyclohexylacetoxy) -4-hydroxytetrahydrofuran-2-yl) methyl (S) -2-amino-3, 3-dimethylbutyrate (compound 371) with mass 573.60 calculated for C ₂₇H₃₅N₅O₉ and m/z found 574.3[M+H]1H NMR(400MHz,DMSO)δ11.28(s,1H),8.42(s,1H),7.30–7.28(s,1H),7.11–7.09(s,1H),6.58(d,J＝6.4Hz,1H),5.84(s,2H),5.31–5.13(m,1H),5.03(t,J＝5.6Hz,1H),4.94(t,J＝6.0Hz,1H),4.28(d,J＝3.6Hz,1H),3.69–3.46(m,2H),2.26(d,J＝6.8Hz,2H),1.88–1.70(m,3H),1.62–1.58(m,3H),1.25–1.10(m,12H),1.02–0.91(m,2H)..

/>

Synthesis of((3 aR,4R,6 aR) -6- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) methyl (S) -2- ((tert-butoxycarbonyl) amino) -3, 3-dimethylbutyrate (371.1).

To a solution of 6.4 (1.50 g,4.53 mmol) in THF (80 mL) was added (2S) -2- { [ (tert-butoxy) carbonyl ] amino } -3, 3-dimethylbutyric acid (1.35 g,5.85 mmol), EDCI (2.59 g,13.5 mmol) and DMAP (1.65 g,13.5 mmol), and the mixture was stirred at 25℃for 16h. After completion, the mixture was concentrated in vacuo to give a residue. The reaction residue was then diluted with water (100 mL) and extracted with EtOAc (100 ml×3). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a crude product. The residue was purified by preparative HPLC [ gradient: 5-40% ACN in water (0.1% FA) ] to obtain 371.1 (1.80 g,69% yield) as a white solid. MS (ESI): the calculated mass for C ₂₆H₃₆N₆O₇ was 544.26, the measured m/z was 545.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.95(br s,3H),7.09(d,J＝8.4Hz,1H),6.90(d,J＝4.4Hz,1H),6.85(d,J＝4.4Hz,1H),5.44(d,J＝6.4Hz,1H),4.94(dd,J＝6.4,3.2Hz,1H),4.52(s,1H),4.27–4.20(m,1H),4.17–4.11(m,1H),3.82(d,J＝8.4Hz,1H),1.64(s,3H),1.40–1.26(m,1H),0.87(s,9H).

((2R, 3S,4R, 5R) -5- (4-Aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl (S) -2- ((tert-butoxycarbonyl) amino) -3, 3-dimethylbutyrate (371.2).

The title compound 371.2 was prepared according to the procedure for step 1 of example 17 using 371.1 and TsOH H ₂ O. MS (ESI): the calculated mass for C ₂₃H₃₂N₆O₇ was 504.23, the measured m/z was 505.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92(br s,3H),7.05(d,J＝8.4Hz,1H),6.92(d,J＝4.4Hz,1H),6.83(d,J＝4.4Hz,1H),6.33(d,J＝6.0Hz,1H),5.39(d,J＝6.0Hz,1H),4.70(t,J＝5.6Hz,1H),4.40–4.14(m,3H),3.96–3.80(m,2H),1.43–1.29(m,9H),0.89(s,9H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3- (2-cyclohexylacetoxy) -4-hydroxytetrahydrofuran-2-yl) methyl (S) -2- ((tert-butoxycarbonyl) amino) -3, 3-dimethylbutyrate (371.3).

The title compound 371.3 was prepared according to the procedure for step 2 of example 17 using 371.2 and 2-cyclohexylacetyl chloride. MS (ESI): the calculated mass for C ₃₁H₄₄N₆O₈ was 628.32, the measured m/z was 629.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.93(br s,3H),7.07(d,J＝8.4Hz,1H),6.93(d,J＝4.8Hz,1H),6.88(d,J＝4.8Hz,1H),6.66–6.59(m,1H),5.09(d,J＝5.2Hz,2H),4.46(d,J＝4.0Hz,1H),4.33–4.25(m,2H),3.84(d,J＝8.4Hz,1H),2.25(d,J＝6.4Hz,2H),1.80–1.68(m,3H),1.66–1.55(m,3H),1.37(s,7H),1.29–1.04(m,5H),1.02–0.91(m,2H),0.85(s,9H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3- (2-cyclohexylacetoxy) -4-hydroxytetrahydrofuran-2-yl) methyl (S) -2-amino-3, 3-dimethylbutyrate (371).

The title compound 371 was prepared according to the procedure for step 2 of example 209 using 371.3. MS (ESI): the calculated mass for C ₂₈H₃₈N₆O₆ was 528.27 and the measured m/z was 529.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92(br s,3H),6.93(d,J＝4.4Hz,1H),6.87(d,J＝4.8Hz,1H),6.62(d,J＝6.0Hz,1H),5.13–5.07(m,2H),4.49–4.44(m,1H),4.37–4.17(m,2H),2.96(s,1H),2.25(d,J＝6.4Hz,2H),1.81–1.55(m,6H),1.31–1.07(m,3H),1.00–0.89(m,2H),0.86–0.78(m,9H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3- (2-cyclohexylacetoxy) -4-hydroxytetrahydrofuran-2-yl) methyl L-phenylalanine ester (Compound 372).

Synthesis of((3 aR,4R,6 aR) -6- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6-cyano-2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) methyl (tert-butoxycarbonyl) -L-phenylalanine ester (372.1).

The title compound 372.1 was prepared according to the procedure for step 1 of example 19 using 6.4 and (tert-butoxycarbonyl) -L-phenylalanine. MS (ESI): the calculated mass for C ₂₉H₃₄N₆O₇ was 578.63 and the m/z found was 579.2[ M+H ] ⁺.

Synthesis of (((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl (tert-butoxycarbonyl) -L-phenylalanine ester (372.2).

The title compound 372.2 was prepared according to the procedure of step 1 of example 17 using 372.2.MS (ESI): the calculated mass for C ₂₆H₃₀N₆O₇ was 538.56 and the m/z found was 539.2[ M+H ] ⁺.

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3- (2-cyclohexylacetoxy) -4-hydroxytetrahydrofuran-2-yl) methyl (tert-butoxycarbonyl) -L-phenylalanine ester (372.3).

The title compound 372.3 was prepared according to the procedure for step 1 of example 19 using 372.2 and 2-cyclohexylacetic acid. MS (ESI): the calculated mass for C ₃₄H₄₂N₆O₈ was 662.74 and the m/z found was 663.4[ M+H ] ⁺.

The title compound 372 was prepared according to the procedure of step 2 of example 19 using 372.3. MS (ESI): the calculated mass for C ₂₉H₃₄N₆O₆ was 562.63 and the measured m/z was 563.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92(brs,3H),7.22–7.09(m,5H),6.93(d,J＝4.4Hz,1H),6.87(d,J＝4.8Hz,1H),6.59(d,J＝6.0Hz,1H),5.08–5.05(m,2H),4.44(dd,J＝8.0,4.0Hz,1H),4.22–4.17(m,2H),3.55(t,J＝6.4Hz,1H),2.75–2.69(m,2H),2.27(d,J＝6.8Hz,2H),1.83–1.59(m,6H),1.25–1.07(m,3H),1.00–0.89(m,2H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-acetamidopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3- (2-cyclohexylacetoxy) -4-hydroxytetrahydrofuran-2-yl) methyl (S) -2-amino-3, 3-dimethylbutyrate (Compound 373).

Synthesis of((2R, 3R,4R, 5R) -5- (4-acetamidopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3- (2-cyclohexylacetoxy) -4- ((trimethylsilyl) oxy) tetrahydrofuran-2-yl) methyl (S) -2- ((tert-butoxycarbonyl) amino) -3, 3-dimethylbutyrate (373.1).

The title compound 373.1 was prepared according to the procedure for step 1 of example 209 using 371.3 and acetyl chloride. MS (ESI): calculated mass for C ₃₆H₅₄N₆O₉ Si was 742.37, measured m/z 743.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.99(s,1H),8.38(s,1H),7.35(d,J＝4.8Hz,1H),7.19–7.06(m,2H),5.31(d,J＝5.2Hz,1H),5.18(t,J＝5.2Hz,1H),4.54(dd,J＝9.2,4.8Hz,1H),4.36(s,2H),3.88(d,J＝8.4Hz,1H),2.39(s,3H),2.29–2.21(m,2H),1.80–1.67(m,3H),1.70–1.54(m,3H),1.45–1.30(m,9H),1.23–1.05(m,3H),1.04–0.92(m,2H),0.87(s,9H),-0.03(s,9H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-acetamidopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3- (2-cyclohexylacetoxy) -4-hydroxytetrahydrofuran-2-yl) methyl (S) -2-amino-3, 3-dimethylbutyrate (373).

The title compound 373 was prepared according to the procedure of step 2 of example 209 using 373.1. MS (ESI): the calculated mass for C ₂₈H₃₈N₆O₇ was 570.28, the measured m/z was 571.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.99(s,1H),8.40(s,1H),7.32(d,J＝4.8Hz,1H),7.11(d,J＝4.8Hz,1H),6.80–6.68(m,1H),5.17–5.11(m,1H),5.09–5.04(m,1H),4.54–4.48(m,1H),4.33–4.22(m,2H),2.98–2.96(m,1H),2.40(s,3H),2.28–2.25(m,2H),1.80–1.69(m,3H),1.67–1.56(m,3H),1.27–1.08(m,3H),1.00–0.89(m,2H),0.85–0.79(m,9H).

