KR20240044452A - Novel spiropyrrolidine-derived antiviral agent - Google Patents

Abstract

The present invention discloses compounds of formula ( I ) below, and pharmaceutically acceptable salts thereof, which inhibit coronavirus replication activity. Additionally, the present invention provides a pharmaceutical composition comprising a compound of formula ( I ) below or a pharmaceutically acceptable salt thereof, and a method for treating or preventing a coronavirus infection in a subject in need of such treatment or prevention. It relates to a method comprising administering to a subject a therapeutically effective amount of a compound of formula ( I ) below or a pharmaceutically acceptable salt thereof.

Description

Novel spiropyrrolidine-derived antiviral agent

Related applications

This application is a continuation-in-part of U.S. Application No. 17/479,248, filed on September 20, 2021, which claims the benefit of U.S. Provisional Patent Application No. 63/227,206, filed on July 29, 2021. In addition, this application also claims priority to U.S. Provisional Patent Application No. 63/324,367, filed on March 28, 2022. The entire teachings of the above applications are incorporated herein by reference.

Technology field

The present invention relates to compounds and methods for inhibiting coronavirus replication activity by contacting a 3C-like protease (sometimes referred to as "3CLpro", "major protease", or "Mpro") with a therapeutically effective amount of a 3C-like protease inhibitor. . Additionally, the present invention relates to pharmaceutical compositions containing coronavirus 3C-like protease inhibitors in mammals by administering an effective amount of such coronavirus 3C-like protease inhibitors.

Coronaviruses are a class of single-stranded, positive-strand RNA viruses with a viral envelope, classified in the order Nidovirus. The coronavirus class includes pathogens of humans and many animal species, including horses, cattle, pigs, birds, cats and monkeys, and has been known for more than 60 years. For example, the isolation of the prototype murine coronavirus strain JHM was reported in 1949. Coronaviruses are common viruses that usually cause mild to moderate upper respiratory tract disease in humans, and are named for the crown-like spikes on the surface of their envelope. There are four major subgroups known as alpha, beta, gamma and delta coronaviruses, and the first coronaviruses were identified in the mid-1960s. Coronaviruses known to infect humans include alphacoronaviruses 229E and NL63; and beta coronaviruses OC43, HKU1, SARS-CoV (the coronavirus that causes severe acute respiratory syndrome, or SARS), and MERS-CoV (the coronavirus that causes Middle East respiratory syndrome, or MERS). People are commonly infected by human coronaviruses 229E, NL63, 0C43 and HKU1, whose symptoms generally include short-term severe to moderate upper respiratory illness, such as runny nose, cough, sore throat and fever. Although this is more common in people with cardiopulmonary disease or a compromised immune system, or in the elderly, sometimes human coronaviruses cause lower respiratory tract illnesses, such as pneumonia. Transmission of common human coronaviruses is not fully understood. However, human coronaviruses can easily spread from an infected person to others through the air by coughing and sneezing, and through close personal contact such as touching or shaking hands. These viruses can also be spread by touching a contaminated object or surface and then touching your mouth, nose, or eyes.

Coronaviruses are enveloped, benign-sense, single-stranded RNA viruses. The genomic RNA of CoV has a 5'-cap structure and a 3'-poly-A tail, and contains at least six open reading frames (ORFs). The first ORF (ORF 1a/b) directly translates two polyproteins: pp1a and pp1ab. This polyprotein is processed into 16 non-structural proteins by 3C-like protease (3CLpro), also known as papain-like protease, and major protease (Mpro). These non-structural proteins are involved in the production of subgenomic RNA, which encodes four structural proteins, namely, envelope, membrane, spike, and nucleocapside proteins, among other accessory proteins. As a result, 3C-like proteases are understood to play an important role in the coronavirus life cycle.

3CLpro is a cysteine protease involved in most cleavage events in the precursor polyprotein. Active 3CLpro is a homodimer containing two protomers and is characterized by a Cys-His dyad located between domains I and II. 3CLpro is conserved among coronaviruses, and several common features are shared among substrates of 3CLpro in different coronaviruses. Because there is no human homolog of 3CLpro, it is an ideal antiviral target. Although compounds that inhibit 3CLpro activity have been reported, these compounds are not approved as coronavirus treatments (WO 2004/101742 A2, US 2005/0143320 Al, US 2006/0014821 Al, US 2009/0137818 Al, WO 2013/ 049382 A2, WO 2013/166319 A1, WO 2018/042343, WO 2018/023054, WO 2005/113580, and WO 2006/061714).

Due to this high unmet clinical need, more effective treatments for coronavirus infections are required. The present invention provides compounds that inhibit the coronavirus life cycle, and methods of making and using the compounds. These compounds are useful for treating or preventing coronavirus infection and reducing the incidence of disease complications such as organ failure or death.

The present invention relates to novel antiviral compounds, pharmaceutical compositions comprising such compounds, as well as methods for treating or preventing viral (particularly coronavirus) infections with said compounds in subjects in need of such therapy. The compounds of the invention inhibit the protein(s) encoded by the coronavirus, or disrupt the life cycle of the coronavirus, and are also useful as antiviral agents. Additionally, the present invention provides methods for preparing the compounds.

The present invention provides a compound represented by the following formula (I), and pharmaceutically acceptable salts, esters, and prodrugs thereof.

In the above equation,

R ₁ , R ₂ , R ₃ , R ₂₁ , R ₂₂ , and R ₂₃ are each independently

1) hydrogen;

2) optionally substituted -C ₁ -C ₈ alkyl;

3) optionally substituted -C ₂ -C ₈ alkenyl;

4) optionally substituted -C ₂ -C ₈ alkynyl;

5) optionally substituted -C ₃ -C ₈ cycloalkyl;

6) optionally substituted 3 to 8 membered heterocycloalkyl;

7) optionally substituted aryl;

8) optionally substituted arylalkyl;

9) optionally substituted heteroaryl; and

10) optionally substituted heteroarylalkyl.

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are attached form an optionally substituted 3 to 8 membered carbocyclic ring or an optionally substituted 3 to 8 membered heterocyclic ring.

Alternatively, R ₁ and R ₃ together with the atoms to which they are attached form an optionally substituted 3 to 8 membered heterocyclic ring.

Alternatively, R ₂₁ and R ₃ taken together with the intervening atoms form an optionally substituted 4 to 8 membered heterocyclic ring.

Alternatively, R ₂₂ is absent and R ₂₁ and R ₃ together with the intervening atoms form an optionally substituted 4-8 membered partially unsaturated heterocyclic ring or an optionally substituted 5-6 membered heteroaryl ring.

Alternatively, R ₂₁ and R ₂₂ together with the carbon atom to which they are attached form an optionally substituted 3 to 8 membered carbocyclic ring or an optionally substituted 3 to 8 membered heterocyclic ring.

R ₂₄ is

1) -C(O)R ₂₅ ;

2) -C(O)OR ₂₅ ;

3) -C(O)NR ₁₃ R ₁₄ ;

4) -S(O) ₂ R ₂₅ ;

5) hydrogen;

6) optionally substituted -C ₁ -C ₈ alkyl;

7) optionally substituted -C ₂ -C ₈ alkenyl;

8) optionally substituted -C ₂ -C ₈ alkynyl;

9) optionally substituted -C ₃ -C ₁₂ cycloalkyl;

10) optionally substituted 3 to 12 membered heterocycloalkyl;

11) optionally substituted aryl;

12) optionally substituted arylalkyl;

13) optionally substituted heteroaryl;

14) optionally substituted heteroarylalkyl;

15) -(CO)(CO)NR ₁₃ R ₁₄ ;

16) -(CO)(CO)R ₂₅ ;

17) -S(O) ₂ NR ₁₃ R ₁₄ ;

18) -C(S)R ₂₅ ; and

19) -C(S)NR ₁₃ R ₁₄ ;

Alternatively, R ₂₃ and R ₂₄ together with the nitrogen atom to which they are attached form an optionally substituted 3 to 12 membered heterocyclic ring or an optionally substituted 5 to 12 membered heteroaryl ring;

R ₂₅ is

1) optionally substituted -C ₁ -C ₈ alkyl;

2) optionally substituted -C ₂ -C ₈ alkenyl;

3) optionally substituted -C ₂ -C ₈ alkynyl;

4) optionally substituted -C ₃ -C ₁₂ cycloalkyl;

5) optionally substituted 3 to 12 membered heterocycloalkyl;

6) optionally substituted aryl;

7) optionally substituted arylalkyl;

8) optionally substituted heteroaryl; and

9) optionally substituted heteroarylalkyl;

R ₄ is hydrogen, optionally substituted -C ₁ -C ₄ alkyl, optionally substituted -C ₂ -C ₄ alkenyl, optionally substituted -C ₃ -C ₆ cycloalkyl, optionally substituted arylalkyl, optionally substituted hetero is an arylalkyl, halogen, -CN, -OH, or prodrug moiety;

B is optionally substituted aryl or optionally substituted heteroaryl;

Alternatively, one of R ₂₁ and R ₂₄ is L-, where L is a saturated or unsaturated linking group of 4 to 20 atoms in length that is attached to B;

X is

1) -CN;

2) -C(O)R ₁₅ ;

3) -CH(OH)SO ₃ R ₁₆ ;

4) -C(O)NR ₁₃ R ₁₄ ;

5) -C(O)C(O)NR ₁₃ R ₁₄ ;

6) -CH=CH-C(O)OR ₂₅ ,

7) -CH=CH-C(O)NR ₁₃ R ₁₄ ,

8) -CH=CH-S(O) ₂ NR ₁₃ R ₁₄ ,

9) -B(OR ₁₃ ) ₂ ;

10) -C≡CR ₁₃ ;

11) -C≡CC(O)OR ₂₅ ;

12) -C≡CC(O)NR ₁₃ R ₁₄ ;

13) -C≡CS(O) ₂ NR ₁₃ R ₁₄ ;

14) -(CR ₁₃ R ₁₄ ) _w -CN; and

15) -(CR ₁₃ R ₁₄ ) _w -(C=O)-R ₂₅ ;

w is 1, 2, 3, 4, or 5;

R ₁₃ and R ₁₄ are each independently

1) hydrogen;

2) optionally substituted -C ₁ -C ₈ alkyl;

3) optionally substituted -C ₂ -C ₈ alkenyl;

4) optionally substituted -C ₂ -C ₈ alkynyl;

5) optionally substituted -C ₃ -C ₈ cycloalkyl;

6) optionally substituted 3 to 8 membered heterocycloalkyl;

7) optionally substituted aryl;

8) optionally substituted arylalkyl;

9) optionally substituted heteroaryl; and

10) optionally substituted heteroarylalkyl;

Alternatively, R ₁₃ and R ₁₄ together with the nitrogen atom to which they are attached form an optionally substituted 3 to 8 membered heterocyclic ring;

R ₁₅ is hydrogen, hydroxy, optionally substituted -C ₁ -C ₈ alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl or optionally substituted heteroarylalkyl;

R ₁₆ is hydrogen or Na ⁺ .

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment of the invention, there is provided a compound of formula ( I ) as described above, or a pharmaceutically acceptable salt thereof.

In certain embodiments of compounds of formula ( I ), R ₄ is hydrogen, optionally substituted -C ₁ -C ₄ alkyl, optionally substituted -C ₂ -C ₄ alkenyl, or optionally substituted -C ₃ -C ₆ is cycloalkyl; X is

1) -CN;

2) -C(O)R ₁₅ ;

3) -CH(OH)SO ₃ R ₁₆ ;

4) -C(O)NR ₁₃ R ₁₄ ; and

5) -C(O)C(O)NR ₁₃ R ₁₄ ;

R ₂₄ is

1) -C(O)R ₂₅ ;

2) -C(O)OR ₂₅ ;

3) -C(O)NR ₁₃ R ₁₄ ;

4) -S(O) ₂ R ₂₅ ;

5) hydrogen;

6) optionally substituted -C ₁ -C ₈ alkyl;

7) optionally substituted -C ₂ -C ₈ alkenyl;

8) optionally substituted -C ₂ -C ₈ alkynyl;

9) optionally substituted -C ₃ -C ₈ cycloalkyl;

10) optionally substituted 3-8 membered heterocycloalkyl;

11) optionally substituted aryl;

12) optionally substituted arylalkyl;

13) optionally substituted heteroaryl; and

14) optionally substituted heteroarylalkyl;

R ₂₅ is

1) optionally substituted -C ₁ -C ₈ alkyl;

2) optionally substituted -C ₂ -C ₈ alkenyl;

3) optionally substituted -C ₂ -C ₈ alkynyl;

4) optionally substituted -C ₃ -C ₈ cycloalkyl;

5) optionally substituted 3 to 8 membered heterocycloalkyl;

6) optionally substituted aryl;

7) optionally substituted arylalkyl;

8) optionally substituted heteroaryl; and

9) optionally substituted heteroarylalkyl;

R ₁₅ is hydrogen, hydroxy, or optionally substituted -C ₁ -C ₈ alkyl.

In one embodiment of the invention, the compound of formula ( I ) is a compound represented by formula ( IA ) or formula ( IB ):

_{In the above formula , B , ​}

In a preferred embodiment, the compound of formula ( I ) has the stereochemistry depicted in formula ( IA ).

In one embodiment of the invention, the compound of formula ( I ) is a compound represented by formula ( II ):

_{In the above formula , B ,}

In one embodiment of the invention, the compound of formula ( I ) is a compound represented by formula ( II-A ) or formula ( II-B ), or a pharmaceutically acceptable salt, ester or prodrug thereof:

_{In the above formula , B ,}

In certain embodiments of compounds of Formula ( I ), R ₁ is hydrogen, optionally substituted —C ₁ -C ₆ alkyl; optionally substituted -C ₃ -C ₆ cycloalkyl; optionally substituted aryl; optionally substituted arylalkyl; or optionally substituted heteroarylalkyl.

In certain embodiments, R ₁ is -C ₁ -C ₆ -alkyl, preferably branched -C ₃ -C ₆ -alkyl, for example isobutyl or neopentyl. In certain embodiments, R ₁ is optionally substituted benzyl.

In certain embodiments, R ₁ is optionally substituted —C ₁ -C ₆ -alkyl, and preferably R ₁ is 2-fluoro-2-methylpropyl, or cyclopropylmethyl.

In certain embodiments of compounds of Formula ( I ), R ₂ is hydrogen or optionally substituted -C ₁ -C ₄ alkyl; optionally substituted -C ₃ -C ₆ cycloalkyl; optionally substituted aryl; optionally substituted arylalkyl; or optionally substituted heteroarylalkyl. In certain embodiments, R ₂ is hydrogen.

In certain embodiments of compounds of Formula ( I ), R ₃ is hydrogen or optionally substituted —C ₁ -C ₄ alkyl; R ₄ is hydrogen or optionally substituted -C ₁ -C ₄ alkyl.

In certain embodiments of compounds of formula ( I ), R ₃ is hydrogen, -Me, -Et, -Pr, -i -Pr, -allyl, -CF ₃ , -CD ₃ or cyclopropyl.

In certain embodiments of compounds of Formula ( I ), R ₄ is hydrogen, -Me, -Et, -Pr, -i -Pr, -allyl, -CF ₃ or cyclopropyl.

In certain embodiments, R ₃ and R ₄ are each independently hydrogen or methyl.

In certain embodiments of compounds of Formula ( I ), X is -CN.

In certain embodiments of compounds of Formula ( I ), X is -C(O)H.

In certain embodiments of compounds of Formula ( I ), X is -C(O)CH ₂ OH, -C(O)CH ₂ Cl, or -C(O)CH ₂ F.

In certain embodiments of compounds of Formula ( I ), X is -C(O)CHFCl.

In certain embodiments of compounds of formula ( I ), X is -C(O)C(O)NR ₁₃ R ₁₄ , where R ₁₃ and R ₁₄ are as defined above.

In certain embodiments of compounds of Formula ( I ), X is -C≡CR ₁₃ , where R ₁₃ is as defined above. Preferably, R ₁₃ is hydrogen.

,

또는

이다.In certain embodiments of compounds of Formula ( I ), R ₂₁ is hydrogen, optionally substituted -C ₁ -C ₄ alkyl; optionally substituted -C ₃ -C ₆ cycloalkyl; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted arylalkyl; or optionally substituted heteroarylalkyl. In certain embodiments, R ₂₁ is optionally substituted phenyl, optionally substituted benzyl, optionally substituted methyl, t-butyl, isopropyl, neopentyl,

,

or

am.

In certain embodiments of compounds of Formula ( I ), R ₂₂ is hydrogen or optionally substituted -C ₁ -C ₄ alkyl; optionally substituted -C ₃ -C ₆ cycloalkyl; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted arylalkyl; It is optionally substituted heteroarylalkyl. In certain embodiments, R ₂₂ is hydrogen.

, 또는

이고, 여기서 m은 1, 2, 3, 4, 또는 5이다. In certain embodiments of compounds of Formula ( I ), R ₁ and R ₂₁ are each independently C ₁ -C ₄ alkyl substituted with one or more fluorine atoms; C ₃ -C ₆ cycloalkyl substituted with one or more fluorine atoms; aryl substituted with one or more fluorine atoms; heteroaryl substituted with one or more fluorine atoms; arylalkyl substituted with one or more fluorine atoms; or heteroarylalkyl substituted with one or more fluorine atoms. Each of the above groups can be substituted with a fluorine number ranging from 1 to the maximum possible number, i.e., every hydrogen atom can be replaced with a fluorine atom. In certain embodiments, R ₁ and R ₂₁ are each independently -CF ₃ , -CF ₂ -CF ₃ , -CH ₂ CH(CF ₃ ) ₂ ,

, or

, where m is 1, 2, 3, 4, or 5.

In certain embodiments of compounds of Formula ( I ), R ₂₃ is hydrogen or optionally substituted —C ₁ -C ₄ alkyl. In certain embodiments R ₂₃ is hydrogen.

In certain embodiments of compounds of Formula ( I ), R ₂₄ is -C(O)R ₂₅ , -C(O)OR ₂₅ , or -C(O)NR ₁₃ R ₁₄ , where R ₁₃ , R ₁₄ and R ₂₅ are as defined above.

In certain embodiments of compounds of Formula ( I ), R ₂ is hydrogen, R ₃ is hydrogen, R ₄ is hydrogen, and R ₂₂ is hydrogen.

In certain embodiments of compounds of formula ( I ), R ₄ is hydrogen or optionally substituted —C ₁ -C ₄ alkyl, such as methyl; R ₂₃ is hydrogen or optionally substituted -C ₁ -C ₄ alkyl, for example methyl; R ₂₄ is -C(O)R ₂₅ , -C(O)OR ₂₅ , or -C(O)NR ₁₃ R ₁₄ , where R ₁₃ , R ₁₄ , and R ₂₅ are as defined above.

In certain embodiments of compounds of formula ( I ), R ₄ is cyano-C ₁ -C ₄ alkyl, cyano-C ₃ -C ₆ cycloalkyl, hydroxy-C ₁ -C ₄ alkyl, or optionally substituted. hydroxy-C ₃ -C ₆ cycloalkyl, wherein each of the above is optionally further substituted.

In certain embodiments of compounds of formula ( I ), R ₄ is a prodrug moiety, wherein the prodrug moiety is an amino acid residue, preferably a naturally occurring L-amino acid residue.

In certain embodiments of compounds of Formula ( I ), R ₄ is

1) -C(O)R ₂₅ ;

2) -S(O) ₂ R ₂₅ ;

3) -P(O)(R ₂₅ ) ₂ ;

4) -C(O)OR ₂₅ ;

5) -S(O) ₂ OR ₂₅ ; and

6) -P(O)(OR ₂₅ ) ₂ is a prodrug moiety selected from the group consisting of,

Here each R ₂₅ is the same or different.

In certain embodiments of compounds of Formula ( I ), R ₄ is

1) -CHR ₁₃ O(CO)R ₂₅ ;

2) -CHR ₁₃ O(CO)CH(NH ₂ )R ₂₅ ;

3) -CHR ₁₃ O(CO)OR ₂₅ ; and

4) -CHR ₁₃ O(PO)(OR ₁₄ ) ₂ is a prodrug moiety selected from the group consisting of,

Here, each R ₁₄ is the same or different.

In certain embodiments of compounds of formula ( I ), R ₂ is hydrogen, R ₃ is methyl, R ₄ is hydrogen or a prodrug moiety, R ₂₂ is hydrogen, R ₂₃ is hydrogen, and R ₂₄ is -C(O)R ₂₅ , -C(O)OR ₂₅ , or -C(O)NR ₁₃ R ₁₄ , where R ₁₃ , R ₁₄ , and R ₂₅ are as defined above.

In certain embodiments of compounds of formula ( I ), R ₂ is hydrogen and R ₃ and R ₄ are independently hydrogen or optionally substituted —C ₁ -C ₄ alkyl, such as methyl; R ₂₃ is hydrogen, and R ₂₄ is -C(O)R ₂₅ , -C(O)OR ₂₅ , or -C(O)NR ₁₃ R ₁₄ , where R ₁₃ , R ₁₄ , and R ₂₅ are as defined above. It's the same as what happened.

In certain embodiments of compounds of Formula ( I ), R ₂₄ is -C(O)R ₂₅ ; C(O)OR ₂₅ ; or -S(O) ₂ R ₂₅ ; R ₂₅ is selected from the following groups by removal of a hydrogen atom, and R ₂₅ is optionally substituted:

In certain embodiments of compounds of Formula ( I ), R ₂₄ is -C(O)R ₂₅ ; C(O)OR ₂₅ ; or -S(O) ₂ R ₂₅ ; R ₂₅ is selected from the following groups, and R ₂₅ is optionally substituted:

Preferably the substituents are independently halogen, CN, NH ₂ , optionally substituted -C ₁ -C ₃ alkoxy, optionally substituted -C ₁ -C ₃ alkyl, optionally substituted -C ₃ -C ₆ cycloalkyl, optionally substituted is selected from aryl, and optionally substituted heteroaryl. Preferably the number of substituents is 0 to 3.

In certain embodiments of compounds of Formula ( I ), R ₂₄ is optionally substituted -C ₁ -C ₈ alkyl, optionally substituted -C ₃ -C ₁₂ cycloalkyl, -C(O)R ₂₅ , C(O) OR ₂₅ , or -S(O) ₂ R ₂₅ ; R ₂₅ is optionally substituted -C ₁ -C ₈ alkyl or optionally substituted -C ₃ -C ₁₂ cycloalkyl; Preferably, R ₂₅ is optionally substituted -C ₁ -C ₈ alkyl.

In certain embodiments of compounds of Formula ( I ), B is selected from the following groups and B is optionally substituted:

In certain embodiments of the invention, the compound of formula ( I ) is a compound represented by one of the following formulas ( III-1 ) to ( III-4 ), or a pharmaceutically acceptable salt, ester or prodrug thereof:

_{In the above formula , B , ​ ​}

In certain embodiments of the invention, the compound of formula ( I ) is a compound represented by formula ( III-5 ):

_{In the above formula , B , ​}

In certain embodiments of the invention, the compound of formula ( I ) is a compound represented by one of the following formulas ( III-1A ) to ( III-4A ), or a pharmaceutically acceptable salt, ester or prodrug thereof:

_{In the above formula , B , ​ ​}

In certain embodiments of the invention, the compound of formula ( I ) is a compound represented by formula ( III-5A ):

_{In the above formula , B , ​}

In certain embodiments of the invention, the compound of formula ( I ) is a compound represented by one of the following formulas ( IV-1 ) to ( IV-4 ), or a pharmaceutically acceptable salt, ester or prodrug thereof:

_{In the} above _{formula , B ,}

In certain embodiments of the invention, the compound of formula ( I ) is a compound represented by formula ( IV-5 ):

In _the above _{formula , B ,}

In certain embodiments of the invention, the compound of formula ( I ) is a compound represented by one of the following formulas ( IV-1A ) to ( IV-4A ), or a pharmaceutically acceptable salt, ester or prodrug thereof:

_{In the} above _{formula , B ,}

In certain embodiments of the invention, the compound of formula ( I ) is a compound represented by formula ( IV-5A ):

In _the above _{formula , B ,}

In certain embodiments, the compound of Formula ( I ) is represented by Formula ( V ):

where R ₁ , R ₂ , R ₃ , R ₄ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ and X are as defined above, preferably R ₄ is hydrogen; Each R ₉ is independently

1) Halogen;

2) -CN;

3) -OR ₁₃ ;

4) -SR ₁₃ ;

5) -NR ₁₃ R ₁₄ ;

6) -OC(O)NR ₁₃ R ₁₄ ;

7) optionally substituted -C ₁ -C ₆ alkyl;

8) optionally substituted -C ₃ -C ₈ cycloalkyl;

9) optionally substituted 3-8 membered heterocycloalkyl;

10) optionally substituted aryl; and

11) is selected from optionally substituted heteroaryl;

n is 0, 1, 2, 3, or 4.

In certain embodiments, the compound of Formula ( I ) is represented by Formula ( V ):

where n, R ₁ , R ₂ , R ₃ , R ₄ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ and X are as defined above, and preferably, R ₄ is hydrogen; Each R ₉ is independently

1) -OC(O)R ₂₅ ;

2) -C(O)NR ₁₃ R ₁₄ ;

3) -S(O)R ₂₅ ;

4) -S(O) ₂ R ₂₅ ;

5) -S(O)(NH)R ₂₅ ;

6) -S(O) ₂ -NR ₁₃ R ₁₄ ;

7) -NR ₁₃ (C=O)R ₂₅ ;

8) -NR ₁₃ (C=O)OR ₂₅ ;

9) -NR ₁₃ (C=O)NR ₁₃ R ₁₄ ;

10) -NR ₁₃ -S(O) ₂ -R ₂₅ ; and

11) -NR ₁₃ -S(O) ₂ -NR ₁₃ R ₁₄ ;

R ₁₃ , R ₁₄ , R ₂₅ are as defined above.

In certain embodiments, the compound of Formula ( I ) is represented by Formula ( VI ):

In the above formula, R ₁ , R ₃ , R ₉ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ and n are as defined above. Preferably, n is 0 or 1.

In certain embodiments, the compound of Formula ( I ) is represented by Formula ( VI-A ) or Formula ( VI-B ):

In the above formula, R ₁ , R ₃ , R ₉ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ and n are as defined above. Preferably, n is 0 or 1.

In certain embodiments, the compound of Formula ( I ) is represented by one of the following Formulas ( VII-1 ) through ( VII-4 ):

In the above formula, R ₁ , R ₃ , R ₂₁ , R ₂₃ , R ₂₅ , R ₁₃ , and R ₁₄ are as defined above. Preferably, R ₃ is hydrogen, Me.

In certain embodiments, the compound of Formula ( I ) is represented by one of Formulas ( VII-1 ) to ( VII-4 ), wherein R ₁ , R ₂₁ , R ₂₃ , R ₂₅ , R ₁₃ , and R ₁₄ are any of the above: As defined, R ₃ is CD ₃ .

In certain embodiments of the invention, the compound of formula ( I ) is a compound represented by formula ( VII-5 ):

In the above formula, R ₁ , R ₃ , R ₂₁ , R ₂₃ , R ₂₅ , R ₁₃ , and R ₁₄ are as defined above. Preferably, R ₃ is hydrogen, Me or CD ₃ .

In certain embodiments, the compound of Formula ( I ) is represented by one of the following Formulas ( VII-1A ) to ( VII-4A ):

In the above formula, R ₁ , R ₃ , R ₂₁ , R ₂₃ , R ₂₅ , R ₁₃ , and R ₁₄ are as defined above. Preferably, R ₃ is hydrogen, Me.

In certain embodiments, the compound of Formula ( I ) is represented by one of Formulas ( VII-1A ) to ( VII-4A ), wherein R ₁ , R ₂₁ , R ₂₃ , R ₂₅ , R ₁₃ , and R ₁₄ are any of the above: As defined, R ₃ is CD ₃ .

In certain embodiments of the invention, the compound of formula ( I ) is a compound represented by formula ( VII-5A ):

In the above formula, R ₁ , R ₃ , R ₂₁ , R ₂₃ , R ₂₅ , R ₁₃ , and R ₁₄ are as defined above. Preferably, R ₃ is hydrogen, Me or CD ₃ .

In certain embodiments of the invention, the compound of formula ( I ) is a compound represented by one of the following formulas ( VIII-1 ) to ( VIII-3 ), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein A1 is an optionally substituted 4-8 membered lactam; A2 is an optionally substituted 3-12 membered heterocyclic ring or an optionally substituted 5-12 membered heteroaryl ring; A3 is an optionally substituted 3-8 membered heterocyclic ring; B, X, _R1 , _R2 , _R3 , _R4 , _R21 , _R22 , _R23 , and _R24 are as defined above.

In certain embodiments of the invention, the compound of formula ( I ) is a compound represented by one of formulas ( VIII-1 ) to ( VIII-3 ), or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein A1 is 2-pyridone; A2 is an optionally substituted 3-12 membered heterocyclic ring or an optionally substituted 5-12 membered heteroaryl ring; A3 is an optionally substituted 3-8 membered heterocyclic ring; _{B , ​ ​ ​ ​ ​ ​}

In certain embodiments of the invention, the compound of formula ( I ) is a compound represented by one of the following formulas ( IX-1 ) to ( IX-3 ), or a pharmaceutically acceptable salt, ester or prodrug thereof:

In the above formula, A1, A2, A3, B, R ₁ , R ₃ , R ₂₁ , R ₂₃ , and R ₂₄ are as defined above.

In certain embodiments of the invention, the compound of formula ( I ) is a compound represented by one of the following formulas ( X-1 ) to ( X-3 ), or a pharmaceutically acceptable salt, ester or prodrug thereof:

In the _{above formula , A1 , A2 , A3 ,}

In certain embodiments of the invention, the compound of formula ( I ) is a compound represented by one of the following formulas ( XI-1 ) to ( XI-3 ), or a pharmaceutically acceptable salt, ester or prodrug thereof:

In the above formula, A1, A2, A3, R ₁ , R ₃ , R ₂₁ , R ₂₃ , and R ₂₄ are as defined above.

In certain embodiments of the invention, the compound of formula ( I ) is a compound represented by one of the following formulas ( XII-1 ) to ( XII-10 ), or a pharmaceutically acceptable salt, ester or prodrug thereof:

In the above formula, A1, A3, R ₁ , R ₁₃ , R ₁₄ , R ₂₁ , R ₂₃ , and R ₂₅ are as defined above.

In certain embodiments of the invention, the compound of formula ( I ) is a compound represented by one of the following formulas ( XII-11 ) to ( XII-12 ), or a pharmaceutically acceptable salt, ester or prodrug thereof:

In the above formula, A1, A3, R ₁ , R ₁₃ , R ₁₄ , R ₂₁ , and R ₂₃ are as defined above.

In certain embodiments of the invention, the compound of formula ( I ) is represented by formula ( XIII ):

where q is 1 or 2 and R ₂₁ , R ₂₂ , R ₂₃ , and R ₂₄ are as defined above.

In certain embodiments of the invention, the compounds of formula ( I ) are represented by one of the following formulas ( XIV-1 ) to ( XIV-5 ):

In the above formula, q, R ₁₃ , R ₁₄ , R ₂₁ , R ₂₃ , and R ₂₅ are as defined above.

In certain embodiments of the invention, the compound of formula ( I ) is represented by formula ( XIV-6 ):

In the above formula, q, R ₁₃ , R ₁₄ , R ₂₁ , and R ₂₃ are as defined above.

In certain embodiments of the invention, the compound of formula ( I ) is represented by one of the following formulas ( XV-1 ) to ( XV-4 ):

where R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , and R ₄ are as defined above; Preferably R ₄ is hydrogen or a prodrug moiety.

In certain embodiments of the invention, the compound of formula ( I ) is represented by one of the formulas ( XVI-1 ) to ( XVI-6 ):

where R ₁ , R ₄ , R ₁₃ , R ₁₄ , R ₂₃ , and R ₂₅ are as defined above; Preferably R ₄ is hydrogen or a prodrug moiety.

In certain embodiments of the invention, the compounds of formula ( I ) are represented by one of the following formulas ( XVII-1 ) to ( XVII-2 ):

where r is 1, 2, 3, or 4 and n, R ₁ , R ₃ , R ₄ , R ₉ , and R ₂₁ are as defined above; Preferably R ₄ is hydrogen or a prodrug moiety.

In certain embodiments of the invention, the compounds of formula ( I ) are represented by one of the following formulas ( XVIII-1 ) to ( XVIII-4 ):

In the above formula, n, R ₁ , R ₃ , R ₉ , R ₁₃ , R ₁₄ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ and R ₂₅ are as defined above.

In certain embodiments of the invention, the compounds of formula ( I ) are represented by one of the following formulas ( XVIII-1a ) to ( XVIII-4a ):

In the above formula, R ₁ , R ₃ , R ₁₃ , R ₁₄ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ and R ₂₅ are as defined above.

In certain embodiments, the compound of Formula ( I ) is represented by Formula ( XIX ):

In the above formula, R ₁ , R ₃ , R ₄ , R ₉ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ and n are as defined above. Preferably, n is 0 or 1 and R ₄ is hydrogen or a prodrug moiety.

In certain embodiments, the compound of Formula ( I ) is represented by Formula ( XIX-A ) or Formula ( XIX-B ):

In the above formula, R ₁ , R ₃ , R ₄ , R ₉ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ and n are as defined above. Preferably, n is 0 or 1 and R ₄ is hydrogen or a prodrug moiety.

In certain embodiments, the compound of Formula ( I ) is represented by one of the following formulas ( XX-1 ) through ( XX-5 ):

In the above formula, R ₁ , R ₃ , R ₄ , R ₂₁ , R ₂₃ , R ₂₅ , R ₁₃ , and R ₁₄ are as defined above. Preferably, R ₃ is hydrogen or Me or CD ₃ and R ₄ is hydrogen or a prodrug moiety.

In certain embodiments, the compound of Formula ( I ) is represented by one of the following formulas ( XX-1A ) through ( XX-5A ):

In the above formula, R ₁ , R ₃ , R ₂₁ , R ₂₃ , R ₂₅ , R ₁₃ , and R ₁₄ are as defined above. Preferably, R ₃ is hydrogen, Me or CD ₃ and R ₄ is hydrogen or a prodrug moiety.

In certain embodiments of the invention, the compound of formula ( I ) is represented by formula ( XXI ):

where q is 1 or 2 and R ₄ , R ₂₁ , R ₂₂ , R ₂₃ , and R ₂₄ are as defined above. Preferably, R ₄ is hydrogen or a prodrug moiety.

In certain embodiments of the invention, the compound of formula ( I ) is represented by formula ( XXII ):

_{wherein B , ​ ​ ​ ​ ​ ​ ​} If not, R _a is connected to B, and if R _a is absent, Q is connected to B;

R _a is absent, optionally substituted -C ₁ -C ₈ alkyl, optionally substituted -C ₂ -C ₈ alkenyl, optionally substituted -C ₂ -C ₈ alkynyl, optionally substituted -C ₃ -C ₈ cyclo. is selected from the group consisting of alkyl, optionally substituted 3-8 membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; In certain embodiments, R _a is absent;

R _b is optionally substituted -C ₁ -C ₈ alkyl, optionally substituted -C ₂ -C ₈ alkenyl, optionally substituted -C ₂ -C ₈ alkynyl, optionally substituted -C ₃ -C ₈ cycloalkyl, is selected from the group consisting of optionally substituted 3-8 membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl;

Q is -CR ₃₁ =CR ₃₂ -, -CR ₃₁ R ₃₃ -CR ₃₂ R ₃₄ -, -CR ₃₁ R ₃₃ C(O)-, -CR ₃₁ R ₃₃ -O-, -CR ₃₁ R ₃₃ -S- , -CR ₃₁ R ₃₃ N(R ₁₇ )-, -NR ₁₃ C(O)-, -NR ₁₃ C(O)O-, -NR ₁₃ C(O)NR ₁₄ -, -C(O)O- , -C(O)S-, -OC(O)O-, -C(O)-, O-, -S-, -S(O)-, -S(O) ₂ -, -S(O )(NH)-, -N(R ₁₇ )-, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -C ₃ -C ₈ cycloalkyl, and optionally substituted 3 to 8 membered heterocycloalkyl. selected from the group;

In certain embodiments, L is optionally substituted C ₄ -C ₁₀ -alkylene or optionally substituted C ₄ -C ₁₀ -alkenylene, wherein said C ₄ -C ₁₀ -alkylene or C ₄ -C ₁₀ -alke One CH ₂ group in nylene is optionally replaced by an oxygen atom or an NH group; Preferably L is C ₄ -C ₈ -alkylene or C ₄ -C ₈ -alkenylene, wherein said C ₄ -C ₈ -alkylene or C ₄ -C ₈ -alkenylene is optionally substituted with oxo;

In each case, R ₃₁ and R ₃₂ are each independently hydrogen, halogen, optionally substituted -C ₁ -C ₈ alkyl, optionally substituted -C ₂ -C ₈ alkenyl, optionally substituted -C ₂ -C ₈ alkyl. Nyl, optionally substituted -C ₃ -C ₈ cycloalkyl, optionally substituted 3 to 8 membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl. is selected from the group consisting of; In certain embodiments, R ₃₁ and R ₃₂ are both hydrogen;

In each case, R ₃₃ and R ₃₄ are each independently hydrogen, halogen, -OH, -OR ₁₂ , -OC(O)R ₁₁ , -OC(O)OR ₁₂ , -OC(O)NR ₁₃ R ₁₄ , -NR ₁₃ R ₁₇ , -N ₃ , -CN, optionally substituted -C ₁ -C ₈ alkyl, optionally substituted -C ₂ -C ₈ alkenyl, optionally substituted -C ₂ -C ₈ alkynyl, optionally substituted selected from the group consisting of -C ₃ -C ₈ cycloalkyl, optionally substituted 3 to 8 membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl. become; In certain embodiments, R ₃₃ and R ₃₄ are both hydrogen;

R ₁₁ and R ₁₂ are each independently optionally substituted -C ₁ -C ₈ alkyl, optionally substituted -C ₂ -C ₈ alkenyl, optionally substituted -C ₂ -C ₈ alkynyl, optionally substituted -C ₃ -C ₈ cycloalkyl, optionally substituted 3 to 8 membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;

In each case R ₁₃ and R ₁₄ are independently hydrogen, optionally substituted -C ₁ -C ₈ alkyl, optionally substituted -C ₂ -C ₈ alkenyl, optionally substituted -C ₂ -C ₈ alkynyl, optionally from the group consisting of substituted -C ₃ -C ₈ cycloalkyl, optionally substituted 3 to 8 membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl being selected; alternatively R ₁₃ and R ₁₄ together with the nitrogen atom to which they are attached form an optionally substituted 3 to 8 membered heterocyclic ring;

R ₁₇ is hydrogen, optionally substituted -C ₁ -C ₈ alkyl, optionally substituted -C ₂ -C ₈ alkenyl, optionally substituted -C ₂ -C ₈ alkynyl, optionally substituted -C ₃ -C ₈ cyclo. Alkyl, optionally substituted 3-8 membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -C(O)R ₁₁ , -C(O) OR ₁₂ , -C(O)NR ₁₃ R ₁₄ , -C(O)C(O)NR ₁₃ R ₁₄ , -S(O) ₂ R ₁₁ , and -S(O) ₂ NR ₁₃ R ₁₄ . is selected from

In certain embodiments of the invention, the compound of formula ( I ) is represented by formula ( XXIII ):

_{In the above formula , B ,}

In certain embodiments, the compound of Formula ( I ) is represented by one of the following Formulas ( XXIV-1 ) through ( XXIV-5 ):

In the above formula, R ₁ , R ₃ , R ₄ , R ₂₂ , R ₂₃ , R ₂₅ , R ₁₃ , and R ₁₄ are as defined above. Preferably, R ₃ is hydrogen or Me or CD ₃ and R ₄ is hydrogen or a prodrug moiety.

In certain embodiments, the compound of Formula ( I ) is represented by one of the following Formulas ( XXV-1 ) through ( XXV-5 ):

In the above formula, R ₁ , R ₃ , R ₄ , R ₂₁ , R ₂₃ , and R ₁₄ are as defined above. Preferably, R ₃ is hydrogen or Me or CD ₃ and R ₄ is hydrogen or a prodrug moiety.

It will be appreciated that the description of the invention herein should be interpreted consistent with the laws and principles of chemical bonding. In some cases, it may be necessary to remove a hydrogen atom to accommodate a substituent at any given position.

The definition of any substituent or variable (eg, R ₁ , R ₂ , etc.) at a particular position in the molecule is intended to be independent of its definition at other positions in the molecule. For example, in formula ( V ), when n is 2, each of the two R ₉ groups can be the same or different.

It will also be appreciated that the compounds of the invention may contain one or more asymmetric carbon atoms and may exist in racemic, diastereomeric, and optically active forms. It will still be appreciated that certain compounds of the invention may exist in different tautomeric forms. All tautomers are considered within the scope of this invention.

Justice

Listed below are definitions of various terms used in describing the present invention. These definitions apply to terms used throughout the specification and claims, individually or as part of a larger group, unless otherwise limited to specific examples.

As used herein, the term “aryl” refers to a monocyclic or polycyclic carboxylic acid containing at least one aromatic ring, including but not limited to phenyl, naphthyl, tetrahydronaphthyl, indanyl, and indenyl. Refers to a click ring system. Polycyclic aryl is a polycyclic ring system containing at least one aromatic ring. Polycyclic aryl may include fused rings, covalently linked rings, or combinations thereof.

As used herein, the term “heteroaryl” refers to a monocyclic or polycyclic aromatic radical having one or more ring atoms selected from S, O and N; The remaining ring atoms are carbon, where any N or S contained in the ring may be optionally oxidized. Heteroaryl is pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl. , isoquinolinyl, benzimidazolyl, benzoxazolyl, and quinoxalinyl. Polycyclic heteroaryls may include fused rings, covalently linked rings, or combinations thereof.

According to the invention, aromatic groups may be substituted or unsubstituted.

The term “bicyclic aryl” or “bicyclic heteroaryl” refers to a ring system consisting of two rings, at least one of which is aromatic; The two rings can be fused or covalently linked.

As used herein, the term “alkyl” refers to a saturated, straight-chain or branched-chain hydrocarbon radical. “C _1- C ₄ alkyl”, “C _1- C ₆ alkyl”, “C _1- C ₈ alkyl”, “C _1- C ₁₂ alkyl”, “C ₂ -C ₄ alkyl”, or “C ₃ - C ₆ alkyl” refers to an alkyl group containing 1 to 4, 1 to 6, 1 to 8, 1 to 12, 2 to 4 and 3 to 6 carbon atoms, respectively. Examples of C _1- C ₈ alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n -butyl, tert -butyl, neopentyl, n-hexyl, heptyl, and octyl radicals.

As used herein, the term “alkenyl” refers to a straight or branched chain hydrocarbon radical having at least one carbon-carbon double bond by the removal of a single hydrogen atom. “C ₂ -C ₈ alkenyl”, “C ₂ -C ₁₂ alkenyl”, “C ₂ -C ₄ alkenyl”, “C ₃ -C ₄ alkenyl,” or “C ₃ -C ₆ alkenyl” refers to an alkenyl group containing 2 to 8, 2 to 12, 2 to 4, 3 to 4 or 3 to 6 carbon atoms, respectively. Alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 2-methyl-2-buten-2-yl, heptenyl, octenyl, etc., for example.

As used herein, the term “alkynyl” refers to a straight or branched chain hydrocarbon radical having at least one carbon-carbon double bond by the removal of a single hydrogen atom. “C ₂ -C ₈ alkynyl,” “C ₂ -C ₁₂ alkynyl,” “C ₂ -C ₄ alkynyl,” “C ₃ -C ₄ alkynyl,” or “C ₃ -C ₆ alkynyl.” refers to an alkynyl group containing 2 to 8, 2 to 12, 2 to 4, 3 to 4 or 3 to 6 carbon atoms, respectively. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, heptynyl, octynyl, etc.

As used herein, the term "cycloalkyl" refers to a monocyclic or polycyclic saturated carbocyclic ring or a bicyclic or tricyclic group fused bridged or spirotype system, wherein the carbon atoms are optionally oxo substituted, or optionally substituted. It may be substituted with an exocyclic olefinic double bond. Preferred cycloalkyl groups include C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₈ cycloalkyl and C ₄ -C ₇ cycloalkyl. Examples of C ₃ -C ₁₂ cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl, 4-methylene-cyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.0. ]Hexyl, spiro[2.5]octyl, 3-methylenebicyclo[3.2.1]octyl, spiro[4.4]nonanyl, etc., but is not limited thereto.

As used herein, the term “cycloalkenyl” refers to a monocyclic or polycyclic carbocyclic ring or bicyclic or tricyclic group having at least one carbon-carbon double bond, or a fused, bridged or spirotype system. And the carbon atom may be optionally oxo substituted, or optionally substituted with an exocyclic olefinic double bond. Preferred cycloalkenyl groups include C ₃ -C ₁₂ cycloalkenyl, C ₃ -C ₈ cycloalkenyl or C ₅ -C ₇ cycloalkenyl groups. Examples of C ₃ -C ₁₂ cycloalkenyl are cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[2.2.1]hept-2-enyl, bicyclo Includes [3.1.0]hex-2-enyl, spiro[2.5]oct-4-enyl, spiro[4.4]non-2-enyl, bicyclo[4.2.1]non-3-en-12-yl, etc. However, it is not limited to this.

As used herein, the term “arylalkyl” refers to a functional group to which an alkylene chain is attached to an aryl group, such as -CH ₂ CH ₂ -phenyl. The term “substituted arylalkyl” refers to an arylalkyl functional group in which an aryl group is substituted. Similarly, the term “heteroarylalkyl” refers to a functional group in which an alkylene chain is attached to a heteroaryl group. The term “substituted heteroarylalkyl” refers to a heteroarylalkyl group in which a heteroaryl group is substituted. Preferably, as used herein, arylalkyl is aryl-C ₁ -C ₆ alkyl and heteroarylalkyl is heteroaryl-C ₁ -C ₆ alkyl.

As used herein, the term "alkoxy", alone or in combination with other terms, means, unless otherwise specified, an alkyl group having the specified number of carbon atoms bonded to the remainder of the molecule through an oxygen atom, e.g. For example, methoxy, ethoxy, 2-propoxy, 2-propoxy (isopropoxy) and higher homologs and isomers. Preferred alkoxy is (C _2- C ₃ ) alkoxy.

It is understood that any of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic and cycloalkenyl moieties described herein may also be aliphatic or cycloaliphatic.

An “aliphatic” group is a non-aromatic moiety containing any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, and optionally containing one or more units of unsaturation, such as double and/or triple bonds. do. Examples of aliphatic groups include functional groups such as alkyl, alkenyl, alkynyl, O, OH, NH, NH ₂ , C(O), S(O) ₂ , C(O)O, C(O)NH , OC(O)O, OC(O)NH, OC(O)NH ₂ , S(O) ₂ NH, S(O) ₂ NH ₂ , NHC(O)NH ₂ , NHC(O)C(O) NH, NHS(O) ₂ NH, NHS(O) ₂ NH ₂ , C(O)NHS(O) _2, C(O)NHS(O) ₂ NH or C(O)NHS(O) ₂ NH ₂ etc. , a group containing one or more functional groups, a non-aromatic hydrocarbon (optionally substituted), and a group in which at least one carbon of the non-aromatic hydrocarbon (optionally substituted) is substituted with a functional group. The carbon atoms of the aliphatic group may be optionally oxo substituted. The aliphatic group may be straight chain, branched, cyclic, or a combination thereof, and preferably contains from about 1 to about 24 carbon atoms, more typically from about 1 to about 12 carbon atoms. In addition to aliphatic hydrocarbon groups, aliphatic groups as used herein specifically include, for example, alkoxyalkyl, polyalkoxyalkyl, such as polyalkylene, glycol, polyamine, and polyimine. The aliphatic group may be optionally substituted.

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

Any alkyl, alkenyl, alkynyl, cycloaliphatic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphatic moiety, etc. described herein may also have atom(s) that may be the same or different. When used as a linking group connecting two or more groups or substituents, it is understood that it may be a divalent or multivalent group. One skilled in the art can readily determine the valency of any such group from the context in which it occurs.

The term “substituted” refers to -F, -Cl, -Br, -I, -OH, C _1- C ₁₂ -alkyl; C ₂ -C ₁₂ -alkenyl, C ₂ -C ₁₂ -alkynyl, -C ₃ -C ₁₂ -cycloalkyl, protected hydroxy, -NO ₂ , -N ₃ , -CN, -NH ₂ , protected Amino, oxo, thioxo, -NH-C _1- C ₁₂ -alkyl, -NH-C ₂ -C ₈ -alkenyl, -NH-C ₂ -C ₈ -alkynyl, -NH-C ₃ -C ₁₂ -cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -OC _1- C ₁₂ -alkyl, -OC ₂ -C ₈ -alkenyl, -OC ₂ -C ₈ -alkynyl, -OC ₃ -C ₁₂ -cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocycloalkyl, -C(O) -C _1- C ₁₂ -alkyl, -C(O)-C ₂ -C ₈ -alkenyl, -C(O)-C ₂ -C ₈ -alkynyl, -C(O)-C ₃ -C ₁₂ -cycloalkyl, -C(O)-aryl, -C(O)-heteroaryl, -C(O)-heterocycloalkyl, -CONH ₂ , -CONH-C _1- C ₁₂ -alkyl, -CONH-C ₂ -C ₈ -alkenyl, -CONH-C ₂ -C ₈ -alkynyl, -CONH-C ₃ -C ₁₂ -cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, -OCO ₂ -C _1- C ₁₂ -alkyl, -OCO ₂ -C ₂ -C ₈ -alkenyl, -OCO ₂ -C ₂ -C ₈ -alkynyl, -OCO ₂ -C ₃ -C ₁₂ -cycloalkyl , -OCO ₂ -aryl, -OCO ₂ -heteroaryl, -OCO ₂ -heterocycloalkyl, -CO ₂ -C _1- C ₁₂ alkyl, -CO ₂ -C ₂ -C ₈ alkenyl, -CO ₂ -C ₂ -C ₈ alkynyl, CO ₂ -C ₃ -C ₁₂ -cycloalkyl, -CO ₂ -aryl, CO ₂ -heteroaryl, CO ₂ -heterocycloalkyl, -OCONH ₂ , -OCONH-C ₁ C ₁₂ - Alkyl, -OCONH-C ₂ -C ₈ -alkenyl, -OCONH-C ₂ -C ₈ -alkynyl, -OCONH-C ₃ -C ₁₂ -cycloalkyl, -OCONH-aryl, -OCONH-heteroaryl, - OCONH-heterocyclo-alkyl, -NHC(O)H, -NHC(O)-C _1- C ₁₂ -alkyl, -NHC(O)-C ₂ -C ₈ -alkenyl, -NHC(O)-C ₂ -C ₈ -alkynyl, -NHC(O)-C ₃ -C ₁₂ -cycloalkyl, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)-heterocyclo-alkyl , -NHCO ₂ -C _1- C ₁₂ -alkyl, -NHCO ₂ -C ₂ -C ₈ -alkenyl, -NHCO ₂ -C ₂ -C ₈ -alkynyl, -NHCO ₂ -C ₃ -C ₁₂ -cyclo Alkyl, -NHCO ₂ -aryl, -NHCO ₂ -heteroaryl, -NHCO ₂ -heterocycloalkyl, -NHC(O)NH ₂ , -NHC(O)NH-C _1- C ₁₂ -alkyl, -NHC(O )NH-C ₂ -C ₈ -alkenyl, -NHC(O)NH-C ₂ -C ₈ -alkynyl, -NHC(O)NH-C ₃ -C ₁₂ -cycloalkyl, -NHC(O)NH -aryl, -NHC(O)NH-heteroaryl, -NHC(O)NH-heterocycloalkyl, NHC(S)NH ₂ , -NHC(S)NH-C _1- C ₁₂ -alkyl, -NHC(S )NH-C ₂ -C ₈ -alkenyl, -NHC(S)NH-C ₂ -C ₈ -alkynyl, -NHC(S)NH-C ₃ -C ₁₂ -cycloalkyl, -NHC(S)NH -aryl, -NHC(S)NH-heteroaryl, -NHC(S)NH-heterocycloalkyl, -NHC(NH)NH ₂ , -NHC(NH)NH-C _1- C ₁₂ -alkyl, -NHC( NH)NH-C ₂ -C ₈ -alkenyl, -NHC(NH)NH-C ₂ -C ₈ -alkynyl, -NHC(NH)NH-C ₃ -C ₁₂ -cycloalkyl, -NHC(NH) NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NH-heterocycloalkyl, -NHC(NH)-C _1- C ₁₂ -alkyl, -NHC(NH)-C ₂ -C ₈ -alkenyl, -NHC(NH)-C ₂ -C ₈ -alkynyl, -NHC(NH)-C ₃ -C ₁₂ -cycloalkyl, -NHC(NH)-aryl, -NHC(NH)-heteroaryl , -NHC(NH)-heterocycloalkyl, -C(NH)NH-C _1- C ₁₂ -alkyl, -C(NH)NH-C ₂ -C ₈ -alkenyl, -C(NH)NH-C ₂ -C ₈ -alkynyl, -C(NH)NH-C ₃ -C ₁₂ -cycloalkyl, -C(NH)NH-aryl, -C(NH)NH-heteroaryl, -C(NH)NH- Heterocycloalkyl, -S(O)-C _1- C ₁₂ -alkyl, -S(O)-C ₂ -C ₈ -alkenyl, -S(O)-C ₂ -C ₈ -alkynyl, -S (O)-C ₃ -C ₁₂ -cycloalkyl, -S(O)-aryl, -S(O)-heteroaryl, -S(O)-heterocycloalkyl, -SO ₂ NH ₂ , -SO ₂ NH -C _1- C ₁₂ -alkyl, -SO ₂ NH-C ₂ -C ₈ -alkenyl, -SO ₂ NH-C ₂ -C ₈ -alkynyl, -SO ₂ NH-C ₃ -C ₁₂ -cycloalkyl , -SO ₂ NH-aryl, -SO ₂ NH-heteroaryl, -SO ₂ NH-heterocycloalkyl, -NHSO ₂ -C _1- C ₁₂ -alkyl, -NHSO ₂ -C ₂ -C ₈ -alkenyl, -NHSO ₂ -C ₂ -C ₈ -alkynyl, -NHSO ₂ -C ₃ -C ₁₂ -cycloalkyl, -NHSO ₂ -aryl, -NHSO ₂ -heteroaryl, -NHSO ₂ -heterocycloalkyl, -CH ₂ NH ₂ , -CH ₂ SO ₂ CH ₃ , -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -C ₃ -C ₁₂ -cycloalkyl, polyalkoxyalkyl, polyalkoxy, - Methoxymethoxy, -methoxyethoxy, -SH, -SC _1- C ₁₂ -alkyl, -SC ₂ -C ₈ -alkenyl, -SC ₂ -C ₈ -alkynyl, -SC ₃ -C ₁₂ - Independent replacement of one, two, or three or more hydrogen atoms by substituents including, but not limited to, cycloalkyl, -S-aryl, -S-heteroaryl, -S-heterocycloalkyl, or methylthio-methyl. refers to substitution by . In certain embodiments, the substituents are independently halo, preferably Cl and F; C _1- C ₄ -alkyl, preferably methyl and ethyl; halo-C _1- C ₄ -alkyl, such as fluoromethyl, difluoromethyl, and trifluoromethyl; C ₂ -C ₄ -alkenyl; halo-C ₂ -C ₄ -alkenyl; C ₃ -C ₆ -cycloalkyl, for example cyclopropyl; C _1- C ₄ -alkoxy, such as methoxy and ethoxy; halo-C _1- C ₄ -alkoxy, such as fluoromethoxy, difluoromethoxy, and trifluoromethoxy; acetyl; -CN; -OH; NH ₂ ; C _1- C ₄ -alkylamino; di(C _1- C ₄ -alkyl)amino; and NO ₂ . It is understood that aryl, heteroaryl, alkyl, etc. may be further substituted. In some cases, each substituent in a substituted moiety is further optionally substituted with one or more groups, and each group is independently C _1- C ₄ -alkyl; -CF ₃ , -OCH ₃ , -OCF ₃ , -F, -Cl, -Br, -I, -OH, -NO ₂ , -CN, and -NH ₂ . Preferably, the substituted alkyl group is substituted with one or more halogen atoms, more preferably with one or more fluorine or chlorine atoms.

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

As used herein, the term “optionally substituted” means that the referenced group may or may not be substituted. In one embodiment, the recited group is optionally substituted with 0 substituents, i.e. the recited group is unsubstituted. In another embodiment, the groups mentioned are optionally substituted with one or more additional group(s) individually and independently selected from the groups described herein.

The term “hydrogen” includes hydrogen and deuterium. Additionally, the listing of an atom includes other isotopes of that atom, so long as the resulting compound is pharmaceutically acceptable.

As used herein, the term “hydroxy activating group” refers to a labile chemical moiety known in the art that activates a hydroxyl group to escape a substitution or elimination reaction during a synthetic process, for example. Examples of hydroxyl activating groups include, but are not limited to, mesylate, tosylate, triflate, p -nitrobenzoate, phosphonate, etc.

As used herein, the term "activated hydroxyl" means activated with a hydroxyl activating group as defined above, including, for example, mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups. refers to a hydroxyl group.

As used herein, the term “hydroxy protecting group” refers to a labile chemical moiety known in the art to protect hydroxyl groups from undesirable reactions during synthetic processes. After the above synthetic process(es), the hydroxy protecting groups described herein may be optionally removed. Hydroxy protecting groups, as known in the art, are generally described in TH Greene and PGM Wuts, Protective Groups in Organic Synthesis , 3rd edition, John Wiley & Sons, New York (1999). Examples of hydroxyl protecting groups are benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxy. Carbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl Ethyl, allyl, benzyl, triphenylmethyl (trityl), methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-(trimethylsilyl)-ethoxymethyl, methanesulfonyl, trimethylsilyl, triisopropylsilyl, etc. Includes.

As used herein, the term “protected hydroxy” refers to a hydroxy protecting group as defined above, including, for example, benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups. It refers to the rock period.

As used herein, the term “hydroxy prodrug group” refers to a promoiety group that alters the physicochemical and therefore biological properties of the parent drug in a transient manner by masking or masking the hydroxy group. After the above synthetic process(es), the hydroxy prodrug group as described herein should be able to be converted back to a hydroxy group in vivo. Hydroxy prodrug groups, as known in the art, are generally described in Kenneth B. Sloan, Prodrugs, Topical and Ocular Drug Delivery , (Drugs and the Pharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York (1992 )]. Preferably, the hydroxy prodrug group is a phosphate, sulfamate, or an acyl group derived from an amino acid, preferably an α-amino acid.

As used herein, the term “amino protecting group” refers to a labile chemical moiety known in the art to protect amino groups from undesirable reactions during synthetic processes. After the above synthetic process(es), the amino protecting group as described herein may be optionally removed. Amino protecting groups, as known in the art, are generally described in TH Greene and PGM Wuts, Protective Groups in Organic Synthesis , 3rd edition, John Wiley & Sons, New York (1999). Examples of amino protecting groups include, but are not limited to, methoxycarbonyl, t-butoxycarbonyl, 12-fluorenylmethoxycarbonyl, benzyloxycarbonyl, etc.

As used herein, the term “protected amino” refers to an amino group protected with an amino protecting group as defined above.

The term “leaving group” refers to a functional group or atom that can be replaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction. By way of example, representative leaving groups include chloro, bromo, and iodo groups; Sulfonic ester groups such as mesylate, tosylate, brosylate, nosylate, etc.; and acyloxy groups such as acetoxy, trifluoroacetoxy, etc.

As used herein, the term “aprotic solvent” refers to a solvent that is relatively inert to proton activity, i.e., a solvent that does not act as a proton donor. Examples include hydrocarbons such as hexane and toluene, halogenated hydrocarbons such as methylene chloride, ethylene chloride, chloroform, etc., heterocyclic compounds such as tetrahydrofuran and N-methylpyrroli. Dinones, and ethers such as diethyl ether, bis-methoxymethyl ether. These compounds are well known to those skilled in the art and it will be apparent to those skilled in the art that individual solvents or mixtures thereof may be preferred for particular compounds and reaction conditions depending on factors such as, for example, the solubility of the reagent, the reactivity of the reagent and the preferred temperature range. something to do. Additional discussion of aprotic solvents can be found in organic chemistry textbooks or professional papers, such as Organic Solvents Physical Properties and Methods of Purification , 4th ed., edited by John A. Riddick et al. , Vol. II, in the Techniques of Chemistry Series , John Wiley & Sons, NY, 1986.

As used herein, the term “protic solvent” refers to solvents that tend to donate protons, such as alcohols such as methanol, ethanol, propanol, isopropanol, butanol, t-butanol, etc. . Such solvents are well known to those skilled in the art, and it will be apparent to those skilled in the art that individual solvents or mixtures thereof may be preferred for particular compounds and reaction conditions depending on factors such as, for example, solubility of the reagent, reactivity of the reagent, and preferred temperature range. something to do. Additional discussions of protic solvents can be found in organic chemistry textbooks or professional papers, such as Organic Solvents Physical Properties and Methods of Purification , 4th ed., edited by John A. Riddick et al. , Vol. II, in the Techniques of Chemistry Series , John Wiley & Sons, NY, 1986.

The combinations of substituents and variables contemplated by the present invention are only those that lead to the formation of stable compounds. As used herein, the term “stable” refers to the condition of a compound that it possesses sufficient stability to permit manufacture and remains intact for a sufficient period of time to be useful for the purposes described herein (e.g., therapeutic or prophylactic administration to a subject). refers to a compound that maintains .

The synthesized compound can be separated from the reaction mixture and further purified by methods such as column chromatography, high pressure liquid chromatography, or recrystallization. As will be appreciated by those skilled in the art, additional methods of synthesizing compounds of the formulas herein will be apparent to those skilled in the art. Additionally, the various synthetic steps can be performed in alternative orders or in an order that provides the desired compound. Synthetic chemical modifications and protecting group methods (protection and deprotection) useful for synthesizing the compounds described herein are known in the art and are described, for example, in R. Larock, Comprehensive Organic Transformations , ^2nd Ed. Wiley-VCH (1999); TW Greene and PGM Wuts, Protective Groups in Organic Synthesis , 3rd Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis , John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis , John Wiley and Sons (1995), and subsequent editions thereof.

As used herein, the term “subject” refers to an animal. Preferably, the animal is a mammal. More preferably, the mammal is a human. Subject also refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, fish, birds, etc.

Compounds of the invention can be modified by adding appropriate functionality to enhance selective biological properties. These modifications are known in the art and are known to increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, and , may include those that alter metabolism and alter excretion rates.

The compounds described herein contain one or more asymmetric centers and are therefore (R)- or (S)-, or (D)- or (L)- with respect to enantiomers, diastereomers, and absolute stereochemistry for amino acids. It produces different stereoisomeric forms that can be defined as The present invention is intended to include all such possible isomers as well as their racemates and optically pure forms. Optical isomers can be prepared from their respective optically active precursors by the procedures described above, or by splitting the racemic mixture. Resolution can be performed in the presence of a resolving agent, by chromatography or repeated recrystallization, or by some combination of these techniques known to those skilled in the art. Additional explanation of partitioning can be found in Jacques, et al ., Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). When the compounds described herein contain olefinic double bonds, other unsaturations, or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers or cis and trans isomers. Likewise, all tautomeric forms are also intended to be included. Tautomers can be cyclic or acyclic. The configurations of any carbon-carbon double bonds appearing herein are chosen for convenience only and are not intended to designate a particular configuration unless the text so indicates; Accordingly, the carbon-carbon double bond or carbon-heteroatom double bond optionally described herein may be cis, trans, or a mixture of the two in any ratio.

Certain compounds of the invention may also exist in different, stable conformational forms that can be isolated. Strain asymmetry due to limited rotation about the asymmetric single bond, for example due to steric hindrance or ring strain, can allow the separation of different isomeric forms. The present invention includes individual conformational isomers of these compounds and mixtures thereof.

As used herein, the term "pharmaceutically acceptable salt" means that it is suitable for use in contact with human and lower animal tissue without undue toxicity, irritation, allergic reaction, etc., within sound medical judgment and with reasonable benefit/risk. Refers to the salt corresponding to the ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge, et al ., J. Pharmaceutical Sciences, 66: 2-19 (1977)] describes pharmaceutically acceptable salts in detail. Salts may be prepared in situ during the final isolation and purification of the compounds of the invention, or may be prepared separately by reacting the free base functionality with a suitable organic acid. Examples of pharmaceutically acceptable salts include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by ion exchange. Non-toxic acid addition salts, which are salts of amino groups formed using other methods used in the same art, include, but are not limited to, non-toxic acid addition salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, and cyclopentane-propio. Nate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydride. Roxy-ethanesulfonate, lactobiotate, lactate, laurate, lauryl sulfate, maleate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate Prolate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p - Including, but not limited to, toluenesulfonate, undecanoate, valerate salt, etc. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Additional pharmaceutically acceptable salts include, where appropriate, non-toxic ammoniums, quaternary ammoniums, and counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, 1 to 6 carbon Includes amine cations formed using alkyl, sulfonate and aryl sulfonate atoms.

As used herein, the term “pharmaceutically acceptable ester” refers to esters that hydrolyze in vivo and include those that readily decompose in the human body to release the parent compound or salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, especially alkanoic acids, alkenoic acids, cycloalkanoic acids and alkanedioic acids, wherein each alkyl or alkenyl moiety is advantageously Has 6 or fewer carbon atoms. Examples of specific esters include, but are not limited to, formate, acetate, propionate, butyrate, acrylate, and ethylsuccinate.

As used herein, the term "pharmaceutically acceptable prodrug" means a prodrug that is suitable for use in contact with human and lower animal tissue without excessive toxicity, irritation, allergic reaction, etc., within sound medical judgment, and has reasonable benefit/ Refers to prodrugs of the compounds of the invention that correspond to the risk ratio and are effective for their intended use, as well as, where possible, zwitterionic forms of the compounds of the invention.

As used herein, the term “prodrug” refers to a compound that can be converted in vivo to a compound of Formula I by metabolic means (e.g., hydrolysis). Various types of prodrugs are described, for example, in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). "Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1-38 (1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975); and Bernard Testa & Joachim Mayer, "Hydrolysis In Drug And Prodrug Metabolism: Chemistry , Biochemistry And Enzymology," John Wiley and Sons, Ltd. (2002). For example, those of formula (I) having free amino, amido, hydroxy or carboxyl groups. A compound can be converted into a prodrug. A prodrug is an amino acid residue, or a polypeptide chain of two or more (e.g., 2, 3 or 4) amino acid residues having the formula ( It includes compounds that are covalently bonded to the free amino, hydroxy or carboxyl group of the compound of I).Amino acid residues include, but are not limited to, the 20 naturally occurring amino acids commonly designated by three letter symbols, and also 4-hydroxy Includes proline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Also included are types of. For example, free carboxyl groups can be derivatized as amides or alkyl esters.Free hydroxy groups can be hemistones as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115. It can be derivatized using groups including, but not limited to, cinate, ethyl succinate, phosphate ester, dimethylaminoacetate, and phosphoryloxymethyloxycarbonyl. Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups. Also included are derivatizations of hydroxy groups, such as (acyloxy)methyl and (acyloxy)ethyl ether, where the acyl group may be an alkyl ester optionally substituted with groups including, but not limited to, ether, amine, and carboxylic acid functional groups, or The group is an amino acid ester as described above. Prodrugs of this type are described in [J. Med. Chem. 1996, 39, 10]. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All such prodrug moieties may contain groups including, but not limited to, ether, amine, and carboxylic acid functional groups.

The term “amino acid” refers to naturally occurring and synthetic α, β, γ, or δ amino acids, amino acids found in proteins, or intermediates in the metabolism of amino acids or proteins, such as glycine, alanine, valine, leucine, isoleucine, Includes, but is not limited to, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, glutamate, lysine, citrulline, arsinine, and histidine. In certain embodiments, the amino acids are in the L-configuration. In certain embodiments, the amino acids are in the D-configuration. In certain embodiments, an amino acid is provided as a substituent for a compound described herein, wherein the amino acid is alanyl, valinyl, leucinyl, isoleucinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl. , glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, ricinyl, arsinyl, histidinyl, β-ala Nyl, β-valinyl, β-leucinyl, β-isoleucinyl, β-prolinyl, β-phenylalaninyl, β-tryptophanyl, β-methioninyl, β-glycinyl, β-Serinyl, β-threoninyl, β-cysteinyl, β-tyrosinyl, β-asparaginyl, β-glutaminyl, β-aspartoyl, β-glutaroyl, β-lysyl. It is a residue selected from the group consisting of nyl, β-arsininyl, and β-histidinyl.

The term “amino acid derivative” refers to a group derivable from a natural or non-naturally occurring amino acid, as described and exemplified herein. Amino acid derivatives will be apparent to those skilled in the art and include, but are not limited to, esters, amino alcohols, amino aldehydes, amino lactones, and N-methyl derivatives of naturally occurring and non-naturally occurring amino acids. In an embodiment, an amino acid derivative is provided as a substituent for a compound described herein, wherein the substituent is -NR ^u -G(S _c )-C(O)-Q ¹ , wherein Q ¹ is -SR ^v , -NR ^v R ^v or alkoxyl, R ^v is hydrogen or alkyl, S _c is the side chain of a naturally occurring or non-naturally occurring amino acid, G is _Cl -C ₂ alkyl, and R ^u is hydrogen; R ^u and S _c together with the atoms to which they are attached form a 5-membered heterocyclic ring. In an embodiment, an amino acid derivative is provided as a substituent for a compound described herein, wherein the substituent is -OC(O)-G(S _c )-NH-Q ² , where Q ² is hydrogen or alkoxyl, and S _c is the side chain of a naturally occurring or non-naturally occurring amino acid, and G is C ₁ -C ₂ alkyl. In certain embodiments, Q ² and S _c together with the atoms to which they are attached form a 5-membered heterocyclic ring. In certain embodiments, G is optionally substituted methylene, and S _c is hydrogen, alkyl, arylalkyl, heterocycloalkyl, carboxylalkyl, heteroarylalkyl, aminoalkyl, hydroxylalkyl, aminoiminoaminoalkyl, aminocarbonylalkyl. , sulfanylalkyl, carbamoylalkyl, alkylsulfanylalkyl, and hydroxyarylalkyl. In embodiments, an amino acid derivative is provided as a substituent for a compound described herein, wherein the amino acid derivative is in the D-configuration. In embodiments, an amino acid derivative is provided as a substituent for a compound described herein, wherein the amino acid derivative is in the L-configuration.

pharmaceutical composition

Pharmaceutical compositions of the invention comprise a therapeutically effective amount of a compound of the invention formulated with one or more pharmaceutically acceptable carriers or excipients.

As used herein, the term “pharmaceutically acceptable carrier or excipient” means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation adjuvant of any type. Some examples of substances that can serve as pharmaceutically acceptable carriers include sugars such as lactose, glucose and sucrose; Starches such as corn starch and potato starch; Cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; Excipients such as cocoa butter and suppository wax; Oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; Glycols, such as propylene glycol; Esters, such as ethyl oleate and ethyl laurate; Buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; Isotonic saline solution; Ringer's solution; ethyl alcohol, and phosphate buffered solutions, as well as other non-toxic miscible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavoring and perfuming agents, preservatives and antioxidants. Isolates may also be present in the composition at the discretion of the manufacturer.

The pharmaceutical composition of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, vaginally or via an implanted reservoir, preferably by oral administration or injection. It can be administered by administration. The pharmaceutical compositions of the present invention may contain any conventional non-toxic pharmaceutically acceptable carrier, adjuvant or vehicle. In some cases, the pH of the formulation can be adjusted by pharmaceutically acceptable acids, bases, or buffers to improve the stability of the formulated compound or its delivery form. As used herein, the term parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

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

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions, suspensions or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, solutions in 1,3-butanediol. Among them, acceptable vehicles and solvents that can be used include water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. Additionally, sterile fixed oils are commonly used as solvents or suspending media. For this purpose, any bland fixed oil may be used, including synthetic mono- or diglycerides. Additionally, fatty acids, such as oleic acid, are used in injectable formulations.

Injectable preparations may be sterilized by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use, for example, by filtration through a bacteria-retaining filter.

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

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

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid formulations, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, for example sodium citrate or dicalcium phosphate and/or: a) filler or bulking agent, for example starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants, such as glycerol, d) Disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retardants, such as paraffin, f) absorption enhancers, such as quaternary ammonium compounds. , g) wetting agents, such as cetyl alcohol and glycerol monostearate, h) absorbents, such as kaolin and bentonite clay, and i) lubricants, such as talc, calcium stearate, magnesium stearate, mixed with solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. For capsules, tablets and pills, the dosage form may also include buffering agents.

Solid compositions of a similar type can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols, etc.

Solid dosage forms of tablets, confections, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents and may also be of composition that releases only the active ingredient(s) or, optionally, in a delayed manner, preferably in specific parts of the intestinal tract. Examples of embedding compositions that can be used include polymeric components and waxes.

Formulations for topical or transdermal administration of the compounds of the invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and, if necessary, any necessary preservatives or buffers. Ophthalmic preparations, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of the present invention.

Ointments, pastes, creams and gels may contain, in addition to the active compounds of the invention, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc. and zinc oxide, or mixtures thereof.

Powders and sprays may contain, in addition to the compounds of the invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powders, or mixtures of these ingredients. The spray may additionally contain certain conventional propellants, for example chlorofluorohydrocarbons.

Transdermal patches have the additional advantage of providing controlled delivery of compounds to the body. Such formulations can be prepared by dissolving or dispersing the compound in an appropriate medium. Absorption enhancers can also be used to increase the flux of compounds across the skin. The rate can be controlled by providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

For pulmonary delivery, the therapeutic compositions of the invention are formulated in the form of solid or liquid particles and administered to the patient by direct administration, for example, by inhalation into the respiratory system. The solid or liquid particle forms of the active compounds prepared for the practice of the present invention include particles of respirable size, that is, particles of sufficiently small size to pass through the oral cavity and larynx and into the bronchi and alveoli by inhalation. The delivery of aerosolized therapeutics, particularly aerosolized antibiotics, is known in the art (e.g., U.S. Pat. No. 5,767,068 to Van Devanter et al ., U.S. Pat. No. 5,508,269 to Smith et al., and See WO 98/43650 (Montgomery), all of which are incorporated herein by reference).

antiviral activity

In certain embodiments, the present invention provides a method of treating or preventing a viral infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. Provides a method for including The viral infection is preferably a coronavirus infection. In certain embodiments, the coronavirus is SARS-CoV-1, SARS-CoV-2, or MERS-CoV. Preferably the coronavirus is SARS-CoV-2.

The viral inhibitory amount or dose of a compound of the invention may range from about 0.01 mg/Kg to about 500 mg/Kg, alternatively from about 1 to about 50 mg/Kg. The amount or dose of inhibition will also vary depending on the route of administration as well as the potential for co-use with other agents.

According to the treatment method of the present invention, viral infection is treated or prevented in a patient, for example a human or another animal, by administering a therapeutically effective amount of a compound of the present invention in the amount and for the time necessary to achieve the desired result.

A “therapeutically effective amount” of a compound of the present invention means that amount of compound that confers a therapeutic effect on the subject being treated with a reasonable benefit/risk ratio applicable to any medical treatment. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject's expression or feeling of an effect). Therapeutically effective amounts of the compounds described above may range, for example, from about 0.1 mg/Kg to about 500 mg/Kg, preferably from about 1 to about 50 mg/Kg. The effective dose will also vary depending on the route of administration as well as the possibility of co-use with other agents. However, it is understood that the total daily usage amount of the compounds and compositions of the present invention can be determined by the attending physician within the scope of sound medical judgment. The particular therapeutically effective dose level for any particular patient will depend on a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; The patient's age, weight, general health, gender and diet; Time of administration, route of administration, and excretion rate of the specific compound used; duration of treatment; Drugs used in combination or simultaneously with the specific compound used; It will depend on a variety of factors, including similar factors well known in the medical field.

The total daily dose of a compound of the invention administered in single or divided doses to a human or other animal may, for example, be in the amount of 0.01 to 50 mg/kg body weight or, more typically, 0.1 to 25 mg/kg body weight. A single dose composition may contain such amounts or multiples thereof to constitute a daily dose. Generally, treatment regimens according to the present invention include administering from about 10 mg to about 1000 mg of the compound(s) of the present invention per day in single or multiple doses to a patient in need of such treatment.

The compounds of the invention described herein may be administered, for example, by injection, intravenously, intraarterially, subcutaneously, intraperitoneally, intramuscularly, or subcutaneously; or orally, bucally, nasally, transmucosally, topically, in an ophthalmic formulation, or by inhalation, in dosages ranging from about 0.1 to about 500 mg/kg body weight, alternatively from 1 mg to 1000. Dosages of mg/dose may be administered every 4 to 120 hours, or depending on the needs of the particular drug. The methods herein contemplate administration of an effective amount of a compound or compound composition to achieve the desired or described effect. Typically, the pharmaceutical compositions of the invention will be administered from about 1 to about 6 times per day or, alternatively, by continuous infusion. This administration can be used as chronic or acute therapy. The amount of active ingredient that can be combined with a pharmaceutical excipient or carrier to prepare a single dosage form will vary depending on the host being treated and the particular mode of administration. A typical formulation will contain from about 5% to about 95% active compound (w/w). Alternatively, such preparations may contain from about 20% to about 80% active compound.

Lower or higher doses than those listed above may be required. The specific dosage and treatment regimen for any particular patient will depend on the activity of the particular compound used, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, severity and course of the disease, condition or symptoms; It will depend on a variety of factors, including the patient's predisposition to the disease, condition or symptoms, and the judgment of the treating physician.

Depending on the improvement of the patient's condition, maintenance doses of the compound, composition or combination of the present invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, depending on the symptoms, to a level where the improved condition is maintained when the symptoms are alleviated to the desired level. However, patients may require long-term intermittent treatment due to any recurrence of disease symptoms.

Combination and alternative therapies

The compounds of the present invention may be used in combination with one or more antiviral therapeutic agents or anti-inflammatory agents useful for the prevention or treatment of viral diseases or related pathophysiology. Accordingly, the compounds of the present invention and their salts, solvates, or other pharmaceutically acceptable derivatives thereof may be used alone or in combination with other antiviral or anti-inflammatory therapeutic agents. The compounds herein and pharmaceutically acceptable salts thereof may be combined with one or more other agents that may be useful in the prevention or treatment of respiratory, inflammatory, and autoimmune diseases, such as antihistamines, corticosteroids (e.g., Plutica Son propionate, fluticasone furoate, beclomethasone dipropionate, budesonide, ciclesonide, mometasone furoate, triamcinolone, flunisolide), NSAIDs, leukotriene modulators (e.g. Montel lukast, zafirlukast, pranlukast), tryptase inhibitors, IKK2 inhibitors, p38 inhibitors, Syk inhibitors, protease inhibitors such as elastase inhibitors, integrin antagonists (e.g. beta-2 integrin antagonists) ), adenosine A2a agonists, mediator release inhibitors such as sodium cromoglycate, 5-lipoxygenase inhibitor (zyflo), DP1 antagonist, DP2 antagonist, PI3K delta inhibitor, ITK inhibitor, LP (lysophosphatidic ) inhibitors or FLAP (5-lipoxygenase activating protein) inhibitors (e.g., sodium 3-(3-(tert-butylthio)-1-(4-(6-ethoxypyridin-3-yl)benzyl )-5-((5-ethylpyridin-2-yl)methoxy)-1H-indol-2-yl)-2,2-dimethylpropanoate), bronchodilator (e.g. muscarinic antagonist, beta -2 agonists), methotrexate, and similar agents; monoclonal antibody therapies such as anti-lgE, anti-TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1 and similar agents; Cytokine receptor therapies such as etanercept and similar agents; Antigen-nonspecific immunotherapies (e.g., interferons or other cytokines/chemokines, chemokine receptor modulators such as CCR3, CCR4 or CXCR2 antagonists, other cytokines/chemokine agonists or antagonists, TLR agonists and similar agents) , suitable drugs including antibiotics, antifungals, anthelmintics, antimalarials, antiprotozoal agents, antitubercular agents, and antiviral agents, including those listed on the site [https://www.drugs.com/drug-class/anti-infectives.html] It can be used in combination with anti-infective agents. In general, combination therapies are typically preferred over alternative therapies because they induce multiple stresses on the virus simultaneously.

When the combinations of the invention include a combination of a compound of the formula described herein and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent are administered at a dosage of about 1 to 100% of the dosage normally administered in a monotherapy regimen. , more preferably at a dosage level of about 5 to 95%. Additional agents may be administered separately from the compounds of the invention, as part of a multiple dose regimen. Alternatively, these agents may be part of a single formulation combined with a compound of the invention in a single composition.

“Additional therapeutic or prophylactic agent” includes immunotherapy (e.g. interferon), therapeutic vaccine, anti-fibrotic agent, anti-inflammatory agent, such as corticosteroid or NSAID, bronchodilator, such as beta-2 adrenergic agent. agents and xanthines (e.g. theophylline), mucolytics, antimuscarinics, anti-leukotrienes, inhibitors of cell adhesion (e.g. ICAM antagonists), antioxidants (e.g. N-acetylcysteine), Including, but not limited to, cytokine agonists, cytokine antagonists, pulmonary surfactants and/or antimicrobial and antiviral agents (e.g., ribavirin and amantidine). Compositions according to the invention can also be used in combination with gene replacement therapy.

abbreviation

Abbreviations that may be used in the description of the schemes and examples are as follows: Ac is acetyl; AcOH is acetic acid; Boc ₂ O is di- tert -butyl-dicarbonate; Boc is t -butoxycarbonyl; Bz is benzoyl; Bn is benzyl; t-BuOK is potassium tert -butoxide; Brine is a solution of sodium chloride in water; CDI is carbonyldiimidazole; DCM or CH ₂ Cl ₂ is dichloromethane; CH ₃ is methyl; CH ₃ CN is acetonitrile; Cs ₂ CO ₃ is cesium carbonate; CuCl is copper(I) chloride; CuI is copper(I) iodide; dba is dibenzylidene acetone; DBU is 1,8-diazabicyclo[5.4.0]-undec-7-ene; DEAD is diethylazodicarboxylate; DIAD is diisopropyl azodicarboxylate; DIPEA or (i-Pr) ₂ EtN is N,N,-diisopropylethyl amine; DMP or Dess-Martin periodinane is 1,1,2-tris(acetyloxy)-1,2-dihydro-1,2-benziodoxol-3-(1H)-one; DMAP is 4-dimethylamino-pyridine; DME is 1,2-dimethoxyethane; DMF is N,N-dimethylformamide; DMSO is dimethyl sulfoxide; EtOAc is ethyl acetate; EtOH is ethanol; Et ₂ O is diethyl ether; HATU is O-(7-azabenzotriazol-2-yl)-N,N,N',N',-tetramethyluronium hexafluoro-phosphate; HCl is hydrogen chloride; K ₂ CO ₃ is potassium carbonate; n -BuLi is n -butyl lithium; DDQ is 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; LDA is lithium diisopropylamide; LiTMP is lithium 2,2,6,6-tetramethyl-piperidinate; MeOH is methanol; Mg is magnesium; MOM is methoxymethyl; Ms is mesyl or -SO ₂ -CH ₃ ; NaHMDS is sodium bis(trimethylsilyl)amide; NaCl is sodium chloride; NaH is sodium hydride; NaHCO ₃ is sodium bicarbonate or sodium bicarbonate; Na ₂ CO ₃ is sodium carbonate; NaOH is sodium hydroxide; Na ₂ SO ₄ is sodium sulfate; NaHSO ₃ is sodium bisulfite or sodium hydrogen sulfite; Na ₂ S ₂ O ₃ is sodium thiosulfate; NH ₂ NH ₂ is hydrazine; NH ₄ Cl is ammonium chloride; Ni is nickel; OH is hydroxyl; OsO ₄ is osmium tetroxide; OTf is triflate; PPA is polyphosphoric acid; PTSA is p -toluenesulfonic acid; PPTS is pyridinium p -toluenesulfonate; TBAF is tetrabutylammonium fluoride; TEA or Et ₃ N is triethylamine; TES is triethylsilyl; TESCl is triethylsilyl chloride; TESOTf is triethylsilyl trifluoromethanesulfonate; TFA is trifluoroacetic acid; THF is tetrahydrofuran; TMEDA is N,N,N',N'-tetramethylethylene-diamine; TPP or PPh ₃ is triphenyl-phosphine; Tos or Ts is tosyl or -SO ₂ -C ₆ H ₄ CH ₃ ; Ts ₂ O is tolylsulfonic anhydride or tosyl-anhydride; TsOH is p-tolylsulfonic acid; Pd is palladium; Ph is phenyl; Pd ₂ (dba) ₃ is tris(dibenzylideneacetone)dipalladium(0); Pd(PPh ₃ ) ₄ is tetrakis(triphenylphosphine)-palladium(0); PdCl ₂ (PPh ₃ ) ₂ is trans-dichlorobis-(triphenylphosphine)palladium(II); Pt is platinum; Rh is rhodium; rt is room temperature; Ru is ruthenium; TBS is tert -butyl dimethylsilyl; TMS is trimethylsilyl; TMSCl is trimethylsilyl chloride.

synthesis method

The compounds and processes of the invention will be better understood in conjunction with the following synthetic schemes, which illustrate how the compounds of the invention may be prepared, which are intended to be illustrative only and are not intended to limit the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art, and such changes and modifications, including without limitation those relating to the chemical structure, substituents, derivatives, and/or methods of the present invention, are consistent with the technical spirit of the present invention and the accompanying This can be accomplished without departing from the scope of the claims.

Scheme 1 illustrates a general method for preparing compounds of formula (VI) .

In the above formula, R ₁ , R ₃ , n, R ₉ , R ₂₁ , R ₂₂ , R ₂₃ , and R ₂₄ are as defined above. Amide coupling of compound 1 and compound 2 under standard peptide coupling conditions provides compound 3 . Standard peptide coupling conditions are described in Chem. Rev. 2011, 111, 11, 6557-6602 by Ayman El-Faham and Fernando Albericio]. PG ₁ and PG ₂ are common protecting groups, such as, but not limited to, Cbz, Boc or Fmoc. PG ₁ and PG ₂ can be removed under standard deprotection conditions outlined in Greene's Protective Groups in Organic Synthesis, 5th Edition, Peter GM Wuts, Wiley 2014. After removal of the PG ₁ protecting group of compound 3 , compound 4 is obtained, and an amide coupling reaction is performed again with compound 5 using standard peptide coupling chemistry to obtain compound 6 . After removal of the PG ₂ protecting group, functionalization of the nitrogen group of compound 7 affords compound 8 with various R ₂₄ substitutions. Final conversion of the primary amide group of compound 8 to a CN group under dehydration conditions, such as but not limited to TFAA/NEt ₃ , Burgess reagent, and Pd(OCOCF ₃ ) ₂ /Cl ₂ CHCN, gives the formula ( VI) Compound 9 is provided.

Scheme 1

Alternatively, as shown in Scheme 2, compound 7 was reacted with the nitrile compound under standard dehydration conditions, such as but not limited to TFAA/NEt ₃ , Burgess reagent, and Pd(OCOCF ₃ ) ₂ /Cl ₂ CHCN. You can convert it to 10 first. Subsequent removal of the PG ₂ protecting group and introduction of R ₂₄ on NH forms compound 9 of formula (VI) .

Scheme 2

Scheme 3 illustrates a general method for preparing compounds of formula (V') .

In the above formula, R ₂₃ and R ₂₄ together with the N atom to which they are attached form an optionally substituted 3 to 8 membered heterocyclic or heteroaryl ring. After the amide coupling reaction, compound 14 can be synthesized from compound 4 and compound 12 through removal of the PG ₂ protecting group. The primary amine group of compound 14 can then be converted following literature procedures to a variety of optionally substituted 3 to 8 membered heterocyclic or heteroaryl rings to form compound 15 , which subsequently gives the compound of formula (V') Converted to 16 . Selected literature courses can be found in the following references: Huang, P.-Q.; Fan, T., European Journal of Organic Chemistry 2017, 43, 6369-6374; Dhingra, S.K.; Arora, S.K.; Singh, K.; Prasad, M.; Kumar, Y., WO 2006090265; Mochizuki, A.; Kishida, M.; Kanno, H., WO 2008111300; Chen, KX; Njoroge, F.; George; S.; Mousumi; