CN101426793A - Methods for the preparation of hcv polymerase inhibitors - Google Patents

Abstract

The present invention relates to processes and compounds useful for the preparation of compounds of formula (I).

Description

Process for the preparation of HCV polymerase inhibitors

Pursuant to 35 U.S.C. §119(e), this application claims U.S. Provisional Patent Application 60/711,042, filed August 24, 2005, U.S. Provisional Patent Application 60/744,273, filed April 4, 2006, and Priority to U.S. Provisional Patent Application 60/804,644, filed on 11 July 2009, which is hereby incorporated by reference in its entirety.

technical field

The present invention relates to the preparation of compounds suitable as hepatitis C virus (HCV) polymerase inhibitors and intermediate compounds useful in their preparation.

Background technique

Hepatitis C virus (HCV, hepatitis C virus) belongs to the Hepavirus genus of the Flaviviridae family. It is the major causative agent of non-A, non-B viral hepatitis, and is the leading cause of transfusion hepatitis and the cause of the majority of hepatitis cases worldwide. Although acute HCV infection is usually asymptomatic, nearly 80% of cases turn into chronic hepatitis. The persistent nature of this HCV infection has been explained by its ability to evade host immune detection through hypermutability of the infected region in the membrane protein E2 (Weiner, et al., Virology, 180:842-848 (1991); Weiner, et al., Proc. Natl. Acad. Sci. USA, 89:3468-3472 (1992)).

Since persistent HCV infection is associated with chronic hepatitis and eventually liver cancer, HCV replication is one of the goals to eliminate HCV regeneration and prevent hepatocellular carcinoma. Unfortunately, current treatments for HCV infection are characterized by poor efficacy and adverse side effects. Therefore, there is a need for all-out efforts to develop a molecule for the treatment of the above-mentioned diseases, which includes the development of drugs to inhibit HC replication, because for non-peptide, small molecule compounds (to have the physical and chemical properties required or improved for pharmaceutical applications) There is a continuing need for HCV RdRp inhibitors with specific properties.

Compounds suitable as HCV polymerase inhibitors are disclosed in U.S. Patent Application No. 10/718,337, filed November 19, 2003, and U.S. Patent Application No. 11/204,269, filed August 15, 2005, which are incorporated by reference in their entirety. into this article. The present invention provides methods and intermediate compounds useful for the preparation of compounds suitable as HCV polymerase inhibitors.

Contents of the invention

The invention provides the method for preparing formula (Ia) compound:

in:

R ¹ is C ₁ to C ₆ alkyl or C ₃ to C ₆ cycloalkyl;

R ^2a , R ^2b and R ^2c are each independently selected from hydrogen, halogen, C ₁ to C ₆ alkyl, C ₃ to C ₆ cycloalkyl, -OR ^12a , -CF ₃ , -CN and -NR ^12a R ^12b ;

R ⁴ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁵ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁶ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁷ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

Each R ⁹ and R ¹⁰ is independently selected from hydrogen and C ₁ to C ₆ alkyl, or R ⁹ and R ¹⁰ form C ₃ to C ₆ cycloalkyl together with the carbon atoms to which they are attached;

each R ¹¹ is independently selected from hydrogen, C ₁ to C ₆ alkyl, halogen, -OR ^12a , -CN, -CF ₃ and -NR ⁹ R ¹⁰ ;

each of R ^12a and R ^12b is independently selected from hydrogen and C ₁ to C ₆ alkyl; and

Each n is independently selected and is an integer from 0 to 5;

The method includes:

a) a compound of formula (X) (wherein R ¹³ is hydrogen, C ₁ to C ₆ alkyl, -Si(C ₁ to C ₆ alkyl) ₃ or -CH ₂ (C ₆ to C ₁₀ aryl), wherein The C ₆ to C ₁₀ aryl is optionally substituted by at least one substituent selected from halogen, C ₁ to C ₆ alkyl, -OH, -OCH ₃ and -N(C ₁ to C ₆ alkyl) ₂ ) anion treatment of a compound of formula (V) (wherein R ¹ is as defined above) to obtain a compound of formula (IV);

b) hydrolyzing said compound of formula (IV) to obtain a compound of formula (IV) wherein ^R is hydrogen;

c) treating said compound of formula (IV) with a combination of reagents to obtain a compound of formula (III), wherein P ¹ is hydrogen or a suitable protecting group, and R ¹⁴ is C ₁ to C ₆ alkyl or -CH ₂ (C ₆ to C ₁₀ aryl), wherein the C ₆ to C ₁₀ aryl can be optionally replaced by at least one selected from halogen, C ₁ to C ₆ alkyl, -OH, -OCH ₃ and -N(C ₁ to C ₆ Alkyl) ₂ is substituted by a substituent;

d) treating said compound of formula (III) with an acid or base to obtain a compound of formula (II); and

e) treating said compound of formula (II) with a compound of formula (IXa) to give a compound of formula (Ia)

Further provided herein are methods wherein in said compound of formula (Ia):

R ¹ is C ₃ to C ₆ cycloalkyl;

R ^2a , R ^2b and R ^2c are each independently selected from hydrogen, halogen, C ₁ to C ₆ alkyl, C ₃ to C ₆ cycloalkyl, -OR ^12a , -CF ₃ , -CN and -NR ^12a R ^12b ;

R ⁴ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁵ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁶ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁷ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

Each R ⁹ and R ¹⁰ is independently selected from hydrogen and C ₁ to C ₆ alkyl, or R ⁹ and R ¹⁰ form C ₃ to C ₆ cycloalkyl together with the carbon atoms to which they are attached;

each R ¹¹ is independently selected from hydrogen, C ₁ to C ₆ alkyl, halogen, -OR ^12a , -CN, -CF ₃ and -NR ^12a R ^12b ;

each of R ^12a and R ^12b is independently selected from hydrogen and C ₁ to C ₆ alkyl; and

Each n is independently selected and is an integer from 0 to 5.

Also provided herein are methods wherein in the compound of formula (Ia):

R ¹ is cyclopentyl;

R ^2a , R ^2b and R ^2c are each independently selected from hydrogen, halogen and C ₁ to C ₆ alkyl;

R ⁴ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁵ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁶ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁷ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

Each R ⁹ and R ¹⁰ is independently selected from hydrogen and C ₁ to C ₆ alkyl, or R ⁹ and R ¹⁰ form C ₃ to C ₆ cycloalkyl together with the carbon atoms to which they are attached;

each R ¹¹ is independently selected from hydrogen, C ₁ to C ₆ alkyl, halogen, -OR ^12a , -CN, -CF ₃ and -NR ^12a R ^12b ;

each of R ^12a and R ^12b is independently selected from hydrogen and C ₁ to C ₆ alkyl; and

Each n is independently selected and is an integer from 0 to 5.

Also included are methods wherein in the compound of formula (Ia):

R ¹ is cyclopentyl;

R ^2a is C ₁ to C ₆ alkyl;

R ^2b is hydrogen;

R ^2c is C ₁ to C ₆ alkyl;

R ⁴ is hydrogen;

R ⁵ is C ₁ to C ₆ alkyl;

^R6 is hydrogen; and

R ⁷ is C ₁ to C ₆ alkyl.

Another aspect provides the following method, wherein in said compound of formula (Ia):

R ¹ is cyclopentyl;

R ^2a is -CH ₃ ;

R ^2b is hydrogen;

R ^2c is -CH ₃ ;

R ⁴ is hydrogen;

R ⁵ is -CH ₂ CH ₃ ;

^R6 is hydrogen; and

R ⁷ is -CH ₂ CH ₃ .

Another aspect also provides the following method, wherein the compound of formula (Ia) is (Iaa),

Additionally, included herein are methods wherein the compound of formula (Ia) is (Iab),

Further provided herein are processes for the preparation of compounds of formula (Ia):

in:

R ¹ is C ₁ to C ₆ alkyl or C ₃ to C ₆ cycloalkyl;

R ^2a , R ^2b and R ^2c are each independently selected from hydrogen, halogen, C ₁ to C ₆ alkyl, C ₃ to C ₆ cycloalkyl, -OR ^12a , -CF ₃ , -CN and -NR ^12a R ^12b ;

R ⁴ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁵ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁶ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁷ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

Each R ⁹ and R ¹⁰ is independently selected from hydrogen and C ₁ to C ₆ alkyl, or R ⁹ and R ¹⁰ form C ₃ to C ₆ cycloalkyl together with the carbon atoms to which they are attached;

each R ¹¹ is independently selected from hydrogen, C ₁ to C ₆ alkyl, halogen, -OR ^12a , -CN, -CF ₃ and -NR ^12a R ^12b ;

each of R ^12a and R ^12b is independently selected from hydrogen and C ₁ to C ₆ alkyl; and

Each n is independently selected and is an integer from 0 to 5;

The methods include:

a) treatment of a compound of formula (IV) (wherein R ¹ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined herein, P ¹ is hydrogen or a suitable protecting group, and R ¹³ is hydrogen, C ₁ to C ₆ alkyl, -Si(C ₁ to C ₆ alkyl) ₃ or -CH ₂ (C ₆ to C ₁₀ aryl), wherein the C ₆ to C ₁₀ aryl can be optionally selected from at least one halogen , C ₁ to C ₆ alkyl, -OH, -OCH ₃ and -N(C ₁ to C ₆ alkyl) ₂ substituents) to obtain compounds of formula (III), wherein R ¹⁴ is C ₁ to C ₆ alkyl, -Si(C ₁ to C ₆ alkyl) ₃ or -CH ₂ (C ₆ to C ₁₀ aryl), wherein the C ₆ to C ₁₀ aryl can be optionally replaced by at least one selected from halogen, C ₁ to C ₆ alkyl, -OH, -OCH ₃ and _-N (C ₁ to C ₆ alkyl) substituent substitution;

b) treating said compound of formula (III) with an acid or base to obtain a compound of formula (II); and

c) treating said compound of formula (II) with a compound of formula (IXa) to give a compound of formula (Ia)

In another aspect, there is provided a process for preparing a compound of formula (II),

in:

R ¹ is C ₁ to C ₆ alkyl or C ₃ to C ₆ cycloalkyl;

R ⁴ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁵ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁶ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁷ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

Each R ⁹ and R 10 are independently selected from hydrogen and C ₁ to C ₆ alkyl, or R ⁹ and R ¹⁰ form C ₃ to C ₆ cycloalkyl together with the carbon atoms to which they are attached;

each R ¹¹ is independently selected from hydrogen, C ₁ to C ₆ alkyl, halogen, -OR ^12a , -CN, -CF ₃ and -NR ⁹ R ¹⁰ ;

each of R ^12a and R ^12b is independently selected from hydrogen and C ₁ to C ₆ alkyl; and

Each n is independently selected and is an integer from 0 to 5;

The methods include:

a) a compound of formula (X) (wherein R ¹³ is hydrogen, C ₁ to C ₆ alkyl, -Si(C ₁ to C ₆ alkyl) ₃ or -CH ₂ (C ₆ to C ₁₀ aryl), wherein The C ₆ to C ₁₀ aryl is optionally substituted by at least one substituent selected from halogen, C ₁ to C ₆ alkyl, -OH, -OCH ₃ and -N(C ₁ to C ₆ alkyl) ₂ ) anion treatment of a compound of formula (V), wherein ^R is as defined above, to obtain a compound of formula (IV):

b) hydrolyzing said compound of formula (IV) to obtain a compound of formula (IV) wherein ^R is hydrogen;

c) treating said compound of formula (IV) with a combination of reagents to obtain a compound of formula (III), wherein P ¹ is hydrogen or a suitable protecting group, and R ¹⁴ is C ₁ to C ₆ alkyl or -CH ₂ (C ₆ to C ₁₀ aryl), wherein the C ₆ to C ₁₀ aryl can be optionally replaced by at least one selected from halogen, C ₁ to C ₆ alkyl, -OH, -OCH ₃ and -N(C ₁ to C ₆ Alkyl) ₂ is substituted by a substituent;

d) treating said compound of formula (III) with an acid or base to obtain a compound of formula (II)

Further provided herein are methods wherein the compound of formula (II) is (IIa):

or wherein said compound of formula (II) is (IIb):

Also included herein is any one of the above methods, wherein in the compound of formula (II):

R ¹ is C ₃ to C ₆ cycloalkyl;

R ⁴ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁵ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁶ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁷ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

Each R ⁹ and R ¹⁰ is independently selected from hydrogen and C ₁ to C ₆ alkyl, or R ⁹ and R ¹⁰ form C ₃ to C ₆ cycloalkyl together with the carbon atoms to which they are attached;

each R ¹¹ is independently selected from hydrogen, C ₁ to C ₆ alkyl, halogen, -OR ^12a , -CN, -CF ₃ and -NR ^12a R ^12b ;

each of R ^12a and R ^12b is independently selected from hydrogen and C ₁ to C ₆ alkyl; and

Each n is independently selected to be an integer from 0 to 5.

And the present invention includes the above-mentioned method as follows, wherein in the compound of formula (II):

R ¹ is C ₃ to C ₆ cycloalkyl;

R ⁴ is hydrogen;

R ⁵ is C ₁ to C ₆ alkyl;

^R6 is hydrogen;

R ⁷ is C ₁ to C ₆ alkyl;

Each R ⁹ and R ¹⁰ is independently selected from hydrogen and C ₁ to C ₆ alkyl, or R ⁹ and R ¹⁰ form C ₃ to C ₆ cycloalkyl together with the carbon atoms to which they are attached;

R ¹¹ is independently selected from hydrogen, C ₁ to C ₆ alkyl, halogen, -OR ^12a , -CN, -CF ₃ and -NR ⁹ R ¹⁰ ;

each of R ^12a and R ^12b is independently selected from hydrogen and C ₁ to C ₆ alkyl; and

Each n is independently selected and is an integer from 0 to 5.

The present invention also includes any one of the above methods, wherein in the compound of formula (II):

R ¹ is cyclopentyl;

R ⁴ is hydrogen;

R ⁵ is -CH ₂ CH ₃ ;

^R6 is hydrogen;

R ⁷ is -CH ₂ CH ₃ ;

Each R ⁹ and R ¹⁰ is independently selected from hydrogen and C ₁ to C ₆ alkyl, or R ⁹ and R ¹⁰ form C ₃ to C ₆ cycloalkyl together with the carbon atoms to which they are attached;

R ¹¹ is independently selected from hydrogen, C ₁ to C ₆ alkyl, halogen, -OR ^12a , -CN, -CF ₃ and -NR ^12a R ^12b ;

Each R ^12a and R ^12b is independently selected from hydrogen and C ₁ to C ₆ alkyl.

Another aspect of the present invention provides a process for the preparation of a stereoisomerically enriched compound of formula (Ia),

in:

R ¹ is C ₁ to C ₆ alkyl or C ₃ to C ₆ cycloalkyl;

R ^2a , R ^2b and R ^2c are each independently selected from hydrogen, halogen, C ₁ to C ₆ alkyl, C ₃ to C ₆ cycloalkyl, -OR ^12a , -CF ₃ , -CN and -NR ^12a R ^12b ;

R ⁴ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁵ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁶ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁷ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

Each R ⁹ and R ¹⁰ is independently selected from hydrogen and C ₁ to C ₆ alkyl, or R ⁹ and R ¹⁰ form C ₃ to C ₆ cycloalkyl together with the carbon atoms to which they are attached;

each R ¹¹ is independently selected from hydrogen, C ₁ to C ₆ alkyl, halogen, -OR ^12a , -CN, -CF ₃ and -NR ⁹ R ¹⁰ ;

each of R ^12a and R ^12b is independently selected from hydrogen and C ₁ to C ₆ alkyl; and

Each n is independently selected and is an integer from 0 to 5;

The methods include:

a) treatment of a compound of formula (IV) with a chiral, non-racemic base, wherein R ¹ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above and P ¹ is hydrogen or a suitable protecting group to obtain the non- Mixtures of enantiomeric salts;

b) separating said diastereoisomeric salts from each other;

c) converting said separated diastereoisomeric salt into a stereoisomerically enriched compound of formula (IV);

d) treating the stereoisomerically enriched compound of formula (IV) (wherein R ¹³ is hydrogen, C ₁ to C ₆ alkyl, -Si(C ₁ to C ₆ alkyl) ₃ or -CH ₂ with a combination of reagents (C ₆ to C ₁₀ aryl), wherein the C ₆ to C ₁₀ aryl can be optionally replaced by at least one selected from halogen, C ₁ to C ₆ alkyl, -OH, -OCH ₃ and -N(C ₁ to C ₆ alkyl) ₂ substituent substitution), to obtain stereoisomerically enriched formula (III) compound, wherein R ¹⁴ is hydrogen, C ₁ to C ₆ alkyl, -Si(C ₁ to C ₆ alkane radical) ₃ or -CH ₂ (C ₆ to C ₁₀ aryl), wherein the C ₆ to C ₁₀ aryl can be optionally replaced by at least one selected from halogen, C ₁ to C ₆ alkyl, -OH, -OCH ₃ and -N (C ₁ to C ₆ alkyl) _substituent substitution;

e) treating said stereoisomerically enriched compound of formula (III), wherein P ^is hydrogen, with an acid or base to give a stereoisomerically enriched compound of formula (II); and

f) treating said stereoisomerically enriched compound of formula (II) with a compound of formula (IXa) to obtain a stereoisomerically enriched compound of formula (Ia)

Another aspect of the present invention provides a method for preparing a stereoisomerically enriched compound of formula (II),

in

R ¹ is C ₁ to C ₆ alkyl or C ₃ to C ₆ cycloalkyl;

R ⁴ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁵ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁶ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁷ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

Each R ⁹ and R ¹⁰ is independently selected from hydrogen and C ₁ to C ₆ alkyl, or R ⁹ and R ¹⁰ form C ₃ to C ₆ cycloalkyl together with the carbon atoms to which they are attached;

each R ¹¹ is independently selected from hydrogen, C ₁ to C ₆ alkyl, halogen, -OR ^12a , -CN, -CF ₃ and -NR ^12a R ^12b ;

each of R ^12a and R ^12b is independently selected from hydrogen and C ₁ to C ₆ alkyl; and

Each n is independently selected and is an integer from 0 to 5;

The methods include:

a) treatment of a compound of formula (IV) with a chiral, non-racemic base, wherein R ¹ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above and P ¹ is hydrogen or a suitable protecting group to obtain the non- Mixtures of enantiomeric salts;

b) separating said diastereoisomeric salts from each other;

c) converting said separated diastereoisomeric salt into a stereoisomerically enriched compound of formula (IV);

d) treating the stereoisomerically enriched compound of formula (IV) (wherein P ¹ is hydrogen or a suitable protecting group and R ¹³ is hydrogen, C ₁ to C ₆ alkyl, -Si(C ₁ to C ₆ alkyl) ₃ or -CH ₂ (C ₆ to C ₁₀ aryl), wherein the C ₆ to C ₁₀ aryl can be optionally replaced by at least one selected from halogen, C ₁ to C ₆ alkyl, -OH , -OCH ₃ and -N(C ₁ to C ₆ alkyl) substituted by substituents of ₂ ) to obtain a stereoisomerically enriched compound of formula (III), wherein R ¹⁴ is hydrogen, C ₁ to C ₆ alkyl , -Si(C ₁ to C ₆ alkyl) ₃ or -CH ₂ (C ₆ to C ₁₀ aryl), wherein the C ₆ to C ₁₀ aryl can be optionally replaced by at least one selected from halogen, C ₁ to Substituents of C ₆ alkyl, -OH, -OCH ₃ and -N(C ₁ to C ₆ alkyl) ₂ ; and

e) treating the stereoisomerically enriched compound of formula (III) with a base, wherein ^P is hydrogen, to obtain a stereoisomerically enriched compound of formula (II)

Another aspect of the present invention provides the preparation of a stereoisomerically enriched compound of formula (IV),

in:

R ¹ is C ₁ to C ₆ alkyl or C ₃ to C ₆ cycloalkyl;

R ⁴ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁵ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁶ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁷ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

Each R ⁹ and R ¹⁰ are independently selected from hydrogen and C ₁ to C ₆ alkyl, or R ⁹ and R ¹⁰ form C ₃ to C ₆ cycloalkyl together with the carbon atoms to which they are attached;

each R ¹¹ is independently selected from hydrogen, C ₁ to C ₆ alkyl, halogen, -OR ^12a , -CN, -CF ₃ and -NR ^12a R ^12b ;

each of R ^12a and R ^12b is independently selected from hydrogen and C ₁ to C ₆ alkyl;

^P is hydrogen or a suitable protecting group; and

Each n is independently selected and is an integer from 0 to 5;

The methods include:

a) treating a compound of formula (IV) with a chiral, nonracemic base to form a mixture of diastereoisomeric salts;

b) separating said diastereoisomeric salts from each other;

c) converting said diastereoisomeric salt into a stereoisomerically enriched compound of formula (IV).

Also included herein is any one of the above methods, wherein the chiral, nonracemic base is a chiral, nonracemic amine; and wherein the chiral, nonracemic amine is selected from the group consisting of cis-1- Amino-2-indanol, cinchonidine, 1-aminoindan, tert-leucinol, 2-amino-1,2-diphenylethanol, α-methylbenzyl amine and 2-amino-1-(4-nitrophenyl)-1,3-propanediol; and wherein the chiral, non-racemic amine is selected from (1R,2S)-(+)-cis- 1-amino-2-indanol, (-)-cinchonidine, (R)-1-aminoindan, (S)-tert-leucinol, (1R,2S)-2-amino-1 , 2-diphenylethanol, (S)-α-methylbenzylamine and (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1,3-propanediol and wherein the chiral, non-racemic amine is (1R, 2R)-(-)-2-amino-1-(4-nitrophenyl)-1,3-propanediol.

Another aspect of the present invention provides a compound of formula (IV),

in:

R ⁴ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁵ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁶ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁷ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

Each R ⁹ and R ¹⁰ are independently selected from hydrogen and C ₁ to C ₆ alkyl, or R ⁹ and R ¹⁰ form C ₃ to C ₆ cycloalkyl together with the carbon atoms to which they are attached;

each R ¹¹ is independently selected from hydrogen, C ₁ to C ₆ alkyl, halogen, -OR ^12a , -CN, -CF ₃ and -NR ^12a R ^12b ;

each of R ^12a and R ^12b is independently selected from hydrogen and C ₁ to C ₆ alkyl;

R ¹³ is hydrogen, C ₁ to C ₆ alkyl, -Si(C ₁ to C ₆ alkyl) ₃ or -CH ₂ (C ₆ to C ₁₀ aryl), wherein the C ₆ to C ₁₀ aryl can be is optionally substituted by at least one substituent selected from halogen, C ₁ to C ₆ alkyl, -OH, -OCH ₃ and -N(C ₁ to C ₆ alkyl) ₂ ;

^P is hydrogen or a suitable protecting group; and

Each n is independently selected and is an integer from 0 to 5.

Further included herein are such compounds wherein P ¹ is -Si(C ₁ to C ₆ alkyl) ₃ or -CH ₂ (C ₆ to C ₁₀ aryl), wherein the C ₆ to C ₁₀ aryl optionally substituted with at least one substituent selected from halogen, C ₁ to C ₆ alkyl, -OH, -OCH ₃ and -N(C ₁ to C ₆ alkyl) ₂ .

Also included herein are such compounds wherein:

R ⁴ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁵ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁶ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁷ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

Each R ⁹ and R ¹⁰ is independently selected from hydrogen and C ₁ to C ₆ alkyl, or R ⁹ and R ¹⁰ form C ₃ to C ₆ cycloalkyl together with the carbon atoms to which they are attached;

R ¹¹ is -CN;

each of R ^12a and R ^12b is independently selected from hydrogen and C ₁ to C ₆ alkyl;

R ¹³ is hydrogen, C ₁ to C ₆ alkyl, -Si(C ₁ to C ₆ alkyl) ₃ or -CH ₂ (C ₆ to C ₁₀ aryl), wherein the C ₆ to C ₁₀ aryl can be is optionally substituted by at least one substituent selected from halogen, C ₁ to C ₆ alkyl, -OH, -OCH ₃ and -N(C ₁ to C ₆ alkyl) ₂ ;

^P is hydrogen or a suitable protecting group; and

Each n is independently selected and is an integer from 0 to 5.

Another aspect of the invention is such compounds, wherein:

R ⁴ is hydrogen;

R ⁵ is C ₁ to C ₆ alkyl;

^R6 is hydrogen; and

R ⁷ is C ₁ to C ₆ alkyl;

Further provided herein are such compounds wherein:

R ⁴ is hydrogen;

R ⁵ is -CH ₂ CH ₃ ;

^R6 is hydrogen;

R ⁷ is -CH ₂ CH ₃ ; and

R ¹³ is hydrogen or C ₁ to C ₆ alkyl.

Another aspect of the present invention provides compounds of the following formula:

Also included herein are compounds wherein P ¹ is -Si(C ₁ to C ₆ alkyl) ₃ or -CH ₂ (C ₆ to C ₁₀ aryl), wherein the C ₆ to C ₁₀ aryl is optionally replaced by At least one substituent selected from halogen, C ₁ to C ₆ alkyl, -OH, -OCH ₃ and -N(C ₁ to C ₆ alkyl) ₂ is substituted.

Another aspect of the invention is a compound of the formula:

Also included herein are compounds wherein P ¹ is -Si(C ₁ to C ₆ alkyl) ₃ or -CH ₂ (C ₆ to C ₁₀ aryl), wherein the C ₆ to C ₁₀ aryl is optionally replaced by At least one substituent selected from halogen, C ₁ to C ₆ alkyl, -OH, -OCH ₃ and -N(C ₁ to C ₆ alkyl) ₂ is substituted.

Another aspect of the present invention provides compounds of the following formula:

in:

P is ^hydrogen or a suitable protecting group;

R ⁴ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁵ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁶ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁷ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

Each R ⁹ and R ¹⁰ are independently selected from hydrogen and C ₁ to C ₆ alkyl, or R ⁹ and R ¹⁰ form C ₃ to C ₆ cycloalkyl together with the carbon atoms to which they are attached;

R ¹¹ is -CN;

each of R ^12a and R ^12b is independently selected from hydrogen and C ₁ to C ₆ alkyl;

each n is independently selected to be an integer from 0 to 5; and

A ⁺ is a suitable counterion.

Also included herein are compounds wherein P ¹ is -Si(C ₁ to C ₆ alkyl) ₃ or -CH ₂ (C ₆ to C ₁₀ aryl), wherein the C ₆ to C ₁₀ aryl can be is optionally substituted with at least one substituent selected from halogen, C ₁ to C ₆ alkyl, -OH, -OCH ₃ and -N(C ₁ to C ₆ alkyl) ₂ .

Also included herein are such compounds wherein:

^P1 is hydrogen;

R ⁴ is hydrogen;

R ⁵ is C ₁ to C ₆ alkyl;

^R6 is hydrogen;

R ⁷ is C ₁ to C ₆ alkyl; and

A ⁺ is a suitable counterion.

Further included herein are any of the above compounds, wherein the suitable counterion is derived from an amine base; and wherein the amine base is dicyclohexylamine; or wherein the amine base is a chiral, nonracemic amine base . Further included herein are compounds wherein the chiral, non-racemic amine is selected from one enantiomer of the following compounds: cis-1-amino-2-indanol, cinchonidine, 1 -aminoindane, tert-leucinol, 2-amino-1,2-diphenylethanol, α-methylbenzylamine and 2-amino-1-(4-nitrophenyl)-1,3 - propylene glycol; or wherein said chiral, non-racemic amine base is selected from (1R,2S)-(+)-cis-1-amino-2-indanol, (-)-cinchonidine, (R)-1-aminoindan, (S)-tert-leucinol, (1R,2S)-2-amino-1,2-diphenylethanol, α-methylbenzylamine and (1R, 2R)-(-)-2-amino-1-(4-nitrophenyl)-1,3-propanediol; or wherein the chiral, non-racemic amine base is (1R,2R)-(- )-2-amino-1-(4-nitrophenyl)-1,3-propanediol.

Another aspect of the present invention provides a compound of formula (IIIa)

R ⁴ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁵ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁶ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁷ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

Each R ⁹ and R ¹⁰ is independently selected from hydrogen and C ₁ to C ₆ alkyl, or R ⁹ and R ¹⁰ form C ₃ to C ₆ cycloalkyl together with the carbon atoms to which they are attached;

each R ¹¹ is independently selected from hydrogen, C ₁ to C ₆ alkyl, halogen, -OR ^12a , -CN, -CF ₃ and -NR ⁹ R ¹⁰ ;

each of R ^12a and R ^12b is independently selected from hydrogen and C ₁ to C ₆ alkyl;

P is ^hydrogen or a suitable protecting group;

R ¹⁴ is C ₁ to C ₆ alkyl or -CH ₂ (C ₆ to C ₁₀ aryl), wherein the C ₆ to C ₁₀ aryl can be optionally replaced by at least one selected from halogen, C ₁ to C ₆ alkane group, -OH, -OCH ₃ and -N(C ₁ to C ₆ alkyl) _substituent substitution; and

Each n is independently selected and is an integer from 0 to 5.

Also included herein are compounds wherein P ¹ is -Si(C ₁ to C ₆ alkyl) ₃ or -CH ₂ (C ₆ to C ₁₀ aryl), wherein the C ₆ to C ₁₀ aryl is optionally replaced by At least one substituent selected from halogen, C ₁ to C ₆ alkyl, -OH, -OCH ₃ and -N(C ₁ to C ₆ alkyl) ₂ is substituted.

Also included herein are such compounds wherein:

R ⁴ is hydrogen;

R ⁵ is C ₁ to C ₆ alkyl;

^R6 is hydrogen;

R ⁷ is C ₁ to C ₆ alkyl;

P ¹ is hydrogen; and

R ¹⁴ is hydrogen or C ₁ to C ₆ alkyl.

Also included herein are such compounds wherein:

R ⁴ is hydrogen;

R ⁵ is -CH ₂ CH ₃ ;

^R6 is hydrogen;

R ⁷ is -CH ₂ CH ₃ ;

P ¹ is hydrogen; and

R ¹⁴ is hydrogen or C ₁ to C ₆ alkyl.

Another aspect of the present invention provides a compound of formula (IIIb):

in:

R ⁴ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁵ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁶ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁷ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

Each R ⁹ and R ¹⁰ are independently selected from hydrogen and C ₁ to C ₆ alkyl, or R ⁹ and R ¹⁰ form C ₃ to C ₆ cycloalkyl together with the carbon atoms to which they are attached;

each R ¹¹ is independently selected from hydrogen, C ₁ to C ₆ alkyl, halogen, -OR ^12a , -CN, -CF ₃ and -NR ⁹ R ¹⁰ ;

each of R ^12a and R ^12b is independently selected from hydrogen and C ₁ to C ₆ alkyl;

P is ^hydrogen or a suitable protecting group;

R ¹⁴ is C ₁ to C ₆ alkyl or -CH ₂ (C ₆ to C ₁₀ aryl), wherein the C ₆ to C ₁₀ aryl can be optionally replaced by at least one selected from halogen, C ₁ to C ₆ alkane group, -OH, -OCH ₃ and -N(C ₁ to C ₆ alkyl) _substituent substitution; and

Each n is independently selected and is an integer from 0 to 5.

Also included herein are compounds wherein P ¹ is -Si(C ₁ to C ₆ alkyl) ₃ or -CH ₂ (C ₆ to C ₁₀ aryl), wherein the C ₆ to C ₁₀ aryl is optionally replaced by At least one substituent selected from halogen, C ₁ to C ₆ alkyl, -OH, -OCH ₃ and -N(C ₁ to C ₆ alkyl) ₂ is substituted.

Also included herein are compounds wherein:

R ⁴ is hydrogen;

R ⁵ is C ₁ to C ₆ alkyl;

^R6 is hydrogen;

R ⁷ is C ₁ to C ₆ alkyl;

P ¹ is hydrogen; and

R ¹⁴ is hydrogen or C ₁ to C ₆ alkyl.

Also included herein are compounds wherein:

R ⁴ is hydrogen;

R ⁵ is -CH ₂ CH ₃ ;

^R6 is hydrogen;

R ⁷ is -CH ₂ CH ₃ ;

P ¹ is hydrogen; and

R ¹⁴ is hydrogen or C ₁ to C ₆ alkyl.

Another aspect of the present invention provides compounds of the following formula:

in:

R ⁴ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁵ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁶ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁷ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

Each R ⁹ and R ¹⁰ is independently selected from hydrogen and C ₁ to C ₆ alkyl, or R ⁹ and R ¹⁰ form C ₃ to C ₆ cycloalkyl together with the carbon atoms to which they are attached;

each R ¹¹ is independently selected from hydrogen, C ₁ to C ₆ alkyl, halogen, -OR ^12a , -CN, -CF ₃ and -NR ⁹ R ¹⁰ ;

each of R ^12a and R ^12b is independently selected from hydrogen and C ₁ to C ₆ alkyl;

R ¹⁴ is hydrogen or C ₁ to C ₆ alkyl; and

Each n is independently selected and is an integer from 0 to 5.

Also included herein are such compounds wherein:

R ⁴ is hydrogen;

R ⁵ is C ₁ to C ₆ alkyl;

^R6 is hydrogen; and

R ⁷ is C ₁ to C ₆ alkyl.

Also included herein are such compounds wherein:

R ⁴ is hydrogen;

R ⁵ is -CH ₂ CH ₃ ;

^R6 is hydrogen; and

R ⁷ is -CH ₂ CH ₃ .

Another aspect of the present invention provides compounds of the following formula:

in:

R ⁴ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁵ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁶ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁷ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

Each R ⁹ and R ¹⁰ is independently selected from hydrogen and C ₁ to C ₆ alkyl, or R ⁹ and R ¹⁰ form C ₃ to C ₆ cycloalkyl together with the carbon atoms to which they are attached;

Each R ¹¹ is independently selected from hydrogen, C ₁ to C ₆ alkyl, halogen, -OR ^12a , -CN, -CF ₃ and -NR ⁹ R ¹⁰ ;

R ^12a and R ^12b are independently selected from hydrogen, C ₁ to C ₆ alkyl;

R ¹⁴ is hydrogen or C ₁ to C ₆ alkyl; and

Each n is independently selected and is an integer from 0 to 5.

Also included herein are such compounds wherein:

R ⁴ is hydrogen;

R ⁵ is C ₁ to C ₆ alkyl;

^R6 is hydrogen; and

R ⁷ is C ₁ to C ₆ alkyl.

Also included herein are such compounds wherein:

R ⁴ is hydrogen;

R ⁵ is -CH ₂ CH ₃ ;

^R6 is hydrogen; and

R ⁷ is -CH ₂ CH ₃ .

Another aspect of the present invention provides a method for preparing a compound of formula (Ie):

in:

R ^2a , R ^2b and R ^2c are each independently selected from hydrogen, halogen, C ₁ to C ₆ alkyl, C ₃ to C ₆ cycloalkyl, -OR ^12a , -CF ₃ , -CN and -NR ^12a R ^12b ;

R ⁴ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁵ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁶ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁷ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

Each R ⁹ and R ¹⁰ is independently selected from hydrogen and C ₁ to C ₆ alkyl, or R ⁹ and R ¹⁰ form C ₃ to C ₆ cycloalkyl together with the carbon atoms to which they are attached;

each R ¹¹ is independently selected from hydrogen, C ₁ to C ₆ alkyl, halogen, -OR ^12a , -CN, -CF ₃ and -NR ^12a R ^12b ;

each of R ^12a and R ^12b is independently selected from hydrogen and C ₁ to C ₆ alkyl; and

Each n is independently selected and is an integer from 0 to 5;

The method comprises treating a compound of formula (IIa) with a compound of formula (IXa), wherein R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above,

To obtain the compound of formula (Ie).

This article also includes such methods as described below, where:

R ^2a , R ^2b and R ^2c are each independently selected from hydrogen, halogen, C ₁ to C ₆ alkyl, C ₃ to C ₆ cycloalkyl, -OR ^12a , -CF ₃ , -CN and -NR ^12a R ^12b ;

R ⁴ is hydrogen;

R ⁵ is C ₁ to C ₆ alkyl;

^R6 is hydrogen;

R ⁷ is C ₁ to C ₆ alkyl; and

Each R ^12a and R ^12b is independently selected from hydrogen and C ₁ to C ₆ alkyl.

This article also includes such methods as described below, where:

R ^2a , R ^2b and R ^2c are each independently selected from hydrogen, halogen and C ₁ to C ₆ alkyl;

R ⁴ is hydrogen;

R ⁵ is -CH ₂ CH ₃ ;

^R6 is hydrogen; and

R ⁷ is -CH ₂ CH ₃ .

Another aspect of the present invention provides a method for preparing a compound of formula (If):

in:

R ^2a , R ^2b and R ^2c are each independently selected from hydrogen, halogen, C ₁ to C ₆ alkyl, C ₃ to C ₆ cycloalkyl, -OR ^12a , -CF ₃ , -CN and -NR ^12a R ^12b ;

R ⁴ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁵ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁶ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁷ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

Each R ⁹ and R ¹⁰ is independently selected from hydrogen and C ₁ to C ₆ alkyl, or R ⁹ and R ¹⁰ form C ₃ to C ₆ cycloalkyl together with the carbon atoms to which they are attached;

each R ¹¹ is independently selected from hydrogen, C ₁ to C ₆ alkyl, halogen, -OR ^12a , -CN, -CF ₃ and -NR ^12a R ^12b ;

each of R ^12a and R ^12b is independently selected from hydrogen and C ₁ to C ₆ alkyl; and

Each n is independently selected and is an integer from 0 to 5;

The method comprises treating a compound of formula (IIa) with a compound of formula (IXa), wherein R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above,

To obtain the compound of formula (If).

This article also includes such methods as described below, where:

R ^2a , R ^2b and R ^2c are each independently selected from hydrogen, halogen, C ₁ to C ₆ alkyl, C ₃ to C ₆ cycloalkyl, -OR ^12a , -CF ₃ , -CN and -NR ^12a R ^12b ;

R ⁴ is hydrogen;

R ⁵ is C ₁ to C ₆ alkyl;

^R6 is hydrogen;

R ⁷ is C ₁ to C ₆ alkyl; and

Each R ^12a and R ^12b is independently selected from hydrogen and C ₁ to C ₆ alkyl.

This article also includes such methods as described below, where:

R ^2a , R ^2b and R ^2c are each independently selected from hydrogen, halogen and C ₁ to C ₆ alkyl;

R ⁴ is hydrogen;

R ⁵ is -CH ₂ CH ₃ ;

^R6 is hydrogen; and

R ⁷ is -CH ₂ CH ₃ .

This paper further provides a kind of (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl - Crystal form of [1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one. The crystal form has any one of characteristic peaks expressed in degrees 2θ selected from about 7.1; or about 12.1; or about 16.1; or about 17.5; or about 23.5 in a powder X-ray diffraction pattern.

Another aspect of the present invention provides a kind of (R)-6-cyclopentyl-6(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-di Crystal form of methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one, or about 7.1 and about 16.1; or about 7.1 and about 17.5; or about 7.1 and about 23.5; or about 12.1 and about 16.1; or about 12.1 and about 17.5; or or about 12.1 and about 23.5; or about 16.1 and about 17.5; or about 16.1 and about 23.5; or about 17.5 and about 23.5 in degrees 2Θ.

Another aspect of the present invention provides a kind of (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7- Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one crystal form , the crystal form has a powder X-ray diffraction pattern selected from about 7.1, about 12.1 and about 16.1; or about 7.1, about 12.1 and about 17.5; or about 7.1, about 12.1 and about 23.5; about 12.1, about 16.1 and about 17.5; or or about 16.1, about 17.5, and about 23.5; or about 7.1, about 17.5, and about 23.5; or about 7.1, about 12.1, and about 23.5; or about 7.1, about 16.1, and about 23.5 in degrees 2-theta peak.

Another aspect of the present invention provides a kind of (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7- Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one crystal form , the crystal form has characteristic peaks expressed in degrees 2θ of about 7.1, about 12.1, about 16.1, about 17.5 and about 23.5 in a powder X-ray diffraction pattern.

This paper also provides a kind of (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl -[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxyl-5,6-dihydropyran-2-one crystal form, the The crystalline form has characteristic peaks in ppm at about 154.6, about 153.0, about 151.2, about 146.4, about 146.0, about 121.6, about 120.4, about 119.7, about 118.8, about 110.2, about 100.7, and about 100.3 in the solid state NMR spectrum.

In another embodiment, there is provided a kind of (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5, 7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxyl-5,6-dihydropyran-2-one A crystalline form having a melting temperature in the range of about 162°C to about 165°C.

This paper also provides a kind of (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl -[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxyl-5,6-dihydropyran-2-one crystal form, the The crystalline form has any combination of any number of any characteristic peaks in the above powder X-ray diffraction pattern and any number of any characteristic peaks in the above solid phase NMR spectrum. For example, in one embodiment, a (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5, 7-Dimethyl-[1,2,4]triazolo[1,5-d]pyrimidin-2-yl)methyl)-4-hydroxyl-5,6-dihydropyran-2-one A crystalline form having a characteristic peak in degrees 2Θ of about 7.1 in a powder X-ray diffraction pattern and a peak in ppm of about 154.6 in a solid phase NMR spectrum.

In another embodiment, there is provided a kind of (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5, 7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxyl-5,6-dihydropyran-2-one A crystalline form having a characteristic peak in a powder X-ray diffraction pattern of about 7.1 in degrees 2θ, a peak in a solid phase NMR spectrum of about 154.6 in ppm and having a temperature range of about 162°C to about 165°C inside the melting temperature.

The present invention also relates to a method of treating hepatitis C virus (HCV) in an HCV-infected mammal, such as a human, comprising administering to said mammal an amount of (R)- 6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1,2,4]triazole A crystal form of [1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one or a pharmaceutically acceptable salt thereof. In other embodiments, the following methods are provided, wherein the (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3- ((5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran- The crystal form of 2-ketone has any one of the characteristic peaks in the powder X-ray diffraction pattern selected from about 7.1; or about 12.1; or about 16.1; or about 17.5; or about 23.5 expressed in degrees 2θ.

Another aspect of the present invention provides a method of treating a mammal (such as a human) infected by hepatitis C virus, said method comprising administering to said mammal a hepatitis C virus inhibitory amount of (R)-6-cyclopentadiene Base-6(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1,2,4]triazolo[1,5 -a] a crystal form of pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one or a pharmaceutically acceptable salt thereof. In other embodiments, the following methods are provided, wherein the (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3- ((5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran- The crystalline form of 2-ketone has any one of the characteristic peaks in the powder X-ray diffraction pattern represented by about 7.1; or about 12.1; or about 16.1; or about 17.5; or about 23.5 expressed in 2θ degrees. .

Also provided herein are compounds containing (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl- Crystal form of [1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxyl-5,6-dihydropyran-2-one or its pharmaceutical A pharmaceutical composition of an acceptable salt and a pharmaceutically acceptable carrier. In other embodiments, the following pharmaceutical compositions are provided, wherein the (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)- 3-((5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyridine The crystal form of pyran-2-one exhibits any one of the characteristic peaks selected from about 7.1; or about 12.1; or about 16.1; or about 17.5; or about 23.5 in 2θ degrees in the powder X-ray diffraction pattern.

Further provided herein is a pharmaceutical composition for treating hepatitis C virus (HCV) in a mammal, such as a human, said composition comprising an amount of (R)- 6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1,2,4]triazole The crystal form of [1,5-a]pyrimidin-2-yl)methyl)-4-hydroxyl-5,6-dihydropyran-2-one or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier agent. In other embodiments, the following pharmaceutical compositions are provided, wherein the (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)- 3-((5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyridine The crystal form of pyran-2-one has any one of the characteristic peaks in the powder X-ray diffraction pattern represented by about 7.1; or about 12.1; or about 16.1; or about 17.5; or about 23.5 expressed in degrees 2θ.

The present invention also relates to a method of inhibiting the replication of hepatitis C virus in an HCV-infected mammal, such as a human, comprising administering to said mammal a hepatitis C virus replication-inhibiting amount of (R)-6-ring Pentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1,2,4]triazolo[1 ,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one crystal form or a pharmaceutically acceptable salt thereof. In other embodiments, the following methods are provided, wherein the (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3- ((5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran- The crystalline form of 2-ketone has any one of the characteristic peaks in the powder X-ray diffraction pattern represented by about 7.1; or about 12.1; or about 16.1; or about 17.5; or about 23.5 expressed in 2θ degrees.

The present invention also relates to (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[ 1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxyl-5,6-dihydropyran-2-one crystal form or its pharmaceutically acceptable Use of an accepted salt for the manufacture of a medicament for the treatment of a mammal infected with hepatitis C virus. The medicament may comprise (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5 , 7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxyl-5,6-dihydropyran-2-one or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or carriers. In other embodiments, the following drug is provided, wherein said (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3- ((5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran- The crystalline form of 2-ketone has any one of the characteristic peaks in the powder X-ray diffraction pattern represented by about 7.1; or about 12.1; or about 16.1; or about 17.5; or about 23.5 expressed in 2θ degrees.

As used herein, the terms "comprises" and "including" are used in an open form and not in a limiting sense.

The term "hydrogen" as used herein refers to the substituent "-H".

The term "C ₁ to C ₆ alkyl" as used herein refers to a saturated monovalent hydrocarbon group having a linear or branched segment and containing 1 to 6 carbon atoms. Examples of such groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, t-butyl, and the like.

式代表。The term " _C3 to _C8 cycloalkyl" as used herein refers to a saturated or partially saturated, monocyclic or fused or spiro polycyclic ring structure having a total of 3 to 8 carbon ring atoms (but no heteroatoms). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, Ldamantin and the like. The term "cyclopentyl" as used herein refers to a cycloalkyl group consisting of 5 carbon atoms and 9 hydrogen atoms, and can be chemically

formula representative.

The term "C ₆ to C ₁₀ aryl" as used herein refers to a group derived from an aromatic hydrocarbon by removing one hydrogen and containing a total of 6 to 10 carbon atoms. The term "phenyl" and the symbol "Ph" as used herein refer to _{a C6H5} group.

The term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine. The term "fluoro" means fluorine, "chloro" means chlorine, "bromo" means bromine and "iodo" means iodine.

The term "cyano" refers to a -C≡N group in which there is a triple bond between the carbon atom and the nitrogen atom. Cyano is also written herein as "-CN".

The term "trifluoromethyl" refers to a _-CF3 group.

The term "treatment" as used herein in reference to a chemical transformation or series of chemical transformations refers to a chemical process in which two or more reactants are brought into contact with each other to effect a chemical reaction, change or transformation. For example, when reactant A and reactant B are brought into contact with each other to obtain a new chemical compound C, A is said to have been "processed" by B to obtain C.

The term "protection" as used herein refers to a method in which a functional group in a chemical compound is selectively masked by a non-reactive functional group to allow selective reaction elsewhere in the chemical compound. Such non-reactive functional groups are referred to herein as "protecting groups". For example, the term "hydroxyl protecting group" as used herein refers to a group that selectively masks the reactivity of a hydroxyl group (-OH). The term "suitable protecting group" as used herein refers to a protecting group suitable for use in the preparation of the compounds of the present invention. Such groups are typically introduced and removed selectively using mild reaction conditions that do not interfere with other moieties of the host compound. Protecting groups suitable for use in the processes and methods of the invention are well known to those skilled in the art. For example, suitable protecting groups for the Ldamanti(-OH) group include, but are not limited to, trialkylsilyl ethers (such as -Si(CH ₃ ) ₃ ), alkyl ethers (such as -CH ₃ ), untreated _Substituted and substituted benzyl ethers (such as _-CH2C6H5 and p- _{methoxybenzyl} ether). The chemical properties, introduction methods and removal methods of these protective groups can be found in, for example, T. Greene and P. Wuts, Protective Groups in Organic Synthesis (3rd edition), John Wiley & Sons, NY (1999). The term "deprotected", "deprotected" or "deprotection" as used herein means the process of removing a protecting group from a compound.

As used herein, the terms "hydrolysis,""hydrolyzed,""hydrolysis," and "hydrolyzed" all mean a chemical reaction in which an ester, amide, or both is degraded by means such as may be present in an acidic or The proton (H ⁺ ) or hydroxyl anion (-OH) in the alkaline aqueous solution is converted into the corresponding carboxylic acid derivative.

The term "leaving group" as used herein refers to a chemical functional group that can undergo a nucleophilic substitution reaction generally at the atom to which it is attached. For example, in the formula Cl-C(O)R acid chloride (wherein R is an alkyl, aryl or heterocyclic ring), the -Cl group is often referred to as a leaving group because it can be at the carbonyl carbon to which it is attached A nucleophilic substitution reaction occurs. Suitable leaving groups are well known to those skilled in the art and may include halo, aromatic heterocycle, cyano, amino (usually under acidic conditions), ammonium, alkoxy, carbonate, Ldamant and Ldamanti groups that have been activated by reaction with compounds such as carbodiimides. For example, suitable leaving groups may include, but are not limited to, chlorine, bromine, iodine, cyano, imidazole, and a carbodiimide (such as dicyclohexylcarbodiimide) (optionally in a compound such as hydroxybenzene The Ldamanti groups reacted in the presence of triazole additives) or carbodiimide derivatives.

The term "combination reagents" refers to chemical reagents or more than one reagent when necessary that can be used to affect a desired chemical reaction. The choice of a particular reagent or combination of reagents depends on factors well known to those skilled in the art, which include, but are not limited to: the identity of the reactants, other functional groups present in the reactants, the solvent used in the particular chemical reaction, the The temperature and method of purifying the desired chemical reaction product. The selection of a reagent or combination of reagents required to effect a particular chemical reaction is within the purview of one skilled in the art and can be made without undue experimentation. In the present invention, compounds of formula (IV) may be treated with anions such as malonic acid derivatives such as malonates. For example a compound of formula (IV) may be treated with a magnesium malonate such as magnesium ethyl malonate to give a compound of formula (III). In this case, the magnesium malonate may be referred to as the "agent". If the magnesium malonate is prepared in situ and used without isolation or further purification, it may be referred to as a "combination reagent".

The term "base" as used herein refers to so-called Bronsted-Lowry bases. Bronsted-Lowry bases are reagents that can accept protons (H ⁺ ) of acids present in the reaction mixture. Examples of Bronsted-Lowry bases include, but are not limited to, inorganic bases such as sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, and cesium carbonate; organic bases such as triethylamine, di Isopropylethylamine, diisopropylamine, dicyclohexylamine, morpholine, pyrrolidone, piperidine, pyridine, 4-N,N-dimethylaminopyridine (DMAP) and imidazole.

The term "acid" as used herein refers to both Bronsted-Lowry acids and Lewis acids as appropriate. A Bronsted-Lowry acid is a compound or reagent capable of donating a proton (H ⁺ ) to a base present in the reaction mixture. Bronsted-Lowry acids include inorganic and organic acids. Inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, sulfuric, and nitric acids. Organic acids include, but are not limited to, sulfonic acids (such as methanesulfonic acid, trifluoromethanesulfonic acid, and p-toluenesulfonic acid) and carboxylic acids (formic acid, acetic acid, and benzoic acid). Lewis acids are chemical compounds capable of accepting an electron pair from the corresponding Lewis base by a coordination reaction to form so-called Lewis adducts. A Lewis base is a chemical compound capable of donating an electron pair to the corresponding Lewis acid. Suitable Lewis acids include, but are not limited to, aluminum(III) chloride, titanium(II) chloride, titanium(IV) chloride, tin(II) chloride, and tin(IV) chloride.

The term "chiral, nonracemic base" as used herein refers to a basic compound which may exist in enantiomeric forms but not in equivalent amounts to its corresponding reverse enantiomer. For example the compound 2-phenylglycol exists in two enantiomeric forms in reverse configuration, the so-called (R)- and (S)-enantiomers. A mixture is said to be "racemic" if the (R)- and (S)-enantiomers are present in equal amounts. However, if one enantiomer is present in greater amounts than the other, the mixture is said to be "nonracemic".

The term "stereoisomer" refers to compounds that have the same chemical structure, but differ in the arrangement of their atoms or groups in space. In more detail, the term "enantiomer" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other. The term "racemic" or "racemic mixture" as used herein refers to a 1:1 mixture of enantiomers of a particular compound. On the other hand, the term "diastereomers" relates to the relationship between a pair of stereoisomers that contain two or more asymmetric centers and are not mirror images of each other.

As used herein, the term "stereochemically enriched" product refers to a reaction product in which a particular stereoisomer is present in a statistically significantly greater amount than another possible stereoisomer. For example, a product in which one enantiomer is present in a higher amount than the other enantiomer constitutes a stereochemically enriched product. Similarly, a product in which one diastereomer is present in a higher amount than the other diastereomer also constitutes a stereochemically enriched product. The methods and procedures encompassed herein are said to result in "stereochemically enriched" products. In such cases, the methods and processes encompassed herein are carried out starting from a mixture of stereoisomeric compounds in which all possible stereoisomers are present in approximately equal amounts initially and which result in products in which at least one One stereoisomer is present in statistically significantly greater amounts than the remaining stereoisomers.

As used herein, the term "diastereoisomerism" refers to the relationship between a pair of stereoisomers that contain two or more asymmetric centers and are not superimposable mirror images of each other. The phrase "diastereomeric salts" or "diastereomeric salts" as used herein refers to salts of diastereomeric compounds, wherein "diastereoisomers" are as defined herein.

The term "racemic" as used herein refers to a composition containing 1:1 enantiomers. The term "scalemic" as used herein refers to compositions containing unequal amounts of enantiomers. For example a composition comprising a 1:1 mixture of (R)- and (S)-enantiomers of the compounds of the invention is referred to as a racemic composition or mixture. As an additional example, compositions containing a 2:1 mixture of (R)- and (S)-enantiomers of the compounds of the invention are referred to as unequal compositions or mixtures. It is expressly contemplated that the process of the invention may be advantageously used to prepare various compounds of the invention from racemic compounds of the invention.

The terms "resolution" and "resolution" refer to the process of physically separating stereoisomeric compounds from a mixture of stereoisomers, such as a racemic mixture containing two enantiomers of a particular compound. As used herein, "split action" and "split" mean both partial split or complete split.

The term "isolated" or "isolated" as used herein refers to a process of physically separating at least two different chemical compounds from each other. For example, if a chemical reaction takes place and produces at least two products, (A) and (B), the process of isolating (A) and (B) from each other is said to "separate" (A) and (B). It is expressly contemplated that such separations of the present invention may be partial separations or complete separations as determined by analytical techniques known to those skilled in the art and those described herein.

As used herein, the term "conversion" refers to the use of a starting material to perform a chemical reaction to produce a different chemical product. For example, if chemical reactants (A) and (B) are reacted with each other to produce product (C), then starting materials (A) and (B) are said to have been "converted" into product (C) or are said to be (A) Is "converted" into (C) or (B) is "converted" into (C).

The term "suitable counterion" as used herein refers to an ion of the opposite charge to the ions present in the compounds of the present invention, such that the overall complex or salt is electrically neutral. For example, if a compound of the invention contains an overall negative 1 (-1) charge, a suitable counterion may be an ion having an overall positive 1 (+1) charge such that the complex or salt has an overall neutral charge. . Examples of suitable positive (+) counterions include, but are not limited to, sodium ions (Na ⁺ ), potassium ions (K ⁺ ), cesium ions (Cs ⁺ ), and protonated amines (such as protonated triethylamine, protonated dicyclohexylamine, protonated morpholine or protonated pyridine). Alternatively, if the compound of the invention contains an overall positive 1 (+1) charge, a suitable counterion may be one with an overall negative 1 (-1) charge, thereby giving the complex or salt an overall neutral charge. of ions. Examples of suitable negative (-) counterions include, but are not limited to, fluoride (F ⁻ ), chloride (Cl ⁻ ), bromide (Br ⁻ ), iodide (I ⁻ ), hydroxide ( ⁻ OH ) and acetate ( ^-OC (O)CH ₃ ). Suitable counterions in compounds of the invention, including compounds used in the methods of the invention, may also have more than one single charge associated with the compound. For example, if a compound of the invention has a negative 1 (-1) charge, and a suitable counterion may have a positive 2 (+2) charge, then two compounds of the invention with a negative 1 charge are associated with one suitable counterion. Examples of suitable counterions having more than one positive charge include, but are not limited to, calcium (Ca ²⁺ ). Finally, it is also contemplated that compounds of the invention may contain more than one charge, with the result that more than one suitable counterion is required to render the complex or salt population neutral. For example, compounds of the invention may contain more than one negative 1 (-1) charge, consequently requiring two suitable counterions (each with a positive 1 (+1) charge) to render the complex or salt population neutral.

The term "substituted" means that the specified group or moiety has one or more substituents. The term "unsubstituted" means that the specified group has no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents.

Solutions of the individual stereoisomeric compounds of the invention can rotate plane polarized light. The notation "(+)" or "(-)" used in the nomenclature of the compounds of the present invention indicates that a solution of a particular stereoisomer can be determined along the (+) or ( -) orientation rotates plane polarized light.

The term "HCV" as used herein refers to hepatitis C virus (hepatitis C virus).

The terms "inhibiting the hepatitis C virus" and "inhibiting the replication of the hepatitis C virus" refer to the inhibition of the hepatitis C virus by contacting the hepatitis C virus with an HCV replication inhibiting amount of the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof. Replication in vitro or in vivo, such as in a mammal such as a human. The above-mentioned inhibitory effect can be carried out in vivo such as in a mammal such as a human by administering a Hepatitis C virus inhibiting amount of the compound of the present invention to the mammal. The amount of a compound of the invention required to inhibit replication of HCV virus in vitro or in vivo in a mammal such as a human can be determined using methods known to those skilled in the art. For example, an amount of a compound of the invention may be administered to a mammal alone or as part of a pharmaceutically acceptable formulation. Blood samples can then be drawn from the mammal, and the amount of Hepatitis C virus in the sample can be quantified using methods known to those skilled in the art. A reduction in the amount of Hepatitis C virus in the sample compared to the amount of Hepatitis C virus in the blood before administration of the compound of the present invention represents an inhibitory effect on the replication of Hepatitis C virus in the mammal. Administration of a compound of the present invention to a mammal may be in the form of a single dose or as a series of doses over consecutive days.

The term "HCV inhibitory agent" as used herein refers to (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7- Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one crystal form or a pharmaceutically acceptable salt thereof.

The term "HCV inhibitory amount" as used herein refers to an amount of a compound of the present invention sufficient to inhibit the replication of hepatitis C virus when administered to a mammal, such as a human.

As used herein, the term "HCV polymerase inhibitory amount" refers to an amount of a compound of the present invention sufficient to inhibit the action of hepatitis C virus polymerase when the compound is contacted with the enzyme.

Unless otherwise stated, the term "treatment" as used herein in relation to the treatment of an HCV-infected mammal means to cause the development of, or one or more symptoms of, the disorder or condition to which the term applies. Reversing, alleviating, inhibiting, or preventing the disorder or condition or one or more symptoms of the disorder or condition. Unless otherwise stated, the term "treatment" as used herein refers to the act of treatment, as "treatment" is defined immediately above.

As used herein, unless otherwise stated, the term "pharmaceutically acceptable salt" includes acidic or basic groups that may be present in the compounds of the present invention. The compounds of the present invention, which are basic in nature, are capable of forming various salts with various inorganic and organic acids. Acids useful in the preparation of pharmaceutically acceptable acid addition salts of basic compounds of the invention are acids which form non-toxic acid addition salts of the following: i.e., salts containing a pharmacologically acceptable anion, such as acetate, benzenesulfonate, Salt, Benzoate, Bicarbonate, Bisulfate, Bitartrate, Borate, Bromide, Calcium Ldamanti, Camphorsulfonate, Carbonate, Chloride, Clavulanate, Citrate, Dihydrochloride, Ldamanti, Hedisulfonate, Lauryl Sulfate, Ethylsulfonate, Ethylsuccinate, Fumarate, Glucoheptonate, Gluconate, Glutamate, glycollylarsanilate, hexylisophthalate, hydrabamine, hydrobromide, hydrochloride, iodide, isosulfurate, lactic acid Salt, Lactobionate, Laurate, Malate, Maleate, Mandelate, Methanesulfonate, Methylsulfate, Mucate, Naphthalenesulfonate, Nitrate, Oleate , oxalate, pamoate (embonate), palmitate, pantothenate, Ldamantin/diphosphate, polygalacturonate, salicylate, stearate, Hypoacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodode and valerate.

The phrases "therapeutically effective amount", "effective amount" and "HCV-inhibitory amount" mean, when administered to a mammal in need of treatment, sufficient to inhibit HCV RNA replication, such as for enhancing anticancer therapy or by inhibiting the The dose of the present invention for therapeutic purposes by alleviating the injury or condition due to neurotoxicity of stroke, head trauma and neurodegenerative disease. The therapeutically effective amount of a particular HCV inhibitor used in the methods of the invention may vary depending on factors such as the particular HCV inhibitor, the condition and its severity, the species and characteristics of the mammal in need of treatment, and can be routinely determined by the skilled artisan .

Description of drawings

Figure 1 shows the crystal form (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl- Illustrative powder X-ray diffraction of [1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one picture.

Figure 2 is the crystal form (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl- Illustrative solid-state NMR spectrum of [1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one .

Figure 3 is the crystal form (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl- Illustrative Differential Scanning Calorimetry of [1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one picture.

Detailed ways

描述片段或取代基与核构或主链结构连接点的键。根据另一常规，在本文一些结构式中，碳原子和其所结合的氢原子并未明确示出，例如代表甲基、代表乙基、

代表环戊基等。According to the routine in this field, the symbols in the structural formula herein

Describe the bond at the point of attachment of the fragment or substituent to the core or backbone structure. According to another convention, in some structural formulas herein, the carbon atom and its bound hydrogen atom are not explicitly shown, for example represents methyl, represents ethyl,

Represents cyclopentyl, etc.

The compounds of the present invention may exist in several tautomeric forms. For example, as shown in (A) below, the compound of the present invention may exist in a form in which two keto groups are present on the ring of the compound. Alternatively, as shown in compounds (B) and (C) below, the compounds of the invention may exist in at least two different enol forms. These 3 forms are in equilibrium, and the compounds of the present invention may exist in more than one of these forms at the same time. For example, in a particular compound of the invention, a certain percentage of the molecule may be present in form (A), with the remainder present in forms (B) and (C). Which form predominates in a particular compound of the invention depends on several factors including, but not limited to, whether the compound is in solid, liquid or crystalline form, whether the compound is dissolved in a solvent, the type of solvent, ambient temperature and Relative humidity. It is expressly contemplated that where a compound of the invention is expressed in a particular form, eg Form (A), all tautomers, eg Forms (B) and (C), are also included.

或虚楔形线

描述本发明化合物的碳-碳键。用实线描述与非对称碳原子的结合键表示，在该碳原子上包括所有可能的立体异构体。用实或虚楔形线描述与非对称碳原子的结合键表示，仅包括唯一的所示立体异构体。本发明的化合物可含有一个以上非对称碳原子。在这些化合物中，用实线描述与非对称碳原子的结合键表示，包括所有可能的立体异构体。用实现描述在本发明的化合物中与一个或更多个非对称碳原子的结合键并用实或虚楔形线描述在同一化合物中与其它非对称碳原子的结合键意指，存在非对映异构体的混合物。The compounds of the present invention may have asymmetric carbon atoms. In this article, solid lines (——), solid wedge-shaped lines can be used

or dotted wedge

Describe the carbon-carbon bonds of the compounds of the invention. Depicting a bond to an asymmetric carbon atom with a solid line indicates that all possible stereoisomers are included at that carbon atom. Bonds to asymmetric carbon atoms are delineated by solid or dashed wedge lines and only the only stereoisomer shown is included. The compounds of the present invention may contain more than one asymmetric carbon atom. In these compounds, all possible stereoisomers are included by using solid lines to describe bonds to asymmetric carbon atoms. Describing a bond to one or more asymmetric carbon atoms in a compound of the invention by realization and describing a bond to another asymmetric carbon atom in the same compound by a solid or dashed wedge means that there is diastereoisometry A mixture of constructs.

Diastereomeric mixtures can be separated into the individual diastereoisomers on the basis of differences in their physicochemical properties by methods known to those skilled in the art, such as chromatography or fractional crystallization. Enantiomers can be separated by converting an enantiomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral, nonracemic base), converting the diastereomeric The isomers are separated and the individual diastereomers are converted (eg hydrolyzed) into the corresponding pure enantiomers. All such isomers, including diastereomeric mixtures and pure enantiomers, are considered as part of the present invention.

Alternatively, individual stereoisomeric compounds of the invention may be prepared in enantiomerically enriched form by asymmetric synthesis. Asymmetric synthesis can be performed using techniques known to those skilled in the art, such as using commercially available or readily prepared asymmetric starting materials using methods known to those skilled in the art, using asymmetric adjuvants that can be removed at the completion of the synthetic method Alternatively, enzymatic catalysis can be used for the resolution of intermediate compounds. The choice of these methods may depend on factors including, but not limited to, the availability of starting materials, the relative efficiency of the method, and whether the method is applicable to compounds of the invention containing a particular functional group. Such selection is within the purview of those skilled in the art.

Furthermore, a "stereoselective process" is a process by which a particular stereoisomer of a reaction product is preferentially produced over other possible stereoisomers of that product. Enantioselectivity is usually quantified as "enantiomeric excess" (ee) as defined below: [enantiomeric excess A(ee)%=(enantiomer A%)−(enantiomeric excess Body B%)], where A and B are enantiomeric products formed from the starting materials.

When the compound of the present invention contains asymmetric carbon atoms, its derivative salts, prodrugs and solvates can be in the form of single stereoisomers, racemates and/or enantiomers and/or diastereoisomers Exist in the form of a mixture of conformers. All such single stereoisomers, racemates and mixtures thereof are included within the scope of the present invention.

Optically pure compounds are enantiomerically pure compounds, as is generally known to those skilled in the art. According to the present invention, optically pure compounds preferably comprise at least 90% (80% enantiomeric excess), more preferably contain at least 95% (90% e.e.), even more preferably contain at least 97.5% (95% e.e.), most preferably Contains at least 99% (98% e.e.) of a single stereoisomer.

The crystalline forms contained in the present invention have been characterized using powder X-ray diffraction (PXRD), solid state NMR (ssNMR) and differential scanning calorimetry (DSC). Those skilled in the art recognize that X-ray diffraction patterns, solid-state NMR spectra, and differential scanning calorimetry scans may be subject to measurement error depending on the assay conditions used. In more detail, it is generally known that the intensity in an X-ray diffraction pattern can fluctuate depending on the measurement conditions used. It should further be understood that relative intensities also vary depending on experimental conditions, and therefore, the exact magnitude of the intensities should not be considered. In addition, the measurement error of the diffraction angle of a conventional X-ray diffraction pattern is generally about 0.1 (expressed in 2θ degrees), and it should be considered that the above-mentioned measurement error degree is applied to the above-mentioned diffraction angle. Also, the ppm measurement error in solid-state NMR spectroscopy is typically about 0.2 ppm, and it should be considered that the above measurement error degrees apply to the above diffraction angles. Furthermore, all "ppm" associated with peaks in solid-state NMR spectra are associated with an external standard of crystalline Ldamantine, whose upfield resonance was set to 29.5 ppm. Therefore, it should be understood that the crystalline form of the present invention is not limited to the crystal form having the same X-ray diffraction pattern, ssNMR spectrum or DSC trace provided as described in the drawings herein. Any crystal form that provides an X-ray diffraction pattern, ssNMR spectrum or DSC trace that is substantially the same as that described in the accompanying drawings falls within the scope of the present invention. The ability to determine the fundamental properties of an X-ray diffraction pattern, ssNMR spectrum or DSC trace is within the skill of the art.

If the derivative used in the process of the invention is a base, the desired salt can be prepared by any suitable method known in the art, including treatment of the free base with an acid such as: a mineral acid such as hydrochloric acid, hydrogen Bromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranose amino acids (such as glucuronic acid or galacturonic acid), alpha-hydroxy acids (such as citric acid or tartaric acid), amino acids (such as aspartic acid or glutamic acid), aromatic acids (such as benzoic acid or cinnamic acid) , sulfonic acid (such as p-toluenesulfonic acid or ethanesulfonic acid) and the like.

If the derivative used in the process of the invention is an acid, the desired salt can be prepared by any suitable method known in the art, including the use of inorganic or organic bases, such as amines (primary, secondary or tertiary), Alkali or alkaline earth metal hydroxides, etc., to treat free acids. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine and piperazine; and inorganic Salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

The preparation method of the compound of the present invention is as follows. It is to be understood that the details of the methods described herein are only representative of methods available to one skilled in the art to prepare the compounds of the invention. In other aspects of the claimed invention, suitable substitutions and equivalents, including alternative reagents, solvents and temperatures, can readily occur to and be used by those skilled in the art to prepare the compounds of the invention without undue experimentation. Accordingly, the following description is not, and should not be construed as, limiting the scope of the claimed invention in any way.

Compounds of formula (Ia) can be prepared by reacting compounds of formula (II) (wherein R ^{and R} are as defined herein) with compounds of formula (IXa),

in:

R ¹ is C ₁ to C ₆ alkyl or C ₃ to C ₆ cycloalkyl;

R ^2a , R ^2b and R ^2c are each independently selected from hydrogen, halogen, C ₁ to C ₆ alkyl, C ₃ to C ₆ cycloalkyl, -OR ^12a , -CF ₃ , -CN and -NR ^12a R ^12b ;

R ⁴ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁵ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁶ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁷ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ;

R ⁹ and R ¹⁰ are each independently selected from hydrogen and C ₁ to C ₆ alkyl, or R ⁹ and R ¹⁰ form C ₃ to C ₆ cycloalkyl together with the atoms they are connected to;

each R ¹¹ is independently selected from hydrogen, C ₁ to C ₆ alkyl, halogen, -OR ¹² , -CN, -CF ₃ and -NR ^12a R ^12b ;

each of R ^12a and R ^12b is independently selected from hydrogen and C ₁ to C ₆ alkyl; and

Each n is independently selected and is an integer from 0 to 5;

These reactions are generally carried out in the presence of a reducing agent such as a source of borane or hydrogen in the presence of a suitable catalyst. Suitable borane sources include, but are not limited to, diborane, borane-THF, borane-dimethylsulfide, borane-trimethylamine complex, borane-dimethylamine complex, borane-tert-butyl Amine complexes and borane-pyridine complexes. Suitable catalysts in the presence of a reducing agent such as hydrogen include, but are not limited to, nickel, palladium, platinum, rhodium, and ruthenium. Also, the reaction is performed in a solvent or solvent mixture that does not interfere with the desired chemical reaction. Moreover, suitable solvents include those known to those skilled in the art to be compatible with the reaction conditions, including alkyl and aryl esters, alkyl ethers, heterocyclic ethers and aryl ethers, hydrocarbons, alkanols and aryl alcohols, alkylhalogenated compounds, and aryl ethers. halogenated compounds, alkanonitriles or aromatic nitriles, alkanones and aryl ketones, and aprotic heterocyclic solvents. Examples of suitable solvents include, but are not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether, chlorine Benzene, dimethylformamide, dimethylacetamide, propionitrile, butyronitrile, tert-amyl alcohol, acetic acid, diethyl ether, methyl-tert-butyl ether, diphenyl ether, methyl phenyl ether, tetrahydrofuran , 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1-propanol, 2-propanol, tert-butanol, n-butanol , 2-butanol, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile, benzene, toluene, anisole, xylene and pyridine, or any mixture of the above solvents. Alternatively, water can be used as a co-solvent provided that it does not interfere with the desired transformation. Finally, the above reaction may be carried out at a temperature ranging from about 0°C to about 75°C, preferably at a temperature ranging from about -20°C to about 32°C, most preferably at room or ambient temperature. The choice of a particular reducing agent, solvent, and temperature can depend on several factors including, but not limited to, the identity of the particular reactants and the functional groups present in the reactants. Such selection is within the purview of those skilled in the art and does not require undue experimentation.

Alternatively, compounds of formula (Ia) may be prepared by reacting compounds of formula (II) with compounds of formula (Ixb) wherein X is a suitable leaving group. Suitable leaving groups include, but are not limited to, halides (such as chlorine, bromine, and iodine) and activated esters (such as mesylate, triflate, and tosylate). The above reaction can be carried out in the presence of a suitable base. Suitable bases include, but are not limited to, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, lithium hydride, potassium hydride, lithium diisopropylamide, pyridine , triethylamine, tributylamine, triethanolamine, N-methylmorpholine, N-ethyl-N, N-diisopropylamine and 4-N, N-dimethylaminopyridine. Furthermore, suitable solvents include solvents known to those skilled in the art to be compatible with the reaction conditions, including alkyl ethers, heterocyclic and aromatic ethers, hydrocarbons, alkyl and aryl halogenated compounds, alkanonitriles or aromatic nitriles and non- Protic heterocyclic solvents. Examples of suitable solvents include, but are not limited to, dimethoxyethane, diisopropyl ether, chlorobenzene, dimethylformamide, dimethylacetamide, propionitrile, butyronitrile, diethyl ether, methyl-tert -Butyl ether, diphenyl ether, methyl phenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane, heptane, acetonitrile, benzonitrile, benzene, Toluene, anisole, xylene and pyridine or any mixture of the above solvents. Alternatively, water can be used as a co-solvent provided that it does not interfere with the desired transformation. Finally, the reaction may be carried out at a temperature ranging from about 0°C to about 150°C, preferably at a temperature ranging from about 0°C to about 32°C, most preferably at room or ambient temperature. Such selection is within the purview of those skilled in the art and does not require undue experimentation.

A compound of formula (II), wherein R ¹ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above,

It can be obtained by reacting a compound of formula (III) (wherein R ¹ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above and R ¹⁴ is C ₁ to C ₆ alkyl or benzyl) with a suitable acid or base to prepare.

Bases suitable for the above reactions include inorganic bases and organic bases. Suitable inorganic bases include, but are not limited to, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, sodium hydride, potassium hydride, and cesium carbonate. The base is preferably potassium carbonate. Suitable organic bases include, but are not limited to, pyridine, triethylamine, tributylamine, triethanolamine, N-methylmorpholine, N-ethyl-N,N-diisopropylamine, DBU and 4-N,N - Dimethylaminopyridine. The reaction can also be carried out in the presence of a catalytic amount of a suitable acid. Suitable acids include both Bronsted-Lowry acids and Lewis acids. Moreover, these reactions are usually performed in a solvent or mixture of solvents that will not interfere with the desired chemical reaction. Furthermore, suitable solvents include those known to those skilled in the art to be compatible with the reaction conditions, including alkyl and aryl esters, alkyl ethers, heterocyclic and aryl ethers, hydrocarbons, alkanols and aryl alcohols, alkylhalogenated compounds and aryl Halogenated compounds, alkanonitriles or aromatic nitriles, alkanones and aryl ketones and aprotic heterocyclic solvents. Examples of suitable solvents include, but are not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether, chlorine Benzene, dimethylformamide, dimethylacetamide, propionitrile, butyronitrile, tert-amyl alcohol, acetic acid, diethyl ether, methyl-tert-butyl ether, diphenyl ether, methyl phenyl ether, tetrahydrofuran , 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1-propanol, 2-propanol, tert-butanol, n-butanol , 2-butanol, methylene chloride, chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene, anisole, xylene and pyridine or any of the above solvents mixture. Alternatively, water can be used as a co-solvent provided that it does not interfere with the desired transformation. Finally, the reaction may be at a temperature ranging from about 0°C to about 110°C, or at a temperature ranging from about 25°C to about 100°C, or at a temperature ranging from about 35°C to about 75°C, Either at a temperature in the range of about 45°C to about 55°C, or at about 50°C. The choice of a particular solvent and temperature can depend on several factors including, but not limited to, the identity of the particular reactants and the functional groups present in the reactants. Such selection is within the purview of those skilled in the art and does not require undue experimentation.

Alternatively, the compound of formula (II) (wherein R ¹ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above) can be obtained by making the compound of formula (III) (wherein R ¹ , R ⁴ , R ⁵ , R ⁶ and R ⁷ is prepared as defined above and R ¹⁴ is hydrogen) by reaction with a suitable reagent or combination of reagents to effect cyclization.

The above reactions may be performed in the presence of a reagent or combination of reagents capable of converting a carboxylated -OH group into a suitable leaving group such as chloro or imidazolyl. The term "suitable leaving group" refers to a chemical group that can be displaced when a suitable nucleophilic group, such as a hydroxyl group, reacts with the carbonyl carbon of the carboxyl group in a compound of formula (III). Such suitable leaving groups may be introduced into compounds of formula (III) wherein ^R14 is hydrogen by reacting compounds of formula (III) with suitable reagents or combinations of reagents known to those skilled in the art. For example, a compound of formula (III) (where R ¹⁴ is hydrogen) can be combined with phosgene (ClC(O)Cl), tricarbonyl chloride ((Cl) ₃ C(O)(Cl) ₃ ), SOCl ₂ or (COCl) ₂ are reacted to give so-called acid chlorides, that is to say compounds in which the carboxyl hydroxyl group has been replaced by a chlorine atom. Furthermore, the compound of formula (III) can be converted into a compound wherein the carboxyhydroxyl group is replaced by another suitable leaving group such as imidazolyl. Such compounds may be prepared using suitable reagents or combinations of reagents such as carbonyldiimidazole. The reaction can be performed in the presence of a suitable base such as triethylamine and in an aprotic solvent such as chloroform or dichloromethane that does not interfere with the desired chemical reaction. Also, the reaction may be carried out at a temperature ranging from about -78°C to about 75°C, or at a temperature ranging from about 0°C to about 50°C, or at a temperature ranging from about 0°C to about 25°C . The selection of suitable reagents, suitable solvents and suitable temperatures for converting the carboxyl group to the acid chloride is within the purview of those skilled in the art and does not require undue experimentation.

Compounds of formula (III), wherein the carboxyhydroxyl group has been converted to a suitable leaving group (eg acid chloride), can then be converted to compounds of formula (II) by reaction in the presence of a suitable base. Suitable bases include, but are not limited to, inorganic bases and organic bases. Suitable inorganic bases include, but are not limited to, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and cesium carbonate. Suitable organic bases include, but are not limited to, pyridine, triethylamine, diethylisopropylamine, and 4-N,N-dimethylaminopyridine. Furthermore, suitable solvents include those known to those skilled in the art to be compatible with the reaction conditions, including alkyl and aryl esters, alkyl ethers, heterocyclic and aryl ethers, hydrocarbons, alkanols and aryl alcohols, alkylhalogenated compounds and aryl Halogenated compounds, alkanonitriles or aromatic nitriles, alkanones and aryl ketones and aprotic heterocyclic solvents. Examples of suitable solvents include, but are not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether, chlorine Benzene, dimethylformamide, dimethylacetamide, propionitrile, butyronitrile, tert-amyl alcohol, acetic acid, diethyl ether, methyl-tert-butyl ether, diphenyl ether, methyl phenyl ether, tetrahydrofuran , 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1-propanol, 2-propanol, tert-butanol, n-butanol , 2-butanol, methylene chloride, chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene, anisole, xylene and pyridine or any of the above solvents mixture. The particular choice of activators, solvents, bases and temperatures to affect the desired transformation is within the purview of those skilled in the art without undue experimentation.

As shown below, compounds of formula (IV) (where R ¹ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above, P ¹ is hydrogen or a suitable protecting group and R ¹³ is hydrogen, C ₁ to C ₆ alkyl, -Si(C ₁ to C ₆ alkyl) ₃ or -CH ₂ (C ₆ to C ₁₀ aryl), wherein the C ₆ to C ₁₀ aryl can be optionally replaced by at least one selected from halogen, C ₁ to C ₆ alkyl, -OH, -OCH ₃ and -N (C ₁ to C ₆ alkyl) ₂ substituents), or by formula (IVa) compound (wherein R ¹ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above, P ¹ is hydrogen or a suitable and protecting group and L is a suitable leaving group) to prepare a compound of formula (III), wherein R ¹ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above, P ¹ is hydrogen or a suitable protecting group and R ¹⁴ is C ₁ to C ₆ alkyl, -Si(C ₁ to C ₆ alkyl) ₃ or -CH ₂ (C ₆ to C ₁₀ aryl), wherein the C ₆ to C ₁₀ aryl can be optionally replaced by at least one selected from halogen, C ₁ to C ₆ alkyl, -OH, -OCH ₃ and -N(C ₁ to C ₆ alkane Base) Substituent substituent of ₂ ,.

Compounds of formula (IV) wherein ^R13 is hydrogen may be reacted with a reagent or combination of reagents which will convert the carboxyhydroxyl group to a suitable leaving group -OA. The leaving group includes activated esters (such as various benzoyl esters, such as 2,6-dinitrobenzoyl ester or perfluorobenzoyl ester), mixed anhydrides or combinations of carboxyl and carbodiimide (such as diethylcarbodiimide or diisopropylcarbodiimide) reacted intermediates derived. Can be at a temperature ranging from about -78°C to about 100°C, or at a temperature ranging from about 0°C to about 75°C, or at a temperature ranging from about 0°C to about 50°C, without interfering with the desired chemical reaction The above intermediate compounds are prepared by reacting the carboxyl group with a suitable reagent such as carbodiimide in a solvent such as chloroform, dichloromethane or tetrahydrofuran. Compounds of formula (IV) containing a suitable leaving group -OA can be isolated or can be reacted in the next step without further purification. Compounds containing a suitable leaving group -OA can be reacted with a reagent or combination of reagents to provide a compound of formula (III). Such suitable reagents include, but are not limited to: malonate anion, which is derived from the deprotonation reaction of a malonate derivative with a suitable base; and magnesium malonate, such as magnesium methylmalonate and magnesium ethyl malonate. Furthermore, suitable solvents include those known to those skilled in the art to be compatible with the reaction conditions, including alkyl and aryl esters, alkyl ethers, heterocyclic ethers and aryl ethers, hydrocarbons, alkanols and aryl alcohols, alkylhalogenated compounds, and aryl ethers. halogenated compounds, alkanonitriles or aromatic nitriles, alkanones and aryl ketones, and aprotic heterocyclic solvents. Examples of suitable solvents include, but are not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether, chlorine Benzene, dimethylformamide, dimethylacetamide, propionitrile, butyronitrile, tert-amyl alcohol, acetic acid, diethyl ether, methyl-tert-butyl ether, diphenyl ether, methyl phenyl ether, tetrahydrofuran , 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1-propanol, 2-propanol, tert-butanol, n-butanol , 2-butanol, methylene chloride, chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene, anisole, xylene and pyridine or any of the above solvents mixture. Moreover, the reaction is at a temperature in the range of about 0°C to about 150°C, or in the range of about 0°C to about 75°C, or in the range of about 20°C to about 75°C, or in the range of about 25°C to about 50°C , or at about 40°C. The particular choice of reagents or groups of reagents combined, solvent or solvents, and temperature are within the purview of those skilled in the art without undue experimentation.

Alternatively, the compound of formula (III) can be prepared from the compound of formula (IV) (wherein R ¹³ is C ₁ to C ₆ alkyl, Si(C ₁ to C ₆ alkyl) ₃ or -CH ₂ (C ₆ to C ₁₀ aryl) , wherein the C ₆ to C ₁₀ aryl is optionally substituted by at least one selected from halogen, C ₁ to C ₆ alkyl, -OH, -OCH ₃ and -N(C ₁ to C ₆ alkyl) ₂ substituted) are prepared by reacting with reagents or combinations of reagents. Such suitable agents include, but are not limited to, magnesium malonates, such as magnesium methyl malonate and magnesium ethyl malonate. Suitable reagents include, but are not limited to, the malonate anion, which is derived from the deprotonation reaction of a malonate derivative with a suitable base; and magnesium malonate, such as magnesium methyl malonate and malonate Magnesium ethyl acetate. Furthermore, suitable solvents include those known to those skilled in the art to be compatible with the reaction conditions, including alkyl and aryl esters, alkyl ethers, heterocyclic and aryl ethers, hydrocarbons, alkanols and aryl alcohols, alkylhalogenated compounds and aryl Halogenated compounds, alkanonitriles or arylonitriles, alkanones and aryl ketones and non-protonated heterocyclic solvents. Examples of suitable solvents include, but are not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether, chlorine Benzene, dimethylformamide, dimethylacetamide, propionitrile, butyronitrile, tert-amyl alcohol, diethyl ether, methyl-tert-butyl ether, diphenyl ether, methyl phenyl ether, tetrahydrofuran, 2 -Methyltetrahydrofuran, 1,4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1-propanol, 2-propanol, tert-butanol, n-butanol, 2 - butanol, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene, anisole, xylene and pyridine or any mixture of the aforementioned solvents. Moreover, the reaction is at a temperature in the range of about 0°C to about 150°C, or in the range of about 0°C to about 75°C, or in the range of about 20°C to about 75°C, or in the range of about 25°C to about 50°C , or at about 40°C. The particular choice of reagents or combinations of reagents, solvent or solvents, and temperature are within the purview of those skilled in the art without undue experimentation.

Alternatively, compounds of formula (III) may be derived from compounds of formula (IVa) wherein R ¹ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above, P ¹ is hydrogen or a suitable protecting group and L is a suitable leaving groups) are made by reacting with reagents or combinations of reagents. Suitable leaving groups include, but are not limited to, chlorine, bromine, iodine, and imidazole. Compounds with a suitable leaving group can be prepared from compounds of formula (IV), wherein ^R13 is -OH, by reaction with an activating reagent or combination of activating reagents capable of substituting L for the carboxy hydroxy group. The activating reagents include, but are not limited to, thionyl chloride (SOCl ₂ ), phosgene, tricarbonyl chloride, oxalyl chloride, and carbonyldiimidazole. These reactions are carried out in the presence of a base that does not interfere with the desired chemical reaction, such as triethylamine, ethyldiisopropylamine, pyridine or 4-N,N-dimethylaminopyridine. Furthermore, the reaction can be performed in aprotic solvents that do not interfere with the desired chemical reaction (such as tetrahydrofuran, methyl butyl ether, diisopropyl ether, diethyl ether, toluene, chloroform, methylene chloride, or 1,2-dichloroethane). alkane). And, the reaction is in the range of about -78°C to about 100°C, or in the range of about -50°C to about 100°C, or in the range of about 0°C to about 75°C, or in the range of about 0°C to about 50°C, or at a temperature in the range of about 0°C to about 25°C. After conversion of a compound of formula (IV) to a compound of formula (IVa), the compound of formula (IVa) can be reacted with a reagent or combination of reagents capable of converting the compound of formula (IVa) into one of the compounds of formula (III). Such suitable agents include, but are not limited to, magnesium malonates, such as magnesium methyl malonate and magnesium ethyl malonate. These reactions are performed in solvents, such as diethyl ether, methyl tert-butyl ether, and tetrahydrofuran, or mixtures thereof, or solvent mixtures that do not interfere with the desired chemical reaction. Additionally, the reaction is at a temperature in the range of about 0°C to about 100°C, or in the range of about 0°C to about 75°C, or in the range of about 20°C to about 75°C, or in the range of about 25°C to about 50°C Or at about 40°C. The particular choice of reagents or combinations of reagents, solvent or solvents, and temperature are within the purview of those skilled in the art without undue experimentation.

The step of reacting the compound of formula (IV), (IVa) or a suitable activated derivative thereof with a reagent or a combination of reagents to obtain a compound of formula (III) needs to introduce a suitable protecting group, P ¹ , to protect the compound of formula (IV) tertiary hydroxyl. The protecting group should be able to be introduced into the compound of formula (IV) under conditions which selectively protect the hydroxyl group. Such reagents and conditions are well known to those skilled in the art and can be found, for example, in T. Greene and P. Wuts, Protective Groups in Organic Synthesis (3rd ed.), John Wiley & Sons, NY (1999). For example a silyl protecting group such as triisopropylsilyl may be introduced into the compound of formula (IV) for selective protection of the tertiary hydroxyl group. An activated silane such as triisopropylsilyl chloride can be used, for example, in the presence of a base such as triethylamine in an aprotic solvent such as chloroform to introduce the above-mentioned groups. The protected compound of formula (IV) can then be reacted as described above to give the compound of formula (III) in protected form. The protected compound (III) can then be deprotected using conditions known to those skilled in the art. For example, if the tertiary hydroxyl group in the compound of formula (III) is protected with, for example, a silyl ether, a fluoride source (such as tetrabutylammonium fluoride) can be used at a temperature ranging from about 0°C to about 100°C, or about Deprotection is performed in a solvent such as THF at a temperature ranging from 0°C to about 25°C. Whether a tertiary hydroxyl group in a compound of formula (IV) needs to be protected prior to conversion to a compound of formula (III) is within the purview of those skilled in the art, and this choice can be made without undue experimentation.

Reagents, such as magnesium malonate, magnesium methyl malonate, or magnesium ethyl malonate, are commercially available or can be prepared using methods known to those skilled in the art. As shown below, magnesium ethyl malonate can be prepared by reacting magnesium ethoxide with ethyl malonate.

Compounds of formula (IV) (wherein R ¹ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above, P ¹ is hydrogen and R ¹³ is hydrogen) can be obtained from compounds of formula (IV)

Wherein R ¹³ is C ₁ to C ₆ alkyl, -Si(C ₁ to C ₆ alkyl) ₃ or -CH ₂ (C ₆ to C ₁₀ aryl), wherein the C ₆ to C ₁₀ aryl is optional Substituted by at least one substituent selected from halogen, C ₁ to C ₆ alkyl, -OH, -OCH ₃ and -N(C ₁ to C ₆ alkyl) ₂ by using a suitable acid or Made by hydrolysis of alkali. Suitable bases include, but are not limited to, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate. Suitable acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, and sulfuric acid. These reactions can be performed in solvents or mixtures of solvents that do not interfere with the desired chemical reactions, including, but not limited to, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, methanol, ethanol, isopropanol, n-propionic acid and tert-butanol. In these reactions, water is preferably used as a co-solvent. Also, these reactions are carried out at a temperature in the range of about -78°C to about 50°C, or in the range of about -35°C to about 50°C, or in the range of about -35°C to about 25°C.

As shown below, a compound of formula (IV), wherein R ¹ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above, P ¹ is hydrogen or a suitable protecting group and R ¹³ is hydrogen, C ₁ to C ₆ alkane group, -Si(C ₁ to C ₆ alkyl) ₃ or -CH ₂ (C ₆ to C ₁₀ aryl), wherein the C ₆ to C ₁₀ aryl can be optionally selected from at least one halogen, C ₁ to C ₆ alkyl, -OH, -OCH ₃ and -N (C ₁ to C ₆ alkyl) ₂ substituents can be substituted by making the compound of formula (V) (wherein R ¹ , R ⁴ , R ⁵ , R ⁶ and R ⁷ as defined above) and formula (X) compound (wherein R ¹³ is hydrogen, C ₁ to C ₆ alkyl, -Si (C ₁ to C ₆ alkyl) ₃ or -CH ₂ (C ₆ to C ₁₀ aryl), wherein the C ₆ to C ₁₀ aryl can be optionally replaced by at least one selected from halogen, C ₁ to C ₆ alkyl, -OH, -OCH ₃ and -N(C ₁ to C ₆ alkyl ) The substituent of ₂ is substituted) to carry out the reaction and make.

These reactions can be achieved by first reacting with a compound of formula (X) in the presence of a strong base to give an anion. Strong bases suitable for this reaction include lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide and diisopropyl Magnesium Amide. Also, the reaction can be performed in the presence of a solvent that does not interfere with the desired chemical reaction. Suitable solvents include, but are not limited to, pure solutions of compounds of formula (X), diethyl ether, methyl tert-butyl ether and tetrahydrofuran. Additionally, the reaction may be performed at a temperature in the range of about -78°C to about 25°C, or in the range of about -50°C to about 25°C, or in the range of about -35°C to about 25°C, or in the range of about -35°C to about 0°C at a temperature within the range.

Alternatively, as shown below, compounds of formula (IV) can be prepared by reacting compounds of formula (V) with silylketene acetals of formula wherein R is, for example, _C1 to _C6 alkyl and ^R13 is as defined above production. These reactions can be carried out in the presence of catalytic or stoichiometric amounts of suitable Lewis acids including, but not limited to, lithium(III) chloride, titanium(II) chloride, titanium(IV) chloride, chloride Tin(II) chloride and tin(IV) chloride. Also, the reaction can be performed in the presence of a solvent that does not interfere with the desired chemical reaction. Suitable solvents include, but are not limited to, diethyl ether, methyl tert-butyl ether, dichloromethane, dichloroethane, and tetrahydrofuran. Additionally, the reaction may be performed at a temperature in the range of about -78°C to about 25°C, or in the range of about -50°C to about 25°C, or in the range of about -35°C to about 25°C, or in the range of about -35°C to about 0°C at a temperature within the range.

Compounds of formula (IV) wherein R ¹ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above, P ¹ is hydrogen or a suitable protecting group and R ¹³ is hydrogen may be resolved or stereoisomerically enriched. The compound can be stereoisomerically enriched by reacting it with a chiral nonracemic base to form a mixture of diastereoisomeric salts. The above diastereoisomeric salts can then be separated using techniques well known to those skilled in the art, such as fractional crystallization. For example a mixture of diastereomeric salts can be dissolved in a suitable solvent and one diastereomeric salt can then crystallize from solution which is thereafter collected, washed and dried. Suitable chiral, non-racemic bases include amine bases, which include, but are not limited to, one enantiomer of the following compounds: cis-1-amino-2-indanol, cinchoni Tine, 1-aminoindane, tert-leucinol, 2-amino-1,2-diphenylethanol, α-methylbenzylamine and 2-amino-1-(4-nitrophenyl)-1 , 3-propanediol. For example, a compound of formula (IV), wherein R ¹ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above and P ¹ is hydrogen or a suitable protecting group such as tri Alkylsilyl ether) and R ¹³ is hydrogen, reacted with (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1,3-propanediol to give the non- A mixture of enantiomeric salts. The solution containing the mixture of diastereoisomeric salts can then be cooled slowly so that only one diastereomeric salt is largely soluble in the cooling solvent. The remaining diastereomeric salt may then precipitate from solution as a crystalline solid containing a substantially pure diastereomeric salt. The desired stereoisomerically enriched compound of formula (IV) can then be obtained from the precipitated diastereomeric salt or from the diastereomeric salt remaining in solution. Compounds of formula (IV) wherein R ¹³ is hydrogen can then be obtained from the substantially pure diastereoisomeric salts by reaction with a suitable acidic compound such as citric acid.

Formula (X) compound, wherein R ¹³ is hydrogen, C ₁ to C ₆ alkyl, -Si(C ₁ to C ₆ alkyl) ₃ or -CH ₂ (C ₆ to C ₁₀ aryl), wherein said C ₆ to _C10 aryl is optionally substituted by at least one substituent selected from halogen, _C1 to _C6 alkyl, -OH, _-OCH3 and -N( _C1 to _C6 alkyl) ₂ , commercially available or can be prepared according to methods known to those skilled in the art.

The compound of formula (V) (wherein R ¹ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above) can be obtained by combining the compound of formula (VI) (wherein R ¹ is as defined above) with the compound of formula (VII) (wherein R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined herein and X is a group suitable for use in a palladium-catalyzed (Pd-catalyzed) Heck-type coupling reaction). Heck-type coupling reactions can be performed using palladium-based catalysts. Suitable catalysts include, but are not limited to, Pd(Oac) ₂ , PdCl ₂ and Pd(PPh ₃ ) ₄ . Also, the reaction can be performed in the presence of a base such as triethylamine, sodium acetate, lithium acetate, potassium acetate, sodium carbonate, potassium carbonate or cesium carbonate. These reactions can be performed in solvents that do not interfere with the desired chemical reactions. Furthermore, suitable solvents include those known to those skilled in the art to be compatible with the reaction conditions, including alkyl and aryl esters, alkyl ethers, heterocyclic ethers and aryl ethers, hydrocarbons, alkanols and aryl alcohols, alkylhalogenated compounds, and aryl ethers. Halogenated compounds, alkanonitriles or aromatic nitriles, alkanones and aromatic ketones, amides and aprotic heterocyclic solvents. Examples of suitable solvents include, but are not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether, chlorobenzene , dimethylformamide, dimethylacetamide, propionitrile, butyronitrile, tert-amyl alcohol, acetic acid, diethyl ether, methyl-tert-butyl ether, diphenyl ether, N-methylpyrrolidone, methyl Phenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1-propanol, 2-propanol, tert-butanol , n-butanol, 2-butanol, methylene chloride, chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene, anisole, xylene, and pyridine Or any mixture of the above solvents. These reactions may then be in the range of about 0°C to about 150°C, or in the range of about 25°C to about 150°C, or in the range of about 25°C to about 100°C, or in the range of about 45°C to about 100°C, or at a temperature in the range of about 45°C to about 75°C. Finally, in compounds of formula (VII), X is a group suitable for use in Heck-type reactions. Suitable groups include chloro, bromo, iodo and _triflate ( _-OSO2CF3 ).

Compounds of formula (VII) are commercially available or can be prepared by methods known to those skilled in the art.

Compounds of formula (VI), wherein ^R is as defined above, can be prepared by reacting compounds of formula (X), wherein ^R is as defined above, with compounds of formula (XI), wherein M is a suitable metal, as shown below .

In compounds of formula (XI), M is selected from suitable metals such as magnesium derivatives (such as magnesium bromide) or lithium. These reactions can be performed in aprotic solvents such as diethyl ether, methyl tert-butyl ether or tetrahydrofuran. In addition, these reactions can be carried out at a temperature in the range of about -78°C to about 50°C, or in the range of about -78°C to about 25°C, or in the range of about -78°C to about 0°C.

Compounds of formula (XI), wherein M is a suitable metal group, are commercially available or can be prepared by methods known to those skilled in the art. For example compounds of formula (XI) wherein M is -MgBr can be prepared from vinyl bromide and a suitable magnesium precursor such as magnesium metal or activated Reike magnesium. These reactions can be performed in an aprotic solvent such as diethyl ether, methyl t-butyl ether or tetrahydrofuran at temperatures ranging from about 0°C to about 25°C. Compounds of formula (XI) wherein M is lithium may be prepared from a vinyl halide such as vinyl bromide or vinyl iodide and a suitable alkyllithium reagent such as butyllithium or tert-butyllithium. These reactions can be performed in an aprotic solvent such as diethyl ether, methyl t-butyl ether or tetrahydrofuran at temperatures ranging from about 0°C to about 25°C.

Compounds of formula (X), wherein R ¹ is as defined above, are commercially available or can be prepared by combining a compound of formula (XII) (wherein L is a suitable leaving group) with a compound of formula (XIII) (wherein R ¹ is as defined above and M is made by reacting with a suitable metal). In compounds of formula (XII), L is a suitable leaving group, such as a -N( _CH3 ) ₂ group. In compounds of formula (XIII), M is a suitable metal, such as -MgBr or Li. The reaction can be carried out in an aprotic solvent such as diethyl ether, methyl tert-butyl ether or tetrahydrofuran at a temperature ranging from about 0°C to about 25°C.

Compounds of formula (XII) are commercially available or can be prepared by methods known to those skilled in the art.

Compounds of formula (XIII), wherein M is a suitable metal, are commercially available or can be prepared by methods known to those skilled in the art. For example compounds of formula (XIII), wherein M is -MgBr, can be prepared from vinyl bromide and a suitable magnesium precursor such as magnesium metal or activated Rieke magnesium. The reaction can be carried out in an aprotic solvent such as diethyl ether, methyl tert-butyl ether or tetrahydrofuran at a temperature ranging from about 0°C to about 25°C. Compounds of formula (XIII), wherein M is Li, can be prepared from a suitable halide such as bromide or iodide and a suitable alkyllithium reagent such as butyllithium or tert-butyllithium. The reaction can be carried out in an aprotic solvent such as diethyl ether, methyl tert-butyl ether or tetrahydrofuran at a temperature ranging from about 0°C to about 25°C.

Compounds of formula (IX), such as (Ixa) below, are commercially available or can be prepared using methods known to those skilled in the art. For example, compounds of formula (Ixa) can be prepared by reacting glycolic acid with aminoguanidine bicarbonate to give (5-amino-1H-1,2,4-triazol-3-yl)methanol. This product is then reacted with 2,4-pentanedione to give (5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methanol, followed by Oxidation using 2,2,6,6-tetramethyl-1-piperidinyloxy and iodobenzene diacetate to give 5,7-dimethyl[1,2,4]triazolo[1,5 -a] pyrimidine-2-carbaldehyde.

(R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl) can be administered according to any one of the acceptable modes available to those skilled in the art -3-((5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxyl-5,6-dihydro A crystal form of pyran-2-one or a pharmaceutically acceptable salt thereof. Illustrative examples of suitable modes of administration include oral, intranasal, parenteral, topical, transdermal and rectal administration. Oral and intravenous delivery are preferred.

(R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-(( 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2- A crystalline form of a ketone or a pharmaceutically acceptable salt thereof. Suitable dosage forms include solid, semi-solid, liquid or Ldamantine L formulations, such as tablets, powders, capsules, suppositories, suspensions, liposomes and aerosols. HCV inhibitors can be formulated into solutions using any method. For example HCV inhibitors can be dissolved in acid (e.g. 1M HCl) and diluted with an appropriate amount of 5% dextrose in water (D5W) to obtain the desired final concentration of HCV inhibitor (e.g. about 15 mM) . Alternatively, a D5W solution containing about 15 mM HCl can be used to provide a suitable concentration of HCV inhibitor solution. Also, HCV inhibitors can be made into suspension using, for example, a 1% carboxymethylcellulose (CMC) solution.

Acceptable methods of preparing suitable dosage forms of pharmaceutical compositions are known or routinely determined by those skilled in the art. Pharmaceutical formulations can be prepared, for example, according to common techniques employed by medicinal chemists, which include steps such as mixing, granulating and, when required, compressing into tablet form; or mixing, filling and dissolving the various ingredients to obtain suitable Desired products for oral, parenteral, topical, vaginal, intranasal, intrabronchial, ocular, otic and/or rectal administration.

According to the end use, the pharmaceutical composition of the present invention also includes suitable adjuvants, diluents, vehicles and carriers, and other pharmaceutically active agents. Pharmaceutically acceptable solid or liquid carriers, diluents, vehicles or adjuvants can be used in pharmaceutical compositions. Examples of solid carriers include starch, lactose, calcium sulfate damantin, terra alba, sucrose, talc, gelatin, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers include syrup, peanut oil, olive oil, saline solution and water. The carrier or diluent may include a suitable long acting substance such as glyceryl monostearate or glyceryl distearate, alone or in combination with a wax. When a liquid carrier is used, the preparation can be in the form of syrup, elixir, emulsion, soft gelatin capsule, sterile injectable solution (eg, solution) or non-aqueous or aqueous liquid suspension.

The doses of the pharmaceutical composition may contain at least a therapeutically effective amount of an HCV inhibitor, and preferably consist of one or more pharmaceutical dosage units. The selected dosage may be administered to a mammal (e.g., a human) in need of treatment by inhibiting the activity of HCV by any known or suitable method of administering the medicament, including, for example, topical administration in an ointment or cream , orally, rectally, eg, as a suppository, parenterally by injection, intravenously, or continuously by intravaginal, intranasal, intrabronchial, ear or ocular infusion. When the composition is administered with a cytotoxic drug, the composition can be administered before, simultaneously and/or after the introduction of the cytotoxic drug. However when the composition is administered in conjunction with radiation therapy, it is preferred that the composition is administered prior to initiation of radiation therapy.

Methods for preparing various active compounds in specific amounts are known or will be apparent to those skilled in the art. See, eg, Remington's Pharmaceutical Sciences , Mack Publishing Company, Easter, Pa., 15th Edition (1975).

It will be appreciated that the actual dosage of the HCV inhibitor in the pharmaceutical compositions of this invention will be selected according to the particular composition formulated, the mode and site of administration, and the host and condition to be treated. Optimal dosages for a particular condition can be ascertained by those skilled in the art using routine dosimetry experiments. For oral administration, for example, a useful dosage is from about 0.001 to about 1000 mg/kg body weight, or from about 0.1 to about 100 mg/kg body weight, or from about 1 to about 50 mg/kg body weight, or from about 0.1 to about 1 mg/kg Body weight, the course of treatment is repeated at appropriate intervals. The dosage form of the pharmaceutical preparation described herein may contain a certain amount of (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-(( 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2- For the crystal form of the ketone or its pharmaceutically acceptable salt, the dosage is considered appropriate by those skilled in the art. For example, the dosage form may contain from about 1 mg to about 1500 mg of the compound or a pharmaceutically acceptable salt thereof, from about 20 mg to about 1600 mg, or from about 5 mg to about 1500 mg, or from about 5 mg to about 1250 mg, or about 10 mg to about 1250 mg, or about 25 mg to about 1250 mg, or about 25 mg to about 1000 mg, or about 50 mg to about 1000 mg, or about 50 mg to about 750 mg, or about 75 mg to About 750 mg, or about 100 mg to about 750 mg, or about 125 mg to about 750 mg, or about 150 mg to about 750 mg, or about 150 mg to about 500 mg of the compound or a pharmaceutically acceptable salt or solvent thereof compounds.

(R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1,2, 4] The crystal form of triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxyl-5,6-dihydropyran-2-one or its pharmaceutically acceptable salt can be used as Used as monotherapy, or may contain one or more other antiviral substances, for example selected from the group consisting of, for example, HCV inhibitors such as interferon alphacon-1, natural interferon, interferon beta-la, interferon omega , interferon gamma-1b, polyethylene glycol modified form of INF-α (Pegasys or PEG-INTRON), interleukin-10 (interleukin-10), BILN 2061 (serine protease), amantadine (Symmetrel), thymosin Alpha-1, ribavirin, viramidine; HIV inhibitors such as nelfinavir, delavirdine, indinavir, nevirapine ( nevirapine), saquinavir and tenofovir. The combination therapy described above can be achieved by simultaneous, sequential or separate administration of the individual components used for the treatment.

While embodiments of the invention are set forth with reference to the following specific examples, those skilled in the art will recognize that changes and modifications to the examples can be made through routine experimentation and practice of the invention. Accordingly, the present invention is not limited to the embodiments described below, but is defined by the appended claims and their equivalents.

Unless otherwise stated, in the following examples, all quantities of ingredients, properties (such as molecular weights), reaction conditions, etc. used in the specification and claims should be understood in all instances to be understood by the term "about". Make corrections. Accordingly, unless otherwise indicated, the numerical parameters set forth in the following specification and appended claims are approximations that may vary depending upon the desired properties to be obtained by the present invention. At the very least, and not as an attempt to limit the application of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

Example

In the following examples, all temperatures in the following descriptions are in degrees Celsius (° C.) unless otherwise stated, and all parts and percentages are by weight unless otherwise stated.

Unless otherwise stated, various starting materials and other reagents were provided by commercial suppliers, such as Aldrich Chemical Company or Lancaster Synthesis Ltd., and were used without further purification.

The following reactions were performed at ambient temperature (unless otherwise stated) in anhydrous solvents under positive pressure of nitrogen, argon or using drying tubes. Thin layer chromatography was performed on glass cloth-backed silica gel 60°F 254 plates (Analtech (0.25 mm)) and eluted with appropriate solvent ratios (v/v). Reactions were analyzed by high pressure liquid chromatography (HPLC) or thin layer chromatography (TLC) and terminated as judged by consumption of starting material. TLC plates were visualized by UV, phosphomolybdic acid staining, or iodine staining.

¹ H-NMR spectra were recorded on a Bruker instrument operating at 300 MHz and ¹³ C-NMR spectra were recorded at 75 MHz. NMR spectra (in ppm) of DMSO-d ₆ or CDCl ₃ solutions were obtained using chloroform (7.25 ppm and 77.00 ppm) or DMSO-d ₆ (2.50 ppm and 39.52 ppm) as reference standards. Other NMR solvents can be used if necessary. When reporting the multiplicity of peaks, the following abbreviations are used: s = singlet, d = doublet, t = triplet, m = multiplet, br = broad, dd = double doublet, dt = double triplet. Coupling constants are given in Hertz.

Infrared spectra were recorded on a Perkin-Elmer FT-IR spectrometer as pure oil, KBr pellets or _CDCl3 solutions and are expressed in wavenumbers (cm ^-1 ). Mass spectra were obtained using LC/MS with APCI or ESI ionization methods. All melting points are uncorrected.

In the following examples and preparation methods, "Et" refers to ethyl, "Ac" refers to acetyl, "Me" refers to methyl, "Ph" refers to phenyl, "HCl" refers to hydrochloric acid, "EtOAc" refers to ethyl acetate , "Na ₂ CO ₃ " refers to sodium carbonate, "NaOH" refers to sodium hydroxide, "NaCl" refers to sodium chloride, "Net ₃ " refers to triethylamine, "THF" refers to tetrahydrofuran, "H ₂ O" refers to water, “NaHCO ₃ ” refers to sodium bicarbonate, “K ₂ CO ₃ ” refers to potassium carbonate, “MeOH” refers to methanol, “i-PrOAc” refers to isopropyl acetate, “MgSO ₄ ” refers to magnesium sulfate, and “DMSO” refers to dimethyl sulfoxide, "CH ₂ Cl ₂ " means dichloromethane, "MTBE" means methyl tert-butyl ether, "DMF" means dimethylformamide, "CH ₃ CN" means acetonitrile, "KOH" means hydrogen Potassium oxide, "CDI" refers to carbonyldiimidazole, "DABCO" refers to 1,4-diazabicyclo[2.2.2]octane, "IPE" refers to isopropyl ether, "L-DBTA" refers to dibenzoyl- L-tartaric acid, "IPAC" means isopropyl acetate, "h" means hours, "min" means minutes, "mol" means moles and "rt" means room temperature.

Embodiment 1 : the preparation method of the glycolic acid salt of (5-amino-1H-1,2,4-triazol-3-yl)methanol

                      

Glycolic acid (1 L, 70% in water, 11.51 mol) was added to the 5 L flask. Aminoguanidine bicarbonate (783.33 g, 5.755 mol) was added in portions to control apparent foaming. As solids were added, the solution cooled due to endothermic dissolution. During the addition, the solution was heated gently to maintain an internal temperature of 25°C. Ten minutes after the aminoguanidine bicarbonate addition was complete, concentrated nitric acid (6.8 mL) was carefully added. The solution was heated to an internal temperature of 104-108°C (gentle reflux) for 22 hours. Heating was interrupted and the solution was allowed to cool with stirring. At an internal temperature of about 81°C, the solid began to crystallize. After the internal temperature was just below 80°C, ethanol (neat, 375 mL) was slowly added to the mixture. After the internal temperature had cooled to about 68°C, the cooling was accelerated using an ice/water bath. Upon cooling to below room temperature, the solution became thick but was still stirrable. The slurry was stirred at T<10°C for 2 hours, then filtered and the solid was rinsed with ethanol (cold 900 mL, then room temperature 250 mL). The solid was dried overnight in a vacuum oven (ca. 3-yl)methanol. ¹ H (300 MHz, d ₆ -DMSO): 3.90 (s, 2), 4.24 (s, 2).

Embodiment 2 : the preparation method of (5,7-dimethyl [1,2,4] triazolo [1,5-a] pyrimidin-2-yl) methanol

(5-Amino-1H-1,2,4-triazol-3-yl)methanol glycolate (99.93 g, 0.526 mol), 2,4-pentanedione (0.578 mol, 60 ml), Acetic acid (6.70 mL) and EtOH (550 mL) were charged into a 2 L 3 neck flask. The mixture was heated to slight reflux. One hour after the addition of the above reagents, _the resulting solution was allowed to cool to ambient temperature, and _CH2Cl2 (500 mL) and Celite (25.03 g) were added. After stirring for one hour, the mixture was filtered through a 4" Buchner funnel filled with Celite (20 g) and rinsed with EtOH (100 mL). The solution was distilled to 5 volumes and then cooled to 0 °C for 1 to 2 hours The slurry was filtered and the filter cake was rinsed with cold EtOH (2 x 100 mL).The solid was dried to yield 76.67 g (81.7%) of the title compound.

¹ H NMR (300MHz, d ₆ -DMSO): 2.57(s, 3), 2.71(d, 3, J=0.8), 4.63 (non-uniform d, 2, J=5.7), 5.49(t, 1, J =6.2), 7.13 (d, 1, J=0.8).

Embodiment 3 : the preparation method of 5,7-dimethyl [1,2,4] triazolo [1,5-a] pyrimidine-2-carbaldehyde

CH ₂ Cl ₂ (5.1 L), (5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methanol (680 g, 3.816 mol) and Iodobenzene diacetate (1352 g, 4.197 moles) was sequentially charged to a 10 L reactor. When the iodobenzene diacetate is dissolved, there is a significant endothermic phenomenon (usually down to 15-16°C). Set the thermal jacket to 23°C. The mixture was warmed to ambient temperature and Tempo (2,2,6,6-tetramethyl-1-piperidinyloxy, radical, 43.75 g, 0.28 mol) was added in one portion. The reaction was stirred until 5% starting alcohol remained as determined by HPLC. Once the starting material is less than about 5%, over-oxidized products start to be found. Further completion of the reaction results in a lower overall yield of the desired product. For this reaction, the desired reaction was completed within 2.75 hours. MTBE (5.1 L) was then slowly added to the reactor, which caused the product to precipitate, and the slurry was stirred for an additional 30 minutes. The mixture was filtered, washed twice with 1:1 DCM/BTBE (2 x 1 L), and dried in a vacuum oven at 50 °C overnight to yield 500.3 g (74%) of 5,7- Dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde. ¹ H NMR (300 MHz, d ₆ -DMSO): 2.64 (s, 3), 2.78 (d, 3, J=0.8), 7.36 (d, 1, J=0.9), 10.13 (s, 1).

Embodiment 4 : the preparation method of the dibenzoyl-L-tartrate of 1-cyclopentyl-3-(2,6-diethylpyridin-4-yl) propan-1-one

LiBr (112.42 g, 1.2944 mol), 1-cyclopentyl-prop-2-en-1-ol (89.84 g, 0.7119 mol), DMAc (625 mL) and _H2O (55.0 mL) were sequentially charged with 4-Bromo-2,6-diethylpyridine (250.0 g, 0.6472 mol) was placed in a 5-liter 3-necked flask purged with nitrogen. The mixture was cooled to 5-10 °C and then purged (subsurface) with _N2 for 30 min. The flask was charged with _Et3N (198.5 mL, 1.4242 mol) and Pd(Oac) ₂ (3.63 g, 0.0162 mol), and the headspace was carefully purged. The reaction was heated until the internal temperature reached 95 °C. After stirring at 95°C for 3 hours, an aliquot was removed and analyzed by HPLC, which showed >99% conversion to 1-cyclopentyl-3-(2,6-diethylpyridin-4-yl)propane- 1-keto. The reaction was then cooled to 30°C for 20 minutes. The flask was charged with _H2O (1500 mL) and MTBE (1500 mL). The solution was stirred well for 5 minutes, then the mixture was allowed to settle and the aqueous layer was removed. Celite (62.50 grams) and Darco G-60 (6.25 grams) were added to the organic layer. The slurry was stirred at 20 to 25°C for 20 minutes. The slurry was then filtered using a Buchner funnel fitted with Celite. The filter cake was rinsed with MTBE (250 mL). The organic layer was extracted with 5% sodium bicarbonate solution (500 mL) and the phases were separated. The organic layer was transferred to a 5-liter 3-neck flask, and MTBE was added to obtain a total reaction volume of 1750 mL. Additional MTBE (1500 mL) was added and distilled atmospherically until an internal volume of 1750 mL was reached. After cooling to below 40°C, take out the sample and analyze the water content. After cooling to 20-25 °C, MTBE (250 mL) was added to bring the total volume to 2000 mL, and the 1-cyclopentyl-3-(2,6-diethylpyridine-4- Crystals of the dibenzoyl-L-tartrate salt of propan-1-one (130 mg) were added to seed the solution. A solution of dibenzoyl-L-tartaric acid (231.89 g, 0.6472 mol) in THF (900 mL) was added over 25 minutes. The slurry was granulated for 1 hour, the mixture was filtered and the filter cake was washed with MTBE (450 mL). The solid was dried in a vacuum oven at 50° C. for 12 hours to afford 366.70 g (92% yield) of the title compound. ¹ H NMR (300 MHz, d ₆ -DMSO): 1.19 (t, 6, J=7.6), 1.47 to 1.81 (m, 8), 2.73 (q, 4, J=7.6), 2.73 to 2.98 (m, 5 ), 5.86 (s, 2), 7.00 (s, 2), 7.55 to 7.63 (m, 4), 7.68 to 7.75 (m, 2), 7.98 to 8.04 (m, 4).

Embodiment 5 : the preparation method of 3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid

Dibenzoyl-L-tartrate of 1-cyclopentyl-3-(2,6-diethylpyridin-4-yl)propan-1-one (174.95 g, 0.2832 mol), MTBE (875 ml ), water (875 milliliters) and triethanolamine (113.0 milliliters, 0.8513 moles) were charged into a 3-liter 3-neck flask. After stirring at room temperature for 2 hours, an aliquot of the aqueous phase was removed and analyzed by HPLC, which showed no starting material to be detected. Transfer the solution to a separatory funnel and separate the layers. The lower aqueous phase was discarded and the upper organic phase was washed with water (150 mL). This organic layer was added to the flask for distillation. The solution was distilled down to about 183 mL and an aliquot was removed for analysis for water content. This anhydrous solution of 1-cyclopentyl-3-(2,6-diethylpyridin-4-yl)propan-1-one (theoretical wt=73.47 g) in MTBE was used directly in the next step.

LiHMDS (1.0 M in THF, 355 mL, 0.355 mol) was charged into a clean 2 L 3-neck flask and purged with nitrogen. The flask was cooled to -34°C. EtOAc (35 mL, 0.3583 mol) was then charged to the addition funnel and the reagent was added slowly to the reaction vessel at a rate to maintain the vessel at low temperature. After complete addition of EtOAc, 1-cyclopentyl-3-(2,6-diethylpyridin-4-yl)propan-1-one solution (crude MTBE solution from previous reaction, theoretical yield 73.47 g, 0.2832 mol) into another addition funnel and rinsed with THF (anhydrous, 5 mL). The 1-cyclopentyl-3-(2,6-diethylpyridin-4-yl)propan-1-one solution was slowly added to the reaction flask at a rate such that the internal temperature was maintained. Five minutes after the addition was complete, an aliquot of the reaction was removed and analyzed by HPLC, which showed <1% 1-cyclopentyl-3-(2,6-diethylpyridin-4-yl)propan-1-one . Ten minutes after the ketone addition was complete, the bath temperature was shifted to 0°C. Once the internal temperature had been warmed to -10°C, 1M NaOH (510 mL) was added. After complete addition of the NaOH solution, the reaction was heated to 50 °C. After 21 hours, the reaction solution was cooled to below 30°C, and an aliquot of the bilayer was removed and analyzed for completion of the reaction. This mixture was added to a separatory funnel containing MTBE (350 mL) and the phases were mixed well and separated. Analysis of an aliquot of the organic phase by HPLC showed no significant product, so this layer was discarded. The aqueous phase was added to a flask with _CH2Cl2 ( ₃₅₀ mL). Concentrated aqueous HCl (about 100 mL) was slowly added to the aqueous phase until pH=5. Pour the mixture back into the separatory funnel and mix well. _The phases were separated and the aqueous layer was extracted a second time with _CH2Cl2 (150 mL). The organic layers were combined and placed in a clean flask for distillation. The solution was distilled down to a volume of 370 mL and then replaced by additions of the solvent THF in portions, and distillation was continued to 370 mL after each addition. When the distillation head temperature stabilized at 65°C for 30 minutes, an aliquot was removed and _analyzed ^by1H NMR, which showed a THF: _CH2Cl2 ratio of 12.5:1. The solution of 3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid in THF was used directly in the next step.

Example 6a : (1R,2R)-(-)-2-amino of (R)-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid -1-(4-nitrophenyl)-1,3-propanediol salt preparation method

3-Cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid (crude product obtained from the previous step, theoretical yield 95.28 g, 0.1792 mol, at about 300 mL), (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1,3-propanediol (38.03 g, 0.1792 mol) and THF (415 mL) were charged sequentially 2 liters in a 3-neck flask. (1R,2R)-(-)-(1R,2R)-(-)- 2-Amino-1-(4-nitrophenyl)-1,3-propanedioxide was seeded and the mixture was stirred, heated to 65° C. and maintained at this temperature for 16 hours. The slurry was cooled slowly to room temperature and stirred for at least 1 hour. The slurry was filtered and the filter cake was rinsed with THF (100 mL). This filtrate ((S)-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid in THF) was used directly in the next process. The solid was dried to afford 67.09 g (42%) of (R)-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid as an off-white crystalline solid (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1,3-propanediol salt. The chiral HPLC analysis of this product showed that the (1R, 2R)-( -)-2-Amino-1-(4-nitrophenyl)-1,3-propanediolate p-(S)-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl The ratio of (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1,3-propanediol salt of )-3-hydroxyvaleric acid was 92.1:7.9.

HPLC conditions: solid dissolved in methanol. HPLC conditions: Chirobiotic TAG column, 4.6×250 mm, column chamber at 40° C., flow rate=0.5 ml/min, mobile phase=100% MeOH (0.05% TEA, 0.05% HOAc). Gradient: initial flow rate = 0.5 ml/min; 10 min flow rate = 0.5 ml/min; 10.10 min flow rate = 2.00 ml/min; 35 min flow rate = 2.00 ml/min; 36 min flow rate = 0.5 ml/min . Percentages are reported at 265 nm. Retention time: (1R, 2R)-(-)-2-amino-1-(4-nitrophenyl)-1,3-propanediol => 30 minutes; (S)-3-cyclopentyl-5- (2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid=5.8 minutes; (R)-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl) -3-Hydroxyvaleric acid = 7.2 minutes. ¹ H NMR (300 MHz, d ₆ -DMSO): 1.19 (t, 6, J=7.6), 1.38 to 1.62 (m, 8), 1.65 to 1.75 (m, 2), 1.93 to 2.07 (m, 1), 2.23 (d, 1, J = 14.4), 2.31 (d, 1, J = 14.4), 2.56 (m, 2), 2.64 (q, 4, J = 7.6), 2.91 to 2.99 (m, 1), 3.22 (dd, 1, J = 5.8, 11.1), 3.42 (dd, 1, J = 4.8, 11.1), 4.77 (d, 1, J = 6.2), 6.0 (brs, 6), 6.84 (s, 2), 7.62 (d, 2, J=8.7), 8.20 (d, 2, J=8.8).

Example 6b : (1R,2R)-(-)-2-amino of (R)-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid -Recrystallization of 1-(4-nitrophenyl)-1,3-propanediol salt

The (1R, 2R)-(-)-2-amino-1- (4-nitrophenyl)-1,3-propanediol salt (66.20 g, 0.1245 mol) and 2B EtOH (970 ml pure EtOH+5 ml toluene) were charged into a 2-liter 3-neck flask. The slurry was stirred and heated to reflux. After 40 minutes at reflux, all solids had dissolved and the solution was cooled to an internal temperature of about 65°C for 30 minutes. The solution was then seeded with crystals of the title compound. The solution was cooled to 50 °C for an additional 2 hours. The solution was then allowed to cool slowly to room temperature ca. over 2 hours. The cold solution was stirred for an additional 10 hours at room temperature. The mixture was then filtered and the solids were rinsed with 2B EtOH (75 mL). The solid was dried to give 52.72 g (80%) of product as an off-white crystalline solid, which was then dried at 50° C. under vacuum (30 mm Hg) for 12 hours under nitrogen flow. Chiral HPLC analysis indicated that the product had an ee of 96%. For determination of e.e, the solid was dissolved in MeOH. HPLC conditions: Chirobiotic TAG column, 4.6×250 mm, 40° C. column chamber, flow rate=0.5 ml/min, 100% MeOH (0.05% TEA, 0.05% HOAc). Gradient: initial flow rate = 0.5 ml/min; 10 min flow rate = 0.5 ml/min; 10.10 min flow rate = 2.00 ml/min; 35 min flow rate = 2.00 ml/min; 36 min flow rate = 0.5 ml/min . Percentages are reported at 265 nm. Retention time: (1R, 2R)-(-)-2-amino-1-(4-nitrophenyl)-1,3-propanediol => 30 minutes, (S)-3-cyclopentyl-5- (2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid=5.8 minutes, (R)-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl) -3-Hydroxyvaleric acid = 7.2 minutes.

Embodiment 7 : Prepare 1-cyclopentyl-3-(2,6- -Diethylpyridin-4-yl)propan-1-one method

(S)-3-Cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid (crude product from last step, theoretical yield 15 g, 0.0470 mol , in about 200 mL THF) and ethanol (100 mL, 1.7126 mol) were charged into the flask. _{H2SO4 (} 5.0 mL, 0.0938 mol) was slowly added to the solution. The solution was heated at reflux for 18 hours. When the reaction was judged complete by HPLC, the solution was cooled and added to a separatory funnel with 0.5M NaOH (400 mL), then extracted with MTBE (200 mL). The phases were separated and the organic layer was washed with aqueous acetic acid _H2O (100 mL _H2O + 3.0 mL HOAc). The phases were separated and the organic layer was washed with 0.5M NaOH (100 mL). The layers were separated, and the organic layer was washed with saturated aqueous NaCl (25 mL). The organic layer was distilled under normal pressure to reduce its internal volume to 150 ml. The solvent was replaced by toluene by atmospheric distillation by adding toluene (100 mL), distilling to 200 mL internal volume, and repeating the process two more times. The final solution was distilled to an internal volume of 130 mL. An aliquot was removed and analyzed by KF titration. The solution was allowed to cool to room temperature and a solution of KotBu (1.0 M in THF, 4.7 mL, 0.0047 mol) was added in one portion. After 5 minutes, an aliquot was removed and analyzed by HPLC. This solution was added to a separatory funnel with 1M HCl (60 mL). The phases were mixed well and separated, which process transferred the product to the aqueous phase. The organic phase was extracted once with water (10 mL), and the aqueous phases were combined. Discard the organic phase. MTBE (60 mL) and 1M NaOH (70 mL) were added to the aqueous phase and the phases were mixed well. The phases were separated and the organic phase was extracted with saturated aqueous NaCl (25 mL). MTBE was added to bring the volume up to 125 ml. The solution was allowed to cool to room temperature, and crystals of the dibenzoyl-L-tartrate salt of 1-cyclopentyl-3-(2,6-diethylpyridin-4-yl)propan-1-one (according to the practice Example 4) to seed the solution. In a separate vessel, L-DBTA (16.89 g, 0.0471 mol) was dissolved in THF (65 mL). The L-DBTA solution was added to the 1-cyclopentyl-3-(2,6-diethylpyridin-4-yl)propan-1-one solution over 45 minutes, and the slurry was granulated for one hour. The slurry was filtered and the filter cake was washed with MTBE (50 mL). The solid was dried to afford 19.54 g of the dibenzoyl-L-tartrate salt of 1-cyclopentyl-3-(2,6-diethylpyridin-4-yl)propan-1-one ( 67%).

Embodiment 8a : (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-4-hydroxyl-5,6-dihydropyran- The preparation method of the dibenzoyl-L-tartrate of 2-keto

CH ₂ Cl ₂ (200 mL) and H ₂ O (100 mL) were charged with (R)-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxy (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1,3-propanedioxide salt of valeric acid (20.00 g, 0.0376 mol), nitrogen purged flask Inside. The pH of the mixture was adjusted to pH 4.75 using 40% aqueous citric acid (10 mL) and stirred for 60 minutes. The layers were allowed to settle for 30 minutes and separated. _CH2Cl2 (50 mL) was charged to the upper (aqueous) layer, stirred for 15 min, then allowed to _settle . This organic layer was combined with the first organic layer and dried over sodium sulfate. The dried organic layer was concentrated under reduced pressure. (R)-3-Cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid residue was dissolved in THF (47 mL) and dissolved in This solution was added to a slurry of carbonyldiimidazole (9.00 g, 0.0555 mol) and 4-N,N-dimethylaminopyridine (DMAP, 0.45 g, 0.0037 mol) in THF (106 mL). Once acyl-imidazole formation was complete, this solution was added to a slurry of potassium ethyl malonate (12.57 g, 0.0738 mol) and magnesium chloride (7.38 g, 0.0775 mol) in 106 mL THF over 5 minutes. The slurry was stirred at 20 to 25°C for 30 hours. An aliquot was removed and analyzed by HPLC, which showed 96% conversion to 5-cyclopentyl-7-(2,6-diethylpyridin-4-yl)-5-hydroxy-3-oxoheptanoic acid (R)-Ethyl ester. A flask was charged with _H2O (64 mL) and MTBE (118 mL). The mixture was stirred well for 5 minutes, then allowed to settle and the aqueous (lower) layer removed. Brine (52 mL) was added to the organic layer. The mixture was stirred well for 5 minutes, then allowed to settle and the aqueous (lower) layer removed. The organic layer was then replaced by methanol (2 x 210 mL) by atmospheric distillation until the total volume reached 140 mL. MTBE (105 mL) was added followed by powdered potassium carbonate (7.65 g, 0.0554 mol) and the slurry was heated to reflux for 12 hours. After cooling to 40°C, MTBE (140 mL) and water (140 mL) were added. The mixture was stirred well for 5 minutes, then allowed to settle, and the aqueous (lower) layer was separated. The organic layer was extracted with water (30 mL), and the aqueous layers were combined. _CH2Cl2 (140 mL) was added to the aqueous layer and the pH was adjusted to 6.4 using 40% aqueous citric acid (29 _mL ). The aqueous layer was extracted a second time with _{CH2Cl2 (} 25 mL). The combined organic layers were then completely replaced by MTBE (140 mL final volume) by atmospheric distillation, allowed to cool, and slowly added to dibenzoyl-D-tartaric acid (9.92 g, 0.0277 mol) in MTBE (100 mL) in the solution. The slurry was heated to reflux for one hour, then allowed to cool to 20-25°C. The mixture was filtered and the filter cake was rinsed with MTBE (50 mL). The solid was dried in a vacuum oven at 50°C for 12 hours to afford 16.40 g (62%) of the title compound.

Embodiment 8b : (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-4-hydroxyl-5,6-dihydropyran- The preparation method of the dibenzoyl-L-tartrate of 2-keto

CH ₂ Cl ₂ (500 mL) and H ₂ O (250 mL) were charged with (R)-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxy (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1,3-propanediol salt of valeric acid (50.00 g, 0.0940 mol), in a flask purged with nitrogen . The pH of the resulting suspension was adjusted to pH 4.6-4.8 (preferred pH 4.75 was determined) using 40% aqueous citric acid (21 mL) and stirred for 30 minutes. The layers were allowed to settle for 30 minutes and separated. _CH2Cl2 (100 _mL ) was added to the upper (aqueous) layer, stirred for 15 minutes and allowed to settle. This organic layer was combined with the first organic layer. Additional _CH2Cl2 (100 mL) was added to the upper (aqueous) layer, stirred for 15 minutes, _and allowed to settle. This organic layer was recombined with the first organic layer. A sample of each combined organic and aqueous layer was taken for HPLC analysis. The combined organic layers were atmospherically distilled until the total volume reached 120 mL. THF (100 mL) was added and atmospheric distillation continued until a total volume of 120 mL was reached. The addition and replacement of THF was repeated 3 times. Samples were removed and analyzed by NMR and KF. The resulting solution was added to a slurry of CDI (22.86 g, 0.1410 mol) and DMAP (1.15 g, 0.0094 mol) in THF (250 mL) over 15 minutes. The addition funnel was then rinsed with 10 mL of THF before adding it to the CDI slurry. After stirring for 15 minutes, a sample was removed and analyzed by HPLC. Once the formation of the acyl-imidazole was complete, the solution was added to potassium ethyl malonate (32.00 g, 0.1880 mol) and magnesium chloride (18.80 g, 0.1974 mol) in 250 mL of THF at 20 to 25 °C over 25 minutes. in the slurry. The slurry was stirred at 20 to 25°C for 21 hours. An aliquot was removed and analyzed by HPLC, showing 96% conversion to 5-cyclopentyl-7-(2,6-diethylpyridin-4-yl)-5-hydroxy-3-oxyheptanoic acid (R)-Ethyl ester. A flask was charged with _H2O (162 mL) and MTBE (300 mL). The mixture was stirred well for 5 minutes, then allowed to settle and the yellow aqueous (lower) layer removed. Brine (100 mL) was charged to the organic layer. The mixture was stirred well for 5 minutes, then allowed to settle and the aqueous (lower) layer removed. The organic layer was then atmospherically distilled down to a total volume of 350 mL. MTBE (250 mL) was added and the solution was distilled to a total volume of 350 mL. Additional MTBE (250 mL) was added and the solution was distilled to a total volume of 350 mL at a temperature of at least 55°C. Samples were removed for KF titration. Methanol (250 mL) was added and the solution was atmospherically distilled until a total volume of 350 mL was reached. Methanol (250 mL) was added and the solution was atmospherically distilled until the total volume reached 350 mL and the temperature reached ~66°C. Powdered potassium carbonate (19.49 g, 0.1410 mol) was added and the slurry was heated to reflux for 4 hours. A sample was removed for HPLC analysis which indicated >99% completion. After cooling to 22°C, MTBE (350 mL) and water (350 mL) were added. The mixture was stirred well for 5 minutes, then allowed to settle and the product-enriched aqueous (lower) layer was isolated. The organic layer was extracted with water (100 mL), and the aqueous layers were combined. MTBE (100 mL) was added to the combined aqueous layers. The mixture was stirred well for 5 minutes, then allowed to settle and the product-enriched aqueous (lower) layer was isolated. _CH2Cl2 (350 mL) was added to the aqueous layer and the pH was adjusted to 6.0-6.4 using ₄₀ % aqueous citric acid (75 mL). The aqueous layer _was extracted a second time with _CH2Cl2 (100 mL). The combined organic layers were then atmospherically distilled to a total volume of 250 mL. MTBE (400 mL) was added and the solution was atmospherically distilled at a temperature of at least 55°C until a final volume of 250 mL was reached. After allowing the solution to cool to 20-25°C, the resulting solution of dibenzoyl-D-tartaric acid (23.58 g, 0.0658 mol) in MTBE (125 mL) was added over 10 minutes. The resulting slurry was heated to reflux for 4 hours, then allowed to cool to 20 to 25°C, and stirred for an additional 4 hours. The slurry was filtered and the filter cake was rinsed with MTBE (125 mL). The solid was dried in a vacuum oven at 50°C for 12 hours to afford 38.19 g (58%) of the title compound. HPLC conditions: An aliquot was taken and dissolved in _CH3CN / _H2O (40:60). HPLC conditions: Kromasil C4 column, 5 microns, 4.6 x 150 mm, 40 °C column chamber, flow rate = 1.0 ml/min, 40% CH ₃ CN/60% aqueous solution ( _1.0 ml, 70% HClO in 1 liter H ₂ O) isocratic eluent. Percentages are reported at 254 nm. Approximate residence time: (R)-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid = 3.4 minutes; 5-cyclopentyl-7-(2 , 6-diethylpyridin-4-yl)-5-hydroxyl-3-oxoheptanoic acid (R)-ethyl ester=7.3 minutes; (R)-6-cyclopentyl-6-(2-(2 , 6-diethylpyridin-4-yl)ethyl)-4-hydroxy-5,6-dihydropyran-2-one = 3.9 minutes; D-DBTA = 5.5 minutes.

Embodiment 9a : (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[ The preparation method of 1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxyl-5,6-dihydropyran-2-one

(R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-4-hydroxy-5,6-dihydropyran-2-one Dibenzoyl-L-tartrate (this material contained 1.5 equivalents of DBTA counterion, 4.00 g, theoretical yield 0.00454 moles), 2-MeTHF (40 mL), MTBE (40 mL) and water (20 mL) were charged inside the flask. Aqueous 5% NaHCO ₃ (about 20 mL) was added until pH 7.4. The solution was adjusted back to pH = 7.2 using a small amount of 40% citric acid solution. The phases were separated and the aqueous layer was extracted with 2-MeTHF (25 mL). The combined organic layers were dried over _Na2SO4 and concentrated to _an oil. This oil can be used directly in the subsequent condensation step. Methanol (32 mL) was added to the crude (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-4-hydroxy-5, 6-dihydropyran-2-one, and the solution was cooled to -40°C. Add pyridine-borane complex (1.30 mL, 0.01287 mol) and 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (1.41 g, 0.00800 mol) into the cold solution. The solution was warmed to 0°C over 45 minutes, then stirred for an additional 2 hours. The reaction was quenched by adding water (10 mL), and the mixture was stirred at room temperature overnight. 1M HCl (10 mL) was added to the mixture, and the solution was stirred for 3 hours. Isopropyl acetate (57 mL) was added and the pH was adjusted to 7 by addition of 1M NaOH. The phases were separated and the organic layer was extracted with water (25 mL x 2). The aqueous phase was extracted with _CH2Cl2 (100 mL, 2 _x 25 mL). The combined IPAc and _CH2Cl2 layers were dried over _Na2SO4 , filtered, and concentrated to give 3.41 g of crude (R)-6 _- cyclopentyl-6-(2- ₍ 2,6-diethyl Basepyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)- 4-Hydroxy-5,6-dihydropyran-2-one. Isopropyl acetate (46 mL) and EtOH (2.5 mL) were added to the residue, and the mixture was heated to reflux until a homogeneous phase formed. The solution was allowed to cool slowly to room temperature and stirred overnight. The slurry was filtered, the solid was rinsed with IPAc (13 mL), and dried to give 1.74 g (76%) of (R)-6-cyclopentyl-6-(2-(2,6- Diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl )-4-hydroxy-5,6-dihydropyran-2-one.

Embodiment 9b : (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[ The preparation method of 1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxyl-5,6-dihydropyran-2-one

The (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-4-hydroxy-5,6-dihydropyran-2- Dibenzoyl-L-tartrate of ketone (15.00 g, 0.02137 mol), THF (75 mL), MeOH (75 mL), pyridine-borane (4.25 mL, 0.034 mol) and 5,7-dimethyl -[1,2,4]Triazolo[1,5-a]pyrimidine-2-carbaldehyde (5.65 g, 0.03207 mol) (last addition) was charged to a 500 mL flask. The resulting mixture was stirred at room temperature and an aliquot was removed after 1.25 hours and analyzed by HPLC, which showed that (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridine -4-yl)ethyl)-4-hydroxy-5,6-dihydropyran-2-one 13.5%. Stirring was continued for an additional 2 hours and HPLC analysis of an aliquot showed 4.8% of (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl) remaining ethyl)-4-hydroxy-5,6-dihydropyran-2-one. _CH2Cl2 (150 mL) and water (150 mL) were charged to the reaction solution, and _the phases were stirred overnight. The lower organic layer was removed and _CH2Cl2 (25 mL) was added to the upper aqueous layer, the _phases were mixed well and separated, and the aqueous layer was discarded. The organic layers were combined and charged to a flask containing water (150 mL) and triethanolamine (7.1 mL, 0.0535 mol), mixed well, and then separated. The lower organic layer was removed and _CH2Cl2 (25 mL) was added to the upper aqueous layer, the _phases were mixed well, separated, and the aqueous layer was discarded. Water (100 mL) and 1M NaOH (25 mL) were added to the combined organic layers, the phases were mixed well, separated, and the lower organic layer was discarded. _CH2Cl2 (75 mL) was added to the upper aqueous layer, and 1 N HCl was added until pH = 6.91 (-25 mL added), _the phases were mixed well, separated, and the aqueous layer was discarded. The combined organic layers were extracted with water (3.2 vol). The layers were separated and the organic layer was transferred to a clean flask with a volume mark of 75 mL. The organic layer was atmospherically distilled to 75 mL. Isopropyl acetate (75 mL x 2) was added to the flask, which was then distilled to a total volume of 75 mL after each addition. The flask was seeded and cooled to room temperature, then stirred overnight. The reaction was filtered and the filter cake was washed with isopropyl acetate (25 mL). The solid was dried to yield 7.20 g (67%) of (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3- ((5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran- 2-Kone, which was dried in a vacuum oven (~25 inches Hg at 50°C) for 12 hours. For HPLC monitoring, an aliquot was taken and dissolved in _CH3CN / _H2O (40:60). HPLC conditions: Kromasil C4 column, 5 microns, 4.6 x 150 mm, 40 °C column chamber, flow rate = 1.0 ml/min, 40% CH ₃ CN/60% aqueous solution ( _1.0 ml, 70% HClO in 1 liter H ₂ O) isocratic eluent. Percentages are reported at 254 nm. Retention time: (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-4-hydroxy-5,6-dihydropyran-2 -ketone=3.85 minutes; (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl -[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxyl-5,6-dihydropyran-2-one=3.56 minutes; DBTA= 5.14 minutes; BH ₃ ·pyr = 3.36 minutes.

Embodiment 10 : (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl) ethyl)-3-((5,7-dimethyl-[ Recrystallization of 1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one

(R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1,2 , 4] Triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxyl-5,6-dihydropyran-2-one (10.05 g, 0.01995 mol)/THF (70 ml) into a 200 ml flask. The mixture was stirred and heated to 30-35°C to obtain a homogeneous solution. The solution was filtered through a 0.45 micron Teflon filter and rinsed with THF (10 mL). The filtrate was added to a flask for atmospheric distillation, and isopropyl acetate (IPAC, 50 mL) was added. The solution was concentrated by distillation to an internal volume of 100 mL. Isopropyl acetate (50 mL) was added and distillation continued at atmospheric pressure until an internal volume of 100 mL was reached. Using (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1,2 , 4] Triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxyl-5,6-dihydropyran-2-one seeded the solution and added IPAC (30 ml). The solution was distilled again to an internal volume of 100 mL and allowed to cool to 50° C. over about 1 hour. The solution was kept at 50°C for 1.5 hours, allowed to cool to room temperature over about 2 hours, and stirred overnight. The resulting slurry was filtered and rinsed with IPAC (30 mL). The resulting solid was dried to afford 9.41 g (94%) of the title compound as an off-white powder, which was dried in vacuo (50°C, ~25 inHg) for 12 hours.

Embodiment 11 : p-(R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl- Characterization of [1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one crystals

(R)-6-cyclopentyl-6-(2-(2, 6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl) The solid form of methyl)-4-hydroxy-5,6-dihydropyran-2-one was characterized. The material was found to be crystalline and contained no water of crystallization. The results of the various analyzes are provided below.

A. X-ray powder diffraction

)。以2.4°2θ/分钟(1秒/0.04°2θ步长)由3.0至40°2θ进行θ双θ连续扫描。在室温(其通常被认为约24℃至28℃)下进行分析。分析氧化铝标准物(NIST标准参考物质1976)以校准仪器。制备试样并将试样放在石英架内以进行分析。使用Bruker AXS Diffrac Plus软件2.0版本收集数据并进行分析。特征峰及其相对强度示于下表1中。代表性的粉末X射线衍射图表示在图1中。X-ray powder diffraction patterns were generated using a Siemens D5000 diffractometer utilizing copper radiation. The instrument is equipped with a linear focused X-ray tube. The tube voltage and amperage were set to 38kV and 38mA, respectively. The divergence slit and the scattering slit were set to 1 mm, and the reception slit was set to 0.6 mm. The diffracted Cu K _α1 radiation (λ=1.54056) was detected using a Sol-X energy dispersive X-ray detector

). Theta dual-theta continuous scan from 3.0 to 40°2θ at 2.4°2θ/min (1 second/0.04°2θ step). The analysis was performed at room temperature (which is generally considered to be about 24°C to 28°C). Alumina standards (NIST Standard Reference Material 1976) were analyzed to calibrate the instrument. Samples were prepared and placed in quartz holders for analysis. Data were collected and analyzed using Bruker AXS Diffrac Plus software version 2.0. The characteristic peaks and their relative intensities are shown in Table 1 below. A representative powder X-ray diffraction pattern is shown in FIG. 1 .

Table 1. 2θ peaks and intensity values obtained from powder X-ray diffraction patterns

B. Deproton-Coupling ¹³ C CPMAS

About 80 mg of the sample is tightly pressed into a 4 mm ZrO rotator. Spectra were collected on a Bruker-Biospin 4 mm BL triple resonance CPMAS probe inside a wide bore Bruker-Biospin Avance DSX 500 MHz NMR spectrometer at ambient temperature and pressure. The sample was positioned at a magic angle and rotated at 15.0 kHz. Adjust the number of scans to obtain a suitable S/N.

¹³ C solid-state spectra were collected using a deproton-coupled cross-polarization magic-angle spinning experiment (CPMAS). Apply a proton decoupling field at about 85 kHz. A cross-polarization contact time of 2 ms was used. 1024 scans were collected. Adjust the relaxation recovery time (recycle delay) to 20 seconds. The Ldamantine crystal external standard was used as a reference for the spectrum, and its high-field resonance was set at 29.5ppm. The characteristic peaks and their relative intensities are shown in Table 2 below. From this structure, 29 peaks are expected in the carbon spectrum. At least 44 peaks and shoulders of fairly uniform intensity can be found in ^this13C CPMAS experiment, indicating the presence of two molecules per asymmetric unit. A representative ssNMR spectrum is shown in Figure 2.

¹³ C chemical shift ±0.2 ^a [ppm] strength ^b 168.6 5.8 168.1 7.3 166.6 3.0 165.6 3.0 164.4 3.1 163.8 3.1 162.3 3.0 161.3 2.6 154.6 2.8 153.0 3.1 151.2 3.0 146.4 2.8 146.0 2.9 121.6 2.1 120.4 2.5 119.7 2.4 118.8 2.0

110.2 3.5 100.7 3.8 100.3 3.8 80.4 4.2 79.2 4.2 50.6 2.2 48.6 0.4 46.3 2.4 44.7 1.9 41.1 2.1 37.6 1.6 33.5 2.2 ^32.4c 4.9 ^32.1c 6.5 32.0 7.1 30.9 4.9 28.6 3.0 28.0 2.4 26.4 6.0 25.1 8.2 24.5 3.4 23.8 2.1 23.3 1.9 16.2 4.4 15.3 4.9 14.7 12.0 12.8 4.4

(a) Reference to solid phase Ldamantine external sample at 29.5 ppm.

(b) is defined as peak height. The intensity may vary according to the actual set of CPMAS experimental parameters and the properties of the specimen, including the cross polarization and relaxation rate. CPMAS strength does not have to be quantified.

(c) Peak shoulder.

C. Differential Scanning Calorimetry

The experiment was performed using a DSC Q1000 instrument (TA Instruments, New castle, DE). Nitrogen was used as the purge gas at a flow rate of 50 ml/min in the DSC chamber and 110 ml/min in the refrigerated cooling system. The calorimeter was calibrated for temperature and cell constant using indium (melting point 156.61°C, enthalpy of fusion 28.71 Joules/gram). A sealed aluminum pan with a pinhole was used and the sample (3 to 5 mg) was heated at a rate of 10°C/min. Data analysis was performed using TA Instruments' Universal Analysis 2000 software (Windows Version 4.2E). The sample had a melting point in the range of about 162°C to about 165°C. Thermogravimetric analysis indicated that melting and decomposition of the sample occurred simultaneously. Representative DSC traces are shown in Figure 3.

Claims (15)

1. A method for preparing a compound of formula (Ia):

in: R ¹ is C ₁ to C ₆ alkyl or C ₃ to C ₆ cycloalkyl; R ^2a , R ^2b and R ^2c are each independently selected from hydrogen, halogen, C ₁ to C ₆ alkyl, C ₃ to C ₆ cycloalkyl, -OR ^12a , -CF ₃ , -CN and -NR ^12a R ^12b ; R ⁴ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ; R ⁵ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ; R ⁶ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ; R ⁷ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ; Each R ⁹ and R ¹⁰ are independently selected from hydrogen and C ₁ to C ₆ alkyl, or R ⁹ and R ¹⁰ form C ₃ to C ₆ cycloalkyl together with the carbon atoms to which they are attached; each R ¹¹ is independently selected from hydrogen, C ₁ to C ₆ alkyl, halogen, -OR ^12a , -CN, -CF ₃ and -NR ⁹ R ¹⁰ ; each R ^12a and R ^12b is independently selected from hydrogen, C ₁ to C ₆ alkyl; and Each n is independently selected and is an integer from 0 to 5; The methods include: a) Treat the compound of formula (V) with the anion of the compound of formula (X) to obtain the compound of formula (IV), wherein R in the compound of formula (X) ¹³ is hydrogen, C ₁ to C ₆ alkyl, -Si(C ₁ to C ₆ alkyl) ₃ or -CH ₂ (C ₆ to C ₁₀ aryl), wherein the C ₆ to C ₁₀ aryl is optionally replaced by at least one selected from halogen, C ₁ to C ₆ alkyl, - OH, -OCH ₃ and -N(C ₁ to C ₆ alkyl) ₂ substituents are substituted, and R ¹ in the compound of formula (V) is as defined above;

b) hydrolyzing said compound of formula (IV) to obtain a compound of formula (IV) wherein ^R is hydrogen; c) treating said compound of formula (IV) with a combination of reagents to obtain a compound of formula (III), wherein P ¹ is hydrogen or a suitable protecting group, and R ¹⁴ is C ₁ to C ₆ alkyl or —CH ₂ (C ₆ to C ₁₀ aryl), wherein the C ₆ to C ₁₀ aryl can be optionally replaced by at least one selected from halogen, C ₁ to C ₆ alkyl, -OH, -OCH ₃ and -N(C ₁ to C ₆ alkyl) substituent substitution of ₂ ; d) treating said compound of formula (III) with an acid or base to obtain a compound of formula (II); and e) Treatment of said compound of formula (II) with a compound of formula (IXa) to give a compound of formula (Ia). 2. The method of claim 1, wherein in the compound of formula (Ia), R ¹ is C ₃ to C ₆ cycloalkyl. 3. The method of claim 2, wherein in the compound of formula (Ia), ^R is cyclopentyl 4. The method of claim 3, wherein in the compound of formula (Ia): R ^2a is C ₁ to C ₆ alkyl; R ^2b is hydrogen; R ^2c is C ₁ to C ₆ alkyl; R ⁴ is hydrogen; R ⁵ is C ₁ to C ₆ alkyl; ^R6 is hydrogen; and R ⁷ is C ₁ to C ₆ alkyl. 5. The method of claim 4, wherein in the compound of formula (Ia), R ^2a and R ^2c are -CH ₃ , and R ^2b is hydrogen. 6. The method of claim 5, wherein the compound of formula (Ia) is: 7. A method for preparing a stereoisomerically enriched compound of formula (IV),

in: R ¹ is C ₁ to C ₆ alkyl or C ₃ to C ₆ cycloalkyl; R ⁴ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ; R ⁵ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ; R ⁶ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ; R ⁷ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ; Each R ⁹ and R ¹⁰ are independently selected from hydrogen and C ₁ to C ₆ alkyl, or R ⁹ and R ¹⁰ form C ₃ to C ₆ cycloalkyl together with the carbon atoms to which they are attached; each R ¹¹ is independently selected from hydrogen, C ₁ to C ₆ alkyl, halogen, -OR ^12a , -CN, -CF ₃ and -NR ⁹ R ¹⁰ ; each of R ^12a and R ^12b is independently selected from hydrogen and C ₁ to C ₆ alkyl; ^P is hydrogen or a suitable protecting group; and Each n is independently selected and is an integer from 0 to 5; The methods include: a) treating a compound of formula (IV) with a chiral nonracemic base to obtain a mixture of diastereomeric salts; b) separating said diastereoisomeric salts from each other; c) converting said diastereoisomeric salt into a stereoisomerically enriched compound of formula (IV). 8. The method of claim 7, wherein the chiral nonracemic base is a chiral nonracemic amine. 9. The method of claim 8, wherein the chiral non-racemic amine is selected from the group consisting of cis-1-amino-indanol, cinchonidine, 1-aminoindan, tert-leucinol , 2-amino-1,2-diphenylethanol, α-methylbenzylamine and 2-amino-1-(4-nitrophenyl)-1,3-propanediol. 10. The method of claim 9, wherein the chiral non-racemic amine is selected from (1R,2S)-(+)-cis-1-amino-2-indanol, (-)- Cinchonidine, (R)-1-aminoindan, (S)-tert-leucinol, (1R,2S)-2-amino-1,2-diphenylethanol, (S)-α- Methylbenzylamine and (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1,3-propanediol. 11. The method of claim 10, wherein the chiral nonracemic amine is (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1,3 - Propylene glycol. 12. A compound of formula (IV),

in: R ⁴ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ; R ⁵ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ; R ⁶ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ; R ⁷ is selected from hydrogen, C ₁ to C ₆ alkyl, -(CR ⁹ R ¹⁰ ) _n R ¹¹ , -CF ₃ , halogen, -OR ^12a , -CN and -NR ^12a R ^12b ; Each R ⁹ and R ¹⁰ are independently selected from hydrogen and C ₁ to C ₆ alkyl, or R ⁹ and R ¹⁰ form C ₃ to C ₆ cycloalkyl together with the carbon atoms to which they are attached; each R ¹¹ is independently selected from hydrogen, C ₁ to C ₆ alkyl, halogen, -OR ^12a , -CN, -CF ₃ and -NR ⁹ R ¹⁰ ; each of R ^12a and R ^12b is independently selected from hydrogen and C ₁ to C ₆ alkyl; R ¹³ is hydrogen, C ₁ to C ₆ alkyl, -Si(C ₁ to C ₆ alkyl) ₃ or -CH ₂ (C ₆ to C ₁₀ aryl), wherein the C ₆ to C ₁₀ aryl can be is optionally substituted by at least one substituent selected from halogen, C ₁ to C ₆ alkyl, -OH, -OCH ₃ and -N(C ₁ to C ₆ alkyl) ₂ ; ^P is hydrogen or a suitable protecting group; and Each n is independently selected and is an integer from 0 to 5. 13. The compound of claim 12, wherein: R ⁴ is hydrogen; R ⁵ is C ₁ to C ₆ alkyl; ^R6 is hydrogen; R ⁷ is C ₁ to C ₆ alkyl; and R ¹³ is hydrogen or C ₁ to C ₆ alkyl. 14. The compound of claim 13, wherein ^R5 and ^R7 are _{-CH2CH3 .} 15. A (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[ Crystalline form of 1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one.

Images