Synthesis of((7- ((2R, 3R,4S, 5R) -5- (((L-phenylalanyl) oxy) methyl) -2-cyano-4- (2-cyclohexylacetoxy) -3-hydroxytetrahydrofuran-2-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) carbamoyl) oxy) methyl pivalate (Compound 374).

Synthesis of (((7- ((2R, 3R,4R, 5R) -5- ((((tert-butoxycarbonyl) -L-phenylalanyl) oxy) methyl) -2-cyano-4- (2-cyclohexylacetoxy) -3- ((trimethylsilyl) oxy) tetrahydrofuran-2-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) carbamoyl) oxy) methyl pivalate (374.1).

The title compound 374.1 was prepared according to the procedure for step 1 of example 206 using 372.3 and ((chlorocarbonyl) oxy) methyl pivalate. MS (ESI): the calculated mass for C ₄₄H₆₀N₆O₁₂ Si was 893.08 and the m/z found was 893.4[ M+H ] ⁺.

Synthesis of (((7- ((2R, 3R,4S, 5R) -5- (((L-phenylalanyl) oxy) methyl) -2-cyano-4- (2-cyclohexylacetoxy) -3-hydroxytetrahydrofuran-2-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) carbamoyl) oxy) methyl pivalate (Compound 374).

Compound 374.1 was prepared according to the procedure of step 2 of example 19 using 374.1.MS (ESI): the calculated mass for C ₃₆H₄₄N₆O₁₀ was 720.78 and the measured m/z was 721.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.35(s,1H),7.27(d,J＝4.0Hz,1H),7.18–7.06(m,6H),6.69(d,J＝6.0Hz,1H),5.83(s,2H),5.15–4.97(m,2H),4.48–4.46(m,1H),4.25–4.17(m,2H),3.55(t,J＝6.8Hz,1H),2.82–2.70(m,2H),2.27(d,J＝6.8Hz,2H),1.87–1.57(m,7H),1.26–1.17(m,11H),0.99–0.90(m,2H).

EXAMPLE 226 Synthesis of ((2R, 3S,4R, 5R) -5-cyano-3, 4-dihydroxy-5- (4- ((((pivaloyloxy) methoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuranyl-2-cyclohexyl-2-methylpropionate (Compound 375).

Synthesis of (((7- ((2R, 3R,4R, 5R) -2-cyano-5- (((2-cyclohexyl-2-methylpropanoyl) oxy) methyl) -3, 4-bis ((trimethylsilyl) oxy) tetrahydrofuran-2-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) carbamoyl) oxy) methyl pivalate (375.1).

The title compound 375.1 was prepared according to the procedure of step 1 of example 206 using 269 and ((chlorocarbonyl) oxy) methyl pivalate. MS (ESI): the calculated mass for C ₃₅H₅₅N₅O₉Si₂ was 746.02 and the m/z found was 746.4[ M+H ] ⁺.

Synthesis of (((2R, 3S,4R, 5R) -5-cyano-3, 4-dihydroxy-5- (4- ((((pivaloyloxy) methoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuranyl-2-yl) methyl 2-cyclohexyl-2-methylpropionate (Compound 375).

The title compound 375 was prepared according to the procedure of step 2 of example 19 using 375.1. MS (ESI): the calculated mass for C ₂₉H₃₉N₅O₉ was 601.66 and the measured m/z was 602.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ11.27(s,1H),8.40(s,1H),7.31–7.30(m,1H),7.05–7.04(m,1H),6.45(d,J＝6.0Hz,1H),5.84(s,2H),5.43(d,J＝6.0Hz,1H),4.71(t,J＝5.6Hz,1H),4.34–4.25(m,1H),4.19(d,J＝3.6Hz,2H),3.99–3.96(m,1H),1.67–1.47(m,3H),1.45–1.29(m,3H),1.17(s,9H),1.05–0.78(m,11H).

Synthesis of((2R, 3S,4R, 5R) -5- (4- ((butoxycarbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2-cyclohexyl-2-methylpropionate (Compound 379).

The title compound was prepared according to the procedure for example 57 using 2-cyclohexyl-2-methylpropanoyl chloride. MS (ESI): the calculated mass for C ₂₇H₃₇N₅O₇ was 543.27 and the m/z found was 544.2[ M+H ] ⁺.

Example 228 synthesis of (2 r,3s,4r,5 r) -5-cyano-4-hydroxy-5- (4- ((((5-methyl-2-oxo-1, 3-dioxol-4-yl) methoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -2- ((2-phenylacetyloxy) methyl) tetrahydrofuran-3-yl L-valine ester (compound 383).

The title compound was prepared according to the procedure for example 206 using (5-methyl-2-oxo-1, 3-dioxol-4-yl) methylcarbonyl chloride in step 1. MS (ESI): the calculated mass for C ₃₁H₃₂N₆O₁₁ was 664.21 and the measured m/z was 665.2[ M+H ] ⁺.

Example 229 synthesis of (2 r,3s,4r,5 r) -5-cyano-2- ((2-cyclohexylacetoxy) methyl) -4-hydroxy-5- (4- ((((5-methyl-2-oxo-1, 3-dioxol-4-yl) methoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuran-3-yl L-valine ester (compound 385).

The title compound was prepared according to the procedure for example 209 using (5-methyl-2-oxo-1, 3-dioxol-4-yl) methylcarbonyl chloride in step 1. MS (ESI): the calculated mass for C ₃₁H₃₈N₆O₁₁ was 670.26 and the m/z found was 671.2[ M+H ] ⁺.

Example 230 synthesis of (2 r,3s,4r,5 r) -5-cyano-2- ((2-cyclohexylacetoxy) methyl) -4-hydroxy-5- (4- ((((5-methyl-2-oxo-1, 3-dioxol-4-yl) methoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuran-3-yl L-valine ester (compound 392).

The title compound was prepared according to the procedure for example 18 using compound 411.2 in step 1.MS (ESI): the calculated mass for C ₂₆H₃₆N₆O₆ was 528.27 and the measured m/z was 529.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.93(br s,3H),6.92(d,J＝4.4Hz,1H),6.86(d,J＝4.8Hz,1H),6.58(d,J＝6.0Hz,1H),5.19–5.14(m,1H),5.11(t,J＝6.0Hz,1H),4.45(dd,J＝8.8,4.4Hz,1H),4.32–4.18(m,2H),2.96(s,1H),2.26(d,J＝6.8Hz,2H),1.78–1.70(m,3H),1.69–1.54(m,3H),1.29–1.08(m,3H),1.28–1.10(m,2H),0.85–0.74(m,9H).

Synthesis of((2R, 3S,4R, 5R) -5-cyano-3, 4-dihydroxy-5- (4- ((((pivaloyloxy) methoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuranyl-2-yl) methyl (S) -2-amino-3, 3-dimethylbutyrate (compound 395).

The title compound was prepared according to the procedure for example 218 using compound 411.2 in step 1. MS (ESI): the calculated mass for C ₂₅H₃₄N₆O₉ was 562.24 and the measured m/z was 563.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.37(s,1H),7.29(d,J＝4.4Hz,1H),7.07(d,J＝4.8Hz,1H),6.45(d,J＝6.0Hz,1H),5.84(s,2H),5.46(d,J＝5.6Hz,1H),4.72–4.67(m,1H),4.31–4.23(m,3H),3.94(d,J＝4.4Hz,1H),3.07(s,1H),1.17(s,9H),0.84(s,9H).

Synthesis of (2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-2- ((2-cyclohexylacetoxy) methyl) -4-hydroxytetrahydrofuran-3-yl (S) -2-amino-3, 3-dimethylbutyrate (Compound 397).

The title compound was prepared according to the procedure for example 16 using (R) -Boc-tert-leucine in step 1. MS (ESI): the calculated mass for C ₂₆H₃₆N₆O₆ was 528.27 and the measured m/z was 529.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.98–7.93(m,3H),6.94(d,J＝4.4Hz,1H),6.86(d,J＝4.4Hz,1H),6.63–6.60(m,1H),5.22–4.98(m,2H),4.46(dd,J＝8.4,4.4Hz,1H),4.30(dd,J＝12.4,3.6Hz,1H),4.25–4.15(m,1H),3.08(s,1H),2.15(dd,J＝6.8,3.6Hz,2H),1.58–1.57(m,6H),1.11–1.08(m,3H),1.00–0.77(m,11H).

Synthesis of (2R, 3S,4R, 5R) -5- (4- (((acetoxymethoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-2- ((2-phenylacetyloxy) methyl) tetrahydrofuran-3-yl (S) -2-amino-3, 3-dimethylbutyrate (Compound 399).

/>

Synthesis of (2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-2- ((2-phenylacetyloxy) methyl) tetrahydrofuran-3-yl (S) -2- ((tert-butoxycarbonyl) amino) -3, 3-dimethylbutyrate (399.1).

The title compound was prepared according to the procedure for example 212 using compound 11 and (R) -Boc-tert-leucine.

Synthesis of (2R, 3S,4R, 5R) -5- (4- (((acetoxymethoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-2- ((2-phenylacetyloxy) methyl) tetrahydrofuran-3-yl (S) -2- ((tert-butoxycarbonyl) amino) -3, 3-dimethylbutyrate (399.2).

The title compound was prepared from compound 399.1 according to the procedure for step 1 of example 206.

The title compound was prepared according to the procedure for step 2 of example 206. MS (ESI): the calculated mass for C ₃₀H₃₄N₆O₁₀ was 638.23 and the measured m/z was 639.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.38(s,1H),7.42–7.14(m,6H),7.04(d,J＝4.4Hz,1H),6.70(d,J＝6.4Hz,1H),5.81(s,2H),5.20–5.10(m,1H),5.04(t,J＝6.0Hz,1H),4.51(dd,J＝8.0,4.4Hz,1H),4.33(dd,J＝12.4,3.6Hz,1H),4.25(dd,J＝12.4,5.2Hz,1H),3.66(s,2H),3.11(s,1H),2.12(s,3H),0.93(s,9H).

Synthesis of (2R, 3S,4R, 5R) -5-cyano-4-hydroxy-5- (4-isobutyramidopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -2- ((2-phenylacetyloxy) methyl) tetrahydrofuran-3-yl (S) -2-amino-3, 3-dimethylbutyrate (Compound 401).

The title compound was prepared according to the procedure for example 198 using compound 399.1 in step 2. MS (ESI): the calculated mass for C ₃₀H₃₆N₆O₇ was 592.26 and the measured m/z was 593.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.92(s,1H),8.41(s,1H),7.32–7.15(m,6H),7.08(d,J＝4.8Hz,1H),6.71(d,J＝6.4Hz,1H),5.17–5.08(m,1H),5.05(t,J＝6.0Hz,1H),4.52(dd,J＝8.0,4.4Hz,1H),4.33(dd,J＝12.0,3.6Hz,1H),4.25(dd,J＝12.4,4.8Hz,1H),3.66(s,2H),3.18–3.11(m,1H),3.09(s,1H),1.16(d,J＝6.8Hz,6H),0.93(s,9H).

Synthesis of (2R, 3S,4R, 5R) -5-cyano-4-hydroxy-5- (4-isobutyramidopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -2- ((2-phenylacetyloxy) methyl) tetrahydrofuran-3-yl (S) -2-amino-3, 3-dimethylbutyrate (Compound 402).

The title compound was prepared according to the procedure for example 224 using ((chlorocarbonyl) oxy) methyl acetate instead of acetyl chloride in step 1. MS (ESI): the calculated mass for C ₃₀H₄₀N₆O₁₀ was 644.28 and the measured m/z was 645.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.37(s,1H),7.29(d,J＝4.8Hz,1H),7.09(d,J＝4.8Hz,1H),6.73(d,J＝6.4Hz,1H),5.81(s,2H),5.22–5.09(m,1H),5.06(t,J＝6.0Hz,1H),4.51(dd,J＝8.4,4.4Hz,1H),4.33–4.22(m,2H),3.00–2.94(m,1H),2.35–2.24(m,2H),2.12(s,3H),1.83–1.68(m,3H),1.67–1.56(m,3H),1.27–1.08(m,3H),1.01–0.92(m,2H),0.86–0.75(m,9H).

Synthesis of (2R, 3S,4R, 5R) -5-cyano-4-hydroxy-5- (4-isobutyramidopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -2- ((2-phenylacetyloxy) methyl) tetrahydrofuran-3-yl (S) -2-amino-3, 3-dimethylbutyrate (Compound 409).

Step 1: synthesis of (((2R, 3R,4R, 5R) -5- (4-butyrylaminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-bis ((trimethylsilyl) oxy) tetrahydrofuran-2-yl) methyl 2-cyclohexylacetate (409.1).

Compound 409.1 was prepared according to the procedure of step 1 of example 206 using 10 and butyryl chloride. MS (ESI): the calculated mass for C ₃₀H₄₇N₅O₆Si₂ was 629.31, the measured m/z was 630.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.93(s,1H),8.38(s,1H),7.33(d,J＝4.8Hz,1H),7.04(d,J＝4.8Hz,1H),4.93(d,J＝4.0Hz,1H),4.41(dd,J＝12.4,3.2Hz,1H),4.28(dt,J＝7.2,3.6Hz,1H),4.18–4.09(m,2H),2.69(t,J＝7.2Hz,2H),2.15(d,J＝6.8Hz,2H),1.70–1.54(m,8H),1.17–1.01(m,3H),0.91(dt,J＝12.8,7.2Hz,5H),0.17–0.04(m,18H).

Step 2: synthesis of (((2R, 3S,4R, 5R) -5- (4-butyrylaminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl 2-cyclohexylacetate (409.2).

Compound 409.2 was prepared according to the procedure of step 2 of example 209 using 409.1. MS (ESI): the calculated mass for C ₂₄H₃₁N₅O₆ was 485.23 and the m/z found was 486.2[ M+H ] ⁺.

Synthesis of(((2R, 3S,4R, 5R) -5- (4-butyrylaminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-2- ((2-cyclohexylacetoxy) methyl) -4-hydroxytetrahydrofuran-3-yl) oxy) methyl pivalate (409).

The title compound was prepared according to the procedure for step 1 of example 24 using 409.2 and iodomethyl pivalate. MS (ESI): the calculated mass for C ₃₀H₄₁N₅O₈ was 599.30, the measured m/z was 600.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.94(s,1H),8.38(s,1H),7.29(d,J＝4.8Hz,1H),7.07(d,J＝4.8Hz,1H),6.65(d,J＝6.4Hz,1H),5.36(d,J＝6.4Hz,1H),5.29(d,J＝6.4Hz,1H),4.96(t,J＝5.6Hz,1H),4.39–4.37(m,1H),4.29(dd,J＝12.4,3.2Hz,1H),4.18–4.08(m,2H),2.69(t,J＝7.2Hz,2H),2.10(dd,J＝6.8,2.8Hz,2H),1.69–1.52(m,9H),1.12–1.10(s,11H),0.94(t,J＝7.6Hz,3H),0.85–0.80(m,2H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl (S) -2-amino-3, 3-dimethylbutyrate (Compound 410).

The title compound was prepared according to the procedure for example 132 using (R) -Boc-tert-leucine in step 1.MS (ESI): the calculated mass for C ₁₈H₂₄N₆O₅ was 404.18, the measured m/z was 405.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92(br s,3H),6.91(d,J＝4.4Hz,1H),6.83(d,J＝4.4Hz,1H),6.40–6.30(m,1H),5.45–5.35(m,1H),4.71(s,1H),4.30–4.19(m,3H),3.96–3.92(m,1H),3.01(s,1H),0.84(s,9H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methyl (R) -2-amino-3, 3-dimethylbutyrate (Compound 411).

The title compound was prepared according to the procedure for example 132 using (S) -Boc-tert-leucine in step 1.MS (ESI): the calculated mass for C ₁₈H₂₄N₆O₅ was 404.18, the measured m/z was 405.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92(br s,3H),6.91(d,J＝4.4Hz,1H),6.82(d,J＝4.4Hz,1H),6.50–6.20(m,1H),5.50–5.25(m,1H),4.72(d,J＝5.2Hz,1H),4.30–4.18(m,1H),3.99–3.94(m,1H),3.07–3.00(m,1H),0.85(s,9H).

Example 239 synthesis of (2 r,3r,4r,5 r) -2- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -2-cyano-5- (((2-cyclohexyl-2-methylpropanoyl) oxy) methyl) tetrahydrofuran-3, 4-diyldiacetate (compound 412).

To a solution of 269 (600 mg,1.35 mmol) in NMP (3 mL) was added 4M HCl in 1-4 dioxane (0.7 mL, 4M) and stirred at 20deg.C for 15 min. The reaction mixture was cooled at 0deg.C and acetyl chloride (2.89 mL,40.6 mmol) was added immediately. The reaction was stirred at 20℃for 16h. The reaction was diluted with ACN (1 mL) and purified by preparative HPLC (column: gemini-C18.times.21.2 mm,5um; mobile phase: ACN-H ₂ O (0.1% FA; gradient: 20% -65%) to give 413 (48.25 mg,6.6% yield) as a white solid. MS (ESI): the calculated mass for C ₂₆H₃₃N₅O₇ was 527.24 and the measured m/z was 528.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.14–7.82(m,3H),6.94(d,J＝4.8Hz,1H),6.76(d,J＝4.8Hz,1H),6.04(d,J＝6.0Hz,1H),5.42–5.39(m,1H),4.64(q,J＝3.6Hz,1H),4.31–4.20(m,2H),2.12(d,J＝1.6Hz,6H),1.61–1.49(m,3H),1.46–1.34(m,3H),1.15–0.93(m,9H),0.90–0.78(m,2H).

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3- (2-cyclohexylacetoxy) -4-hydroxytetrahydrofuran-2-yl) methyl (S) -2-acetamido-3, 3-dimethylbutyrate (Compound 413).

The title compound 413 was prepared according to the procedure of step 2 of example 17 using 371. MS (ESI): the calculated mass for C ₂₈H₃₈N₆O₇ was 570.28, the measured m/z was 571.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.07(d,J＝8.4Hz,1H),7.92(br s,3H),6.92(d,J＝4.4Hz,1H),6.88(d,J＝4.8Hz,1H),6.65–6.60(m,1H),5.13–5.01(m,2H),4.48–4.45(m,1H),4.30(d,J＝4.4Hz,2H),4.15(d,J＝8.4Hz,1H),2.25(d,J＝6.8Hz,2H),1.89(s,3H),1.83–1.57(m,6H),1.27–1.09(m,3H),0.98–0.93(m,2H),0.86(s,9H)

Synthesis of((2R, 3S,4R, 5R) -5-cyano-5- (4- (2-cyclohexylacetamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methyl (S) -2-amino-3, 3-dimethylbutyrate (Compound 414).

Synthesis of((3 aR,4R,6 aR) -6-cyano-6- (4- (2-cyclohexylacetamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -2, 2-dimethyltetrahydrofurano [3,4-d ] [1,3] dioxol-4-yl) methyl (S) -2- ((tert-butoxycarbonyl) amino) -3, 3-dimethylbutyrate (414.1).

The title compound 414.1 was prepared according to the procedure of step 1 of example 210 using 371.7 and 2-cyclohexylacetyl chloride. MS (ESI): the calculated mass for C ₃₄H₄₈N₆O₈ was 668.35, the measured m/z was 669.4[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.91(s,1H),8.43(s,1H),7.24(d,J＝4.8Hz,1H),7.14–7.08(m,2H),5.44(d,J＝6.4Hz,1H),4.94(dd,J＝6.4,2.8Hz,1H),4.61–4.55(m,1H),4.24(dd,J＝12.0,4.4Hz,1H),4.13(dd,J＝12.0,6.8Hz,1H),3.80(d,J＝8.4Hz,1H),2.57(d,J＝6.8Hz,2H),1.88–1.78(m,1H),1.76–1.67(m,3H),1.66–1.57(m,5H),1.38–1.32(m,11H),1.30–1.21(m,4H),1.05–0.95(m,2H),0.86(s,9H).

Synthesis of((2R, 3S,4R, 5R) -5-cyano-5- (4- (2-cyclohexylacetamido) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methyl (S) -2-amino-3, 3-dimethylbutyrate (414).

The title compound 416 was prepared according to the procedure of step 2 of example 210 using 414.1. MS (ESI): synthesis of (((2R, 3S,4R, 5R) -5-cyano-4-hydroxy-5- (4- ((((pivaloyloxy) methoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3- (propionyloxy) tetrahydrofuran-2-yl) methyl (S) -2-amino-3, 3-dimethylbutyrate (compound 415)) for a calculated mass of C ₂₆H₃₆N₆O₆ of 528.27, found m/z of 529.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ10.88(s,1H),8.39(s,1H),7.26(d,J＝4.8Hz,1H),7.09(d,J＝4.4Hz,1H),6.46(d,J＝5.6Hz,1H),5.50–5.40(m,1H),4.69(t,J＝4.8Hz,1H),4.32–4.19(m,3H),3.97–3.90(m,1H),2.99(s,1H),2.57(d,J＝6.8Hz,2H),1.88–1.78(m,1H),1.77–1.57(m,5H),1.31–1.09(m,3H),1.06–0.94(m,2H),0.90–0.80(m,9H)..

Synthesis of((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-4-hydroxy-3- (propionyloxy) tetrahydrofuran-2-yl) methyl (S) -2- ((tert-butoxycarbonyl) amino) -3, 3-dimethylbutyrate (415.1).

The title compound 415.1 was prepared according to the procedure for step 2 of example 17 using 371.2 and propionyl chloride. MS (ESI): the calculated mass for C ₂₆H₃₆N₆O₈ was 560.26, m/z found to be 561.2[M+H]⁺.¹H NMR(400MHz,DMSO)δ7.92(br s,3H),7.07(d,J＝8.4Hz,1H),6.92(d,J＝4.8Hz,1H),6.87(d,J＝4.8Hz,1H),6.60(d,J＝6.0Hz,1H),5.13–5.08(m,2H),4.50–4.42(m,1H),4.30(d,J＝4.4Hz,2H),3.84(d,J＝8.4Hz,1H),2.40(q,J＝7.6Hz,2H),1.42–1.20(m,9H),1.07(t,J＝7.6Hz,3H),0.86(s,9H).

((2R, 3R,4R, 5R) -5-cyano-5- (4- ((((pivaloyloxy) methoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3- (propionyloxy) -4- ((trimethylsilyl) oxy) tetrahydrofuran-2-yl) methyl (S) -2- ((tert-butoxycarbonyl) amino) -3, 3-dimethylbutyrate (415.2).

The title compound 415.2 was prepared according to the procedure for step 1 of example 209 using 417.1 and ((chlorocarbonyl) oxy) methyl pivalate. MS (ESI): the calculated mass for C ₃₆H₅₄N₆O₁₂ Si was 790.36 and the m/z found was 791.3[ M+H ] ⁺.

Synthesis of (((2R, 3S,4R, 5R) -5-cyano-4-hydroxy-5- (4- ((((pivaloyloxy) methoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3- (propionyloxy) tetrahydrofuran-2-yl) methyl (S) -2-amino-3, 3-dimethylbutyrate (415).

The title compound 415 was prepared according to the procedure of step 2 of example 209 using 415.2. MS (ESI): the calculated mass for C ₂₈H₃₈N₆O₁₀ was 618.26, the measured m/z was 619.3[M+H]⁺.¹H NMR(400MHz,DMSO)δ8.30(s,1H),7.20–7.18(m,1H),7.05–7.02(m,1H),6.68(d,J＝6.4Hz,1H),5.81(s,2H),5.16(t,J＝5.2Hz,1H),5.07(t,J＝5.6Hz,1H),4.51–4.48(m,1H),4.32–4.21(m,2H),2.96(s,1H),2.40(q,J＝7.6Hz,2H),1.17(s,9H),1.08(t,J＝7.6Hz,3H),0.81(s,9H).

Compounds 11, 13, 17-26, 28-32, 41, 42, 44-48, 53, 57, 60, 62, 63, 65, 68, 70, 71, 96, 174, 175, 177, 178, 183, 187, 195, 207, 211, 227, and 235 were prepared in a similar manner to the procedure of the previous examples, and MS (ESI) data are shown in table 1.

Example I: an oral composition of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II), (III), (IV), (V), (VIa), (VIb) and (VIc), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

To prepare a pharmaceutical composition for oral delivery, 400mg of a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and the following ingredients are intimately mixed and compressed into a single scored tablet.

Tablet formulation

The following ingredients were intimately mixed and filled into hard shell gelatin capsules.

Capsule preparation

Example II: assessment of cell permeability in Caco-2 cell monolayers.

The bi-directional permeability of compounds across Caco-2 cell monolayers was evaluated. The Caco-2 model is an in vitro model widely used for small intestine absorption and potential excretion.

And (5) culturing the cells. Caco-2 cells were grown in DMEM supplemented with 10% Fetal Bovine Serum (FBS), 1% penicillin-streptomycin and 1% MEM NEAA. Cells were incubated at 37℃with 5% CO ₂/95% air and saturated humidity. After reaching 80-90% confluence, cells were gently separated with trypsin. The 39 th generation cells were seeded at a density of 8×10 ⁴ cells/cm ² on a 24-well BD insertion system and cultured for 19 days with medium changed every 2-3 days. Transepithelial resistance (TEER) values were measured for each well. The holes can only be used when their TEER value is greater than 600 ohm/cm ².

And (5) measuring transportation. After removal of the cell culture medium from the 24-well insert plate, the cells were rinsed with warm transport buffer. Appropriate dosing and receiving solutions were applied to the donor and acceptor chambers to initiate apical to basal side (a to B) or basal side to apical (B to a) direction transport assays (500 and 1300 μl for apical and basal side holes, respectively). Duplicate wells in each direction were used for test and control compounds. Plates were incubated at 37℃in a CO ₂ incubator with 5% CO ₂/95% air and saturated humidity without shaking. The sample after 10 minutes of incubation was used as the T ₀ sample, and the sample after 90 minutes of incubation was used as the T ₉₀ sample. T ₀ and T ₉₀ samples were collected from the donor and acceptor sides of each well at the designed time points and mixed with transport buffer and acetonitrile/MeOH (1:1, v/v) and internal standards for LC/MS/MS analysis. All samples were vortexed and centrifuged at 4000rpm for 15 minutes at 4 ℃, diluted with pure water and stored at 4 ℃ before bioanalysis by LC/MS.

And (5) analyzing the sample. After protein precipitation, the concentrations of the test and control compounds in Caco-2 cells were quantitatively determined by LC/MS/MS method.

And (5) calculating. Apparent permeability (P _app, cm/s), outflow ratio (ER) and recovery parameters of the Caco-2 drug transport assay were calculated using the following equations:

Where V _R is the solution volume in the receptor chamber (top side 0.4mL, base side 1.2 mL); the area is the surface area of the insert film, i.e. the area of the monolayer is 0.3cm ²; time is incubation time in seconds, i.e., 5400s (90 min) for the current experiment; c ₀ is the initial concentration of test compound in the donor chamber or peak area ratio (μm) of control compound; v _D is the volume of the donor chamber (top side 0.4mL, base side 1.2 mL); c _D and C _R are the final concentration of the test compound or the peak area ratio of the control compound in the donor and acceptor chambers, respectively.

Data for representative compounds are shown in table 2. Compounds with P _app <1.0 are classified as low permeability, compounds with P _app between 1-10 are classified as medium permeability, and compounds with P _app ≡10 are classified as high permeability. The Efflux Ratio (ER) >2 indicates that this compound is a potential substrate for intestinal cell efflux transporters.

Table 2. Bidirectional Caco-2 permeability measurements.

/>

Example III: oral bioavailability was evaluated in Sprague-Dawley rats.

Following oral gavage, single dose pharmacokinetics of exemplary compounds were assessed in fasted male Sprague-Dawley rats. The compounds are administered as solutions or acceptable suspensions in vehicles that are generally considered safe for in vivo studies. Three rats per compound were used and blood samples were collected 0.25, 0.5, 1,2, 4, 8 and 24h after dosing and stored on ice before plasma was prepared by centrifugation at 6000rpm for 5min at 4 ℃. Plasma samples were stored at-80 ℃. Ultra-high performance liquid chromatography-triple quadrupole mass spectrometry and internal standards were used to determine the concentrations of exemplary compounds and corresponding nucleosides produced by metabolic processes. Pharmacokinetic parameters were derived from the resulting plasma concentration/time profile and included the following: plasma half-life (T _1/2), time to maximum plasma concentration (T _max), maximum plasma concentration (C _max), area under the curve of plasma concentration/time plot (AUC _last and AUC _Inf obtained by last time point, including extrapolated area) and mean residence time (MRT _Inf). The resulting AUC _Inf of the resulting nucleosides was compared to AUC _Inf resulting from intravenous bolus administration of the corresponding nucleosides in three rats and the oral bioavailability (F,%) was calculated as follows:

The rat pharmacokinetic parameters of representative compounds are shown in table 3. After 3mg/kg IV administration of the parent nucleoside, the bioavailability was calculated using the following AUC _inf values: compounds 6-15, 18, 20, 25, 29-32, 41 and 44-47 were used with 2110ng h/mL; compounds 3, 180, 221 and 254 were used with 2069ng h/mL.

Table 3 pharmacokinetic parameters of Sprague-Dawley rats after oral administration of 10 mg/kg. The deduced C _max and AUC _inf for the parent nucleosides are shown, as well as the formula weight corrected bioavailability of the compounds.

/>

Claims

1. A compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

Wherein:

X is hydrogen or-CN;

G is

or two R ^11a on the same atom are taken together to form oxo;

R ²¹ is C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^21a;

each R ^21a is independently halogen 、-CN、-NO₂、-OH、-OR^a、-OC(＝O)R^a、-OC(＝O)OR^b、-OC(＝O)NR^cR^d、-S(＝O)R^a、-S(＝O)₂R^a、-S(＝O)₂NR^cR^d、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ heteroalkyl, C ₂-C₆ alkenyl, C ₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R;

Or two R ^21a on the same atom are taken together to form oxo;

Or two R ^12a on the same atom are taken together to form oxo;

r ²² is C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^22a;

Each R ^22a is independently halogen 、-CN、-NO₂、-OH、-OR^a、-OC(＝O)R^a、-OC(＝O)OR^b、-OC(＝O)NR^cR^d、-S(＝O)R^a、-S(＝O)₂R^a、-S(＝O)₂NR^cR^d、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ heteroalkyl, C ₂-C₆ alkenyl, C ₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R;

or two R ^22a on the same atom are taken together to form oxo;

R ¹³ is hydrogen or C ₁-C₆ alkyl;

r ¹⁴ is-OH or fluoro;

R ¹⁵ is hydrogen, -C (=O) R ²⁵、-C(＝O)OR²⁵、-CH₂-O-C(＝O)R²⁵,

-CH ₂-O-C(＝O)OR²⁵ or C ₁-C₆ alkyl optionally substituted with one or more R ^15a;

or two R ^15a on the same atom are taken together to form oxo;

R ²⁵ is C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^25a;

Each R ^25a is independently halogen 、-CN、-NO₂、-OH、-OR^a、-OC(＝O)R^a、-OC(＝O)OR^b、-OC(＝O)NR^cR^d、-S(＝O)R^a、-S(＝O)₂R^a、-S(＝O)₂NR^cR^d、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ heteroalkyl, C ₂-C₆ alkenyl, C ₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R;

Or two R ^25a on the same atom are taken together to form oxo;

R ¹⁶ is-C (=O) R ²⁶、-C(＝O)OR²⁶、-CH₂-O-C(＝O)R²⁶ or

-CH₂-O-C(＝O)OR²⁶；

R ²⁶ is C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl) or C ₁-C₆ alkylene (heteroaryl); wherein the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^26a;

or two R ^26a on the same atom are taken together to form oxo;

Or two R ^26a on the same carbon are taken together to form cycloalkyl or heterocycloalkyl; each of which is optionally substituted with one or more R;

Each R ^a is independently C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ heteroalkyl, C ₂-C₆ alkenyl, C ₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkyl (cycloalkyl), C ₁-C₆ alkyl (heterocycloalkyl), C ₁-C₆ alkyl (aryl), or C ₁-C₆ alkyl (heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R;

Each R ^b is independently hydrogen, C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ heteroalkyl, C ₂-C₆ alkenyl, C ₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkyl (cycloalkyl), C ₁-C₆ alkyl (heterocycloalkyl), C ₁-C₆ alkyl (aryl), or C ₁-C₆ alkyl (heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R;

R ^c and R ^d are each independently hydrogen, C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ heteroalkyl, C ₂-C₆ alkenyl, C ₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkyl (cycloalkyl), C ₁-C₆ alkyl (heterocycloalkyl), C ₁-C₆ alkyl (aryl), or C ₁-C₆ alkyl (heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R;

Or two R groups on the same atom together to form oxo;

2. The compound of claim 1, wherein X is hydrogen.

3. The compound of claim 1, wherein X is-CN.

4. A compound according to any one of claims 1-3, wherein R ¹³ is hydrogen.

5. A compound according to any one of claims 1-3, wherein R ¹³ is C ₁-C₆ alkyl.

6. The compound of any one of claims 1-5, wherein R ¹⁴ is-OH.

7. The compound of any one of claims 1-5, wherein R ¹⁴ is fluoro.

8. The compound of any one of claims 1-7, wherein G is

9. The compound of any one of claims 1-7, wherein G is

10. The compound of any one of claims 1-7, wherein G is

11. The compound of any one of claims 1-7, wherein G is

12. A compound according to any one of claims 1-11, wherein:

R ¹⁵ is-C (=O) R ²⁵、-C(＝O)OR²⁵、-CH₂-O-C(＝O)R²⁵、-CH₂-O-C(＝O)OR²⁵

Or C ₁-C₆ alkyl optionally substituted with one or more R ^15a; and

R ¹⁶ is-C (=O) R ²⁶、-C(＝O)OR²⁶、-CH₂-O-C(＝O)R²⁶ or

-CH₂-O-C(＝O)OR²⁶。

13. A compound according to any one of claims 1-11, wherein:

-CH ₂-O-C(＝O)OR²⁵ or C ₁-C₆ alkyl optionally substituted with one or more R ^15a; and

R ¹⁶ is-C (=O) R ²⁶、-C(＝O)OR²⁶、-CH₂-O-C(＝O)R²⁶ or

-CH₂-O-C(＝O)OR²⁶。

14. A compound according to any one of claims 1-11, wherein:

R ¹⁶ is-C (=O) R ²⁶、-C(＝O)OR²⁶、-CH₂-O-C(＝O)R²⁶ or

-CH₂-O-C(＝O)OR²⁶。

15. A compound according to any one of claims 1-11, wherein:

Or C ₁-C₆ alkyl optionally substituted with one or more R ^15a; and

R ¹⁶ is-C (=O) R ²⁶、-C(＝O)OR²⁶、-CH₂-O-C(＝O)R²⁶ or

-CH₂-O-C(＝O)OR²⁶。

16. A compound according to any one of claims 1-11, wherein:

Or C ₁-C₆ alkyl optionally substituted with one or more R ^15a; and

R ¹⁶ is-C (=O) R ²⁶、-C(＝O)OR²⁶、-CH₂-O-C(＝O)R²⁶ or

-CH₂-O-C(＝O)OR²⁶。

17. A compound according to any one of claims 1-11, wherein:

R ¹⁶ is-C (=O) R ²⁶、-C(＝O)OR²⁶、-CH₂-O-C(＝O)R²⁶ or

-CH₂-O-C(＝O)OR²⁶。

18. A compound according to any one of claims 1-11, wherein:

Or C ₁-C₆ alkyl optionally substituted with one or more R ^15a; and

R ¹⁶ is-C (=O) R ²⁶、-C(＝O)OR²⁶、-CH₂-O-C(＝O)R²⁶ or

-CH₂-O-C(＝O)OR²⁶。

19. The compound of any one of claims 1-18, wherein R ¹¹ is hydrogen, -C (=o) R ²¹, or C ₁-C₆ alkyl optionally substituted with one or more R ^11a.

20. The compound of any one of claims 1-19, wherein R ¹¹ is hydrogen or-C (=o) R ²¹.

21. The compound of any one of claims 1-20, wherein R ¹¹ is hydrogen.

22. The compound of any one of claims 1-20, wherein R ¹¹ is-C (=o) R ²¹.

23. The compound of any one of claims 1-22, wherein R ²¹ is C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^21a.

24. The compound of any one of claims 1-23, wherein R ²¹ is C ₁-C₆ alkyl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl).

25. The compound of any one of claims 1-24, wherein R ²¹ is C ₁-C₆ alkyl, C ₁-C₆ alkylene (cycloalkyl) or C ₁-C₆ alkylene (aryl).

26. The compound of any one of claims 1-25, wherein R ¹² is hydrogen, -C (=o) R ²²、-C(＝O)OR²², or C ₁-C₆ alkyl.

27. The compound of any one of claims 1-26, wherein R ¹² is-C (=o) R ²²、-C(＝O)OR²² or C ₁-C₆ alkyl.

28. The compound of any one of claims 1-26, wherein R ¹² is hydrogen or-C (=o) R ²².

29. The compound of any one of claims 1-26, wherein R ¹² is hydrogen OR-C (=o) OR ²².

30. The compound of any one of claims 1-26, wherein R ¹² is hydrogen or C ₁-C₆ alkyl.

31. The compound of any one of claims 1-30, wherein R ²² is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^22a.

32. The compound of any one of claims 1-31, wherein R ²² is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl).

33. The compound of any one of claims 1-32, wherein R ²² is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, aryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl).

34. The compound of any one of claims 1-33, wherein R ²² is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, aryl, C ₁-C₆ alkylene (cycloalkyl) or C ₁-C₆ alkylene (aryl).

35. The compound of any one of claims 1-30, wherein R ²² is C ₁-C₆ alkyl or C ₁-C₆ alkylene (aryl); wherein the alkyl, alkylene, and aryl groups are optionally and independently substituted with one or more R ^22a.

36. The compound of any one of claims 1-30, wherein each R ^22a is independently halogen 、-CN、-OH、-OR^a、-OC(＝O)R^a、-OC(＝O)OR^b、-OC(＝O)NR^cR^d、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl.

37. The compound of any one of claims 1-36, wherein each R ^22a is independently halogen 、-CN、-OH、-OR^a、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl.

38. The compound of any one of claims 1-36, wherein each R ^22a is independently halogen, -OH, -OR ^a、-NR^cR^d、C₁-C₆ alkyl, OR C ₁-C₆ haloalkyl.

39. The compound of any one of claims 1-36, wherein each R ^22a is independently halogen, -OC (=o) R ^a, or-NR ^cR^d.

40. The compound of any one of claims 1-39, wherein R ¹⁵ is hydrogen, -C (=o) R ²⁵, or-CH ₂-O-C(＝O)R²⁵.

41. The compound of any one of claims 1-40, wherein R ¹⁵ is hydrogen or-C (=o) R ²⁵.

42. The compound of any one of claims 1-41, wherein R ¹⁵ is-C (=o) R ²⁵.

43. The compound of any one of claims 1-41, wherein R ¹⁵ is hydrogen.

44. The compound of any one of claims 1-43, wherein R ²⁵ is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^25a.

45. The compound of any one of claims 1-43, wherein R ²⁵ is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ alkylene (cycloalkyl) or C ₁-C₆ alkylene (aryl); wherein the alkyl, alkylene, cycloalkyl, and aryl groups are optionally and independently substituted with one or more R ^25a.

46. The compound of any one of claims 1-43, wherein R ²⁵ is C ₁-C₆ alkylene (cycloalkyl) or C ₁-C₆ alkylene (aryl); wherein the alkylene, cycloalkyl and aryl groups are optionally and independently substituted with one or more R ^25a.

47. The compound of any one of claims 1-46, wherein each R ^25a is independently halogen 、-CN、-OH、-OR^a、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl.

48. The compound of any one of claims 1-46, wherein each R ^25a is independently halogen, -OH, -OR ^a、-NR^cR^d、C₁-C₆ alkyl, OR C ₁-C₆ haloalkyl.

49. The compound of any one of claims 1-48, wherein R ¹⁶ is-C (=o) R ²⁶.

50. The compound of any one of claims 1-49, wherein R ²⁶ is C ₁-C₆ alkylene (cycloalkyl) or C ₁-C₆ alkylene (aryl); wherein the alkylene, cycloalkyl and aryl groups are optionally and independently substituted with one or more R ^26a.

51. The compound of any one of claims 1-49, wherein R ²⁶ is C ₁-C₆ alkylene (cycloalkyl); wherein the alkylene and cycloalkyl groups are optionally and independently substituted with one or more R ^26a.

52. The compound of any one of claims 1-49, wherein R ²⁶ is C ₁-C₆ alkylene (aryl); wherein the alkylene and aryl groups are optionally and independently substituted with one or more R ^26a.

53. The compound of any one of claims 1-52, wherein each R ^26a is independently halogen 、-CN、-OH、-OR^a、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl.

54. The compound of any one of claims 1-52, wherein each R ^26a is independently halogen, -OH, -OR ^a、-NR^cR^d、C₁-C₆ alkyl, OR C ₁-C₆ haloalkyl.

55. A compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

Wherein:

X is hydrogen or-CN;

G is

or two R ^11a on the same atom together to form oxo;

Or two R ^21a on the same atom together to form oxo;

Or two R ^12a on the same atom together to form oxo;

or two R ^22a on the same atom together to form oxo;

R ¹³ is hydrogen or C ₁-C₆ alkyl;

r ¹⁴ is-OH or fluoro;

R ¹⁵ is-C (=O) R ²⁵、-C(＝O)OR²⁵、-CH₂-O-C(＝O)R²⁵ or

-CH₂-O-C(＝O)OR²⁵；

R ²⁵ is C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl) or C ₁-C₆ alkylene (heteroaryl); wherein the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^26a;

Or two R ^25a on the same atom together to form oxo;

R ¹⁶ is hydrogen, -C (=O) R ²⁶、-C(＝O)OR²⁶、-CH₂-O-C(＝O)R²⁶,

-CH ₂-O-C(＝O)OR²⁶ or C ₁-C₆ alkyl optionally substituted with one or more R ^16a;

or two R ^16a on the same atom together to form oxo;

R ²⁶ is C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^26a;

Each R ^26a is independently halogen 、-CN、-NO₂、-OH、-OR^a、-OC(＝O)R^a、-OC(＝O)OR^b、-OC(＝O)NR^cR^d、-S(＝O)R^a、-S(＝O)₂R^a、-S(＝O)₂NR^cR^d、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ heteroalkyl, C ₂-C₆ alkenyl, C ₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R;

or two R ^26a on the same atom together to form oxo;

Or two R groups on the same atom together to form oxo;

56. The compound of claim 55, wherein X is hydrogen.

57. The compound of claim 55, wherein X is-CN.

58. The compound of any of claims 55-57, wherein R ¹³ is hydrogen.

59. The compound of any of claims 55-57, wherein R ¹³ is C ₁-C₆ alkyl.

60. The compound of any of claims 55-59, wherein R ¹⁴ is-OH.

61. The compound of any of claims 55-59, wherein R ¹⁴ is fluoro.

62. The compound of any of claims 55-61, wherein G is

63. The compound of any of claims 55-61, wherein G is

64. The compound of any of claims 55-61, wherein G is

65. The compound of any of claims 55-61, wherein G is

66. A compound according to any one of claims 55-65, wherein:

R ¹⁵ is-C (=O) R ²⁵、-C(＝O)OR²⁵、-CH₂-O-C(＝O)R²⁵ or

-CH ₂-O-C(＝O)OR²⁵; and

R ¹⁶ is-C (=O) R ²⁶、-C(＝O)OR²⁶、-CH₂-O-C(＝O)R²⁶、-CH₂-O-C(＝O)OR²⁶

Or C ₁-C₆ alkyl optionally substituted with one or more R ^16a.

67. A compound according to any one of claims 55-65, wherein:

R ¹⁵ is-C (=O) R ²⁵、-C(＝O)OR²⁵、-CH₂-O-C(＝O)R²⁵ or

-CH ₂-O-C(＝O)OR²⁵; and

-CH ₂-O-C(＝O)OR²⁶ or C ₁-C₆ alkyl optionally substituted with one or more R ^16a.

68. A compound according to any one of claims 55-65, wherein:

R ¹⁵ is-C (=O) R ²⁵、-C(＝O)OR²⁵、-CH₂-O-C(＝O)R²⁵ or

-CH ₂-O-C(＝O)OR²⁵; and

69. A compound according to any one of claims 55-65, wherein:

R ¹⁵ is-C (=O) R ²⁵、-C(＝O)OR²⁵、-CH₂-O-C(＝O)R²⁵ or

-CH ₂-O-C(＝O)OR²⁵; and

Or C ₁-C₆ alkyl optionally substituted with one or more R ^16a.

70. A compound according to any one of claims 55-65, wherein:

R ¹⁵ is-C (=O) R ²⁵、-C(＝O)OR²⁵、-CH₂-O-C(＝O)R²⁵ or

-CH ₂-O-C(＝O)OR²⁵; and

Or C ₁-C₆ alkyl optionally substituted with one or more R ^16a.

71. A compound according to any one of claims 55-65, wherein:

R ¹⁵ is-C (=O) R ²⁵、-C(＝O)OR²⁵、-CH₂-O-C(＝O)R²⁵ or

-CH ₂-O-C(＝O)OR²⁵; and

72. A compound according to any one of claims 55-65, wherein:

R ¹⁵ is-C (=O) R ²⁵、-C(＝O)OR²⁵、-CH₂-O-C(＝O)R²⁵ or

-CH ₂-O-C(＝O)OR²⁵; and

Or C ₁-C₆ alkyl optionally substituted with one or more R ^16a.

73. The compound of any one of claims 52-69, wherein R ¹¹ is hydrogen, -C (=o) R ²¹, or C ₁-C₆ alkyl optionally substituted with one or more R ^11a.

74. The compound of any one of claims 55-73, wherein R ¹¹ is hydrogen or-C (=o) R ²¹.

75. The compound of any of claims 55-73, wherein R ¹¹ is hydrogen.

76. The compound of any one of claims 55-73, wherein R ¹¹ is-C (=o) R ²¹.

77. The compound of any one of claims 55-76, wherein R ²¹ is C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^21a.

78. The compound of any one of claims 55-76, wherein R ²¹ is C ₁-C₆ alkyl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl).

79. The compound of any one of claims 55-76, wherein R ²¹ is C ₁-C₆ alkyl, C ₁-C₆ alkylene (cycloalkyl) or C ₁-C₆ alkylene (aryl).

80. The compound of any one of claims 55-79, wherein R ¹² is hydrogen, -C (=o) R ²²、-C(＝O)OR²², or C ₁-C₆ alkyl.

81. The compound of any one of claims 55-79, wherein R ¹² is-C (=o) R ²²、-C(＝O)OR²² or C ₁-C₆ alkyl.

82. The compound of any one of claims 55-79, wherein R ¹² is hydrogen or-C (=o) R ²².

83. The compound of any one of claims 55-79, wherein R ¹² is hydrogen OR-C (=o) OR ²².

84. The compound of any one of claims 55-79, wherein R ¹² is hydrogen or C ₁-C₆ alkyl.

85. The compound of any one of claims 55-79, wherein R ¹² is-C (=o) OR ²².

86. The compound of any one of claims 55-85, wherein R ²² is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^22a.

87. The compound of any one of claims 55-85, wherein R ²² is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl).

88. The compound of any one of claims 55-85, wherein R ²² is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, aryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl).

89. The compound of any one of claims 55-85, wherein R ²² is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, aryl, C ₁-C₆ alkylene (cycloalkyl) or C ₁-C₆ alkylene (aryl).

90. The compound of any one of claims 55-85, wherein R ²² is C ₁-C₆ alkyl or C ₁-C₆ alkylene (aryl); wherein the alkyl, alkylene, and aryl groups are optionally and independently substituted with one or more R ^22a.

91. The compound of any one of claims 55-90, wherein each R ^22a is independently halogen 、-CN、-OH、-OR^a、-OC(＝O)R^a、-OC(＝O)OR^b、-OC(＝O)NR^cR^d、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl.

92. The compound of any one of claims 55-90, wherein each R ^22a is independently halogen 、-CN、-OH、-OR^a、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl.

93. The compound of any one of claims 55-90, wherein each R ^22a is independently halogen, -OH, -OR ^a、-NR^cR^d、C₁-C₆ alkyl, OR C ₁-C₆ haloalkyl.

94. The compound of any one of claims 55-90, wherein each R ^22a is independently halogen, -OC (=o) R ^a, or-NR ^cR^d.

95. The compound of any one of claims 55-94, wherein R ¹⁵ is-C (=o) R ²⁵.

96. The compound of any one of claims 55-95, wherein R ²⁵ is C ₁-C₆ alkylene (cycloalkyl) or C ₁-C₆ alkylene (aryl); wherein the alkylene, cycloalkyl and aryl groups are optionally and independently substituted with one or more R ^25a.

97. The compound of any one of claims 55-95, wherein R ²⁵ is C ₁-C₆ alkylene (cycloalkyl); wherein the alkylene and cycloalkyl groups are optionally and independently substituted with one or more R ^25a.

98. The compound of any one of claims 55-95, wherein R ²⁵ is C ₁-C₆ alkylene (aryl); wherein the alkylene and aryl groups are optionally and independently substituted with one or more R ^25a.

99. The compound of any one of claims 55-95, wherein each R ^25a is independently halogen 、-CN、-OH、-OR^a、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl.

100. The compound of any one of claims 55-99, wherein each R ^25a is independently halogen, -OH, -OR ^a、-NR^cR^d、C₁-C₆ alkyl, OR C ₁-C₆ haloalkyl.

101. The compound of any one of claims 55-99, wherein R ¹⁶ is hydrogen, -C (=o) R ²⁶, or-CH ₂-O-C(＝O)R²⁶.

102. The compound of any one of claims 55-99, wherein R ¹⁶ is hydrogen or-C (=o) R ²⁶.

103. The compound of any one of claims 55-99, wherein R ¹⁶ is-C (=o) R ²⁶.

104. The compound of any one of claims 55-99, wherein R ¹⁶ is hydrogen.

105. The compound of any one of claims 55-99, wherein R ¹⁶ is-CH ₂-O-C(＝O)R²⁶.

106. The compound of any one of claims 55-105, wherein R ²⁶ is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^26a.

107. The compound of any of claims 55-105, wherein R ²⁶ is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, C ₁-C₆ alkylene (cycloalkyl) or C ₁-C₆ alkylene (aryl); wherein the alkyl, alkylene, cycloalkyl, and aryl groups are optionally and independently substituted with one or more R ^26a.

108. The compound of any one of claims 55-105, wherein R ²⁶ is C ₁-C₆ alkylene (cycloalkyl) or C ₁-C₆ alkylene (aryl); wherein the alkylene, cycloalkyl and aryl groups are optionally and independently substituted with one or more R ^26a.

109. The compound of any one of claims 55-108, wherein each R ^26a is independently halogen 、-CN、-OH、-OR^a、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl.

110. The compound of any one of claims 55-108, wherein each R ^26a is independently halogen, -OH, -OR ^a、-NR^cR^d、C₁-C₆ alkyl, OR C ₁-C₆ haloalkyl.

111. A compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

Wherein:

X is hydrogen or-CN;

G is

Or two R ^12a on the same atom together to form oxo;

or two R ^22a on the same atom together to form oxo;

R ¹³ is hydrogen or C ₁-C₆ alkyl;

r ¹⁴ is-OH or fluoro;

R ¹⁵ is-C (=O) R ²⁵、-C(＝O)OR²⁵、-CH₂-O-C(＝O)R²⁵ or

-CH₂-O-C(＝O)OR²⁵；

Or two R ^25a on the same atom together to form oxo;

Or two R groups on the same atom together to form oxo.

112. The compound of claim 111, wherein X is hydrogen.

113. The compound of claim 111, wherein X is-CN.

114. The compound of any of claims 111-113, wherein R ¹³ is hydrogen.

115. The compound of any of claims 111-113, wherein R ¹³ is C ₁-C₆ alkyl.

116. The compound of any of claims 111-115, wherein R ¹⁴ is-OH.

117. The compound of any of claims 111-115, wherein R ¹⁴ is fluoro.

118. The compound of any of claims 111-117, wherein R ¹² is-C (=o) R ²²、-C(＝O)OR²² or C ₁-C₆ alkyl.

119. The compound of any of claims 111-117, wherein R ¹² is-C (=o) R ²².

120. The compound of any of claims 111-117, wherein R ¹² is-C (=o) OR ²².

121. The compound of any of claims 111-117, wherein R ¹² is C ₁-C₆ alkyl.

122. The compound of any of claims 111-121, wherein R ²² is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^22a.

123. The compound of any of claims 111-121, wherein R ²² is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl).

124. The compound of any of claims 111-121, wherein R ²² is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, aryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl).

125. The compound of any of claims 111-121, wherein R ²² is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, aryl, C ₁-C₆ alkylene (cycloalkyl) or C ₁-C₆ alkylene (aryl).

126. The compound of any of claims 111-121, wherein R ²² is C ₁-C₆ alkyl or C ₁-C₆ alkylene (aryl); wherein the alkyl, alkylene, and aryl groups are optionally and independently substituted with one or more R ^22a.

127. The compound of any of claims 111-126, wherein each R ^22a is independently halogen 、-CN、-OH、-OR^a、-OC(＝O)R^a、-OC(＝O)OR^b、-OC(＝O)NR^cR^d、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl.

128. The compound of any of claims 111-126, wherein each R ^22a is independently halogen 、-CN、-OH、-OR^a、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl.

129. The compound of any of claims 111-126, wherein each R ^22a is independently halogen, -OH, -OR ^a、-NR^cR^d、C₁-C₆ alkyl, OR C ₁-C₆ haloalkyl.

130. The compound of any of claims 111-126, wherein each R ^22a is independently halogen, -OC (=o) R ^a, or-NR ^cR^d.

131. The compound of any one of claims 111-130, wherein R ¹⁵ is-C (=o) R ²⁵.

132. The compound of any one of claims 111-130, wherein R ¹⁵ is-C (=o) OR ²⁵.

133. The compound of any of claims 111-130, wherein R ¹⁵ is-CH ₂-O-C(＝O)R²⁵.

134. The compound of any of claims 111-133, wherein R ²⁵ is C ₁-C₆ alkylene (cycloalkyl) or C ₁-C₆ alkylene (aryl); wherein the alkylene, cycloalkyl and aryl groups are optionally and independently substituted with one or more R ^25a.

135. The compound of any of claims 111-133, wherein R ²⁵ is C ₁-C₆ alkylene (cycloalkyl); wherein the alkylene and cycloalkyl groups are optionally and independently substituted with one or more R ^25a.

136. The compound of any of claims 111-133, wherein R ²⁵ is C ₁-C₆ alkylene (aryl); wherein the alkylene and aryl groups are optionally and independently substituted with one or more R ^25a.

137. The compound of any of claims 111-136, wherein each R ^25a is independently halogen 、-CN、-OH、-OR^a、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl.

138. The compound of any of claims 111-136, wherein each R ^25a is independently halogen, -OH, -OR ^a、-NR^cR^d、C₁-C₆ alkyl, OR C ₁-C₆ haloalkyl.

139. A compound of formula (V), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

Wherein:

X is hydrogen or-CN;

G is

Or two R ^12a on the same atom together to form oxo;

or two R ^22a on the same atom together to form oxo;

R ¹³ is hydrogen or C ₁-C₆ alkyl;

r ¹⁴ is-OH or fluoro;

r ¹⁵ is hydrogen, -C (=O) R ²⁵、-C(＝O)OR²⁵、-CH₂-O-C(＝O)R²⁵ or

-CH₂-O-C(＝O)OR²⁵；

Or two R ^25a on the same atom together to form oxo;

Or C ₁-C₆ alkyl optionally substituted with one or more R ^16a;

or two R ^16a on the same atom together to form oxo;

or two R ^26a on the same atom together to form oxo;

Or two R groups on the same atom together to form oxo.

140. The compound of claim 139, wherein X is hydrogen.

141. The compound of claim 139, wherein X is-CN.

142. The compound of any of claims 139-141, wherein R ¹³ is hydrogen.

143. The compound of any of claims 139-141, wherein R ¹³ is C ₁-C₆ alkyl.

144. The compound of any of claims 139-143, wherein R ¹⁴ is-OH.

145. The compound of any of claims 139-143, wherein R ¹⁴ is fluoro.

146. The compound of any of claims 139-145, wherein R ¹² is-C (=o) R ²²、-C(＝O)OR²² or C ₁-C₆ alkyl.

147. The compound of any of claims 139-146, wherein R ¹² is-C (=o) R ²².

148. The compound of any of claims 139-146, wherein R ¹² is-C (=o) OR ²².

149. The compound of any of claims 139-146, wherein R ¹² is C ₁-C₆ alkyl.

150. The compound of any of claims 139-149, wherein R ²² is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^22a.

151. The compound of any of claims 139-149, wherein R ²² is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl).

152. The compound of any of claims 139-149, wherein R ²² is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, aryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl).

153. The compound of any of claims 139-149, wherein R ²² is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, aryl, C ₁-C₆ alkylene (cycloalkyl) or C ₁-C₆ alkylene (aryl).

154. The compound of any of claims 139-149, wherein R ²² is C ₁-C₆ alkyl or C ₁-C₆ alkylene (aryl); wherein the alkyl, alkylene, and aryl groups are optionally and independently substituted with one or more R ^22a.

155. The compound of any of claims 139-154, wherein each R ^22a is independently halogen 、-CN、-OH、-OR^a、-OC(＝O)R^a、-OC(＝O)OR^b、-OC(＝O)NR^cR^d、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl.

156. The compound of any of claims 139-154, wherein each R ^22a is independently halogen 、-CN、-OH、-OR^a、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl.

157. The compound of any of claims 139-154, wherein each R ^22a is independently halogen, -OH, -OR ^a、-NR^cR^d、C₁-C₆ alkyl, OR C ₁-C₆ haloalkyl.

158. The compound of any of claims 139-154, wherein each R ^22a is independently halogen, -OC (=o) R ^a, or-NR ^cR^d.

159. The compound of any of claims 139-158, wherein R ¹⁵ is hydrogen.

160. The compound of any of claims 139-158, wherein R ¹⁵ is-C (=o) R ²⁵.

161. The compound of any of claims 139-158, wherein R ¹⁵ is-C (=o) OR ²⁵.

162. The compound of any of claims 139-161, wherein R ²⁵ is C ₁-C₆ alkylene (cycloalkyl) or C ₁-C₆ alkylene (aryl); wherein the alkylene, cycloalkyl and aryl groups are optionally and independently substituted with one or more R ^25a.

163. The compound of any of claims 139-161, wherein R ²⁵ is C ₁-C₆ alkylene (cycloalkyl); wherein the alkylene and cycloalkyl groups are optionally and independently substituted with one or more R ^25a.

164. The compound of any of claims 139-161, wherein R ²⁵ is C ₁-C₆ alkylene (aryl); wherein the alkylene and aryl groups are optionally and independently substituted with one or more R ^25a.

165. The compound of any of claims 139-164, wherein each R ^25a is independently halogen 、-CN、-OH、-OR^a、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl.

166. The compound of any of claims 139-164, wherein each R ^25a is independently halogen, -OH, -OR ^a、-NR^cR^d、C₁-C₆ alkyl, OR C ₁-C₆ haloalkyl.

167. The compound of any of claims 139-166, wherein R ¹⁶ is-C (=o) R ²⁶.

168. The compound of any of claims 139-166, wherein R ¹⁶ is-C (=o) OR ²⁶.

169. The compound of any of claims 139-168, wherein R ²⁶ is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^26a.

170. The compound of any of claims 139-169, wherein R ²⁶ is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl).

171. The compound of any of claims 139-168, wherein R ²⁶ is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, aryl, C ₁-C₆ alkylene (cycloalkyl), C ₁-C₆ alkylene (heterocycloalkyl), C ₁-C₆ alkylene (aryl), or C ₁-C₆ alkylene (heteroaryl).

172. The compound of any of claims 139-168, wherein R ²⁶ is C ₁-C₆ alkyl, C ₁-C₆ aminoalkyl, aryl, C ₁-C₆ alkylene (cycloalkyl) or C ₁-C₆ alkylene (aryl).

173. The compound of any of claims 139-168, wherein R ²⁶ is C ₁-C₆ alkyl or C ₁-C₆ aminoalkyl.

174. The compound of any of claims 139-173, wherein each R ^26a is independently halogen 、-CN、-OH、-OR^a、-OC(＝O)R^a、-OC(＝O)OR^b、-OC(＝O)NR^cR^d、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl.

175. The compound of any of claims 139-173, wherein each R ^26a is independently halogen 、-CN、-OH、-OR^a、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C₁-C₆ alkyl or C ₁-C₆ haloalkyl.

176. The compound of any of claims 139-173, wherein each R ^26a is independently halogen, -OH, -OR ^a、-NR^cR^d、C₁-C₆ alkyl, OR C ₁-C₆ haloalkyl.

177. The compound of any one of claims 139-173, wherein each R ^26a is independently-OC (=o) R ^a or-NR ^cR^d.

178. A compound of formula (VIa), (VIb) or (VIc), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

Wherein:

X is hydrogen or-CN;

Or two R ^12a on the same atom together to form oxo;

or two R ^22a on the same atom together to form oxo;

R ¹³ is hydrogen or C ₁-C₆ alkyl;

r ¹⁴ is-OH or fluoro;

-CH₂-O-C(＝O)OR²⁵；

Or two R ^25a on the same atom together to form oxo;

or two R ^16a on the same atom together to form oxo;

or two R ^26a on the same atom together to form oxo;

Or two R groups on the same atom together to form oxo.

179. A compound selected from the compounds shown in table 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

180. A pharmaceutical composition comprising a compound according to any one of claims 1-179, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable carrier.

181. A method of treating a viral infection comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1-179, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition according to claim 180.

182. The method of claim 181, further comprising administering at least one antiviral agent in combination with a compound according to any one of claims 1-179, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition according to claim 180.

183. The method of claim 181 or 182, wherein the viral infection is caused by a virus selected from the group consisting of: coronavirus disease 2019 (SARS-CoV-2), yellow fever, eastern equine encephalitis virus, human Immunodeficiency Virus (HIV), "african swine fever virus", arboviridae, adenoviridae, arenaviridae, arterivirus, astroviridae, rhabdoviridae, sinviridae, biglyaviridae, bunyaviridae, calicivviridae, cauliflower viridae, circoviridae, coronaviridae, vesicular phage, ebola virus, delta viridae, filoviridae, flaviviridae, iridoviridae, mononegavirales, myotail phage, papilloma virus, papovaviridae, paramyxoviridae, prions, parvoviridae, algae deoxyriboviridae, poxviridae, potyviridae, reoviridae, sinoviridae, retrovirus, multilayer phage, togaviridae, poxviridae, papilloma, coronavirus, influenza, sendai virus (SeV), sindbis virus, han virus, western poxvirus, common cold of any combination thereof.

184. The method of any of claims 181-183, wherein the viral infection is caused by a coronavirus disease 2019 (SARS-CoV-2).

185. The method of any one of claims 181-183 wherein the viral infection is caused by ebola virus.

186. The method of claim 185, wherein the ebola virus is zaire ebola virus (ebola virus).

187. A method of any one of claims 181-186 wherein the at least one antiviral agent is adefovir, ribavirin, fampicvir, T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, ST-193, iodate, idarubicin, trifluoracetin, vidarabine, brivudine, acyclovir, ganciclovir, valganciclovir, penciclovir, famciclovir, zidovudine, didanosine, zalcitabine, stavudine, abacavir, lamivudine, emtricitabine, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, adefovir dipivoxil, entecavir, telbivudine, sofosbuvir or a mixture thereof.

188. The method of any of claims 181-186 wherein the at least one antiviral agent is Mo Nuola.

189. The method of any one of claims 181-186, wherein the at least one antiviral agent is a ribonucleic acid (RNA) -dependent RNA polymerase inhibitor, a checkpoint inhibitor, or a PD-1/PD-L1 inhibitor, a therapeutic vaccine, an RNA interference (RNAi) therapeutic, an antisense-based therapeutic, a coronavirus entry inhibitor, a TLR agonist, a RIG-I agonist, or an interferon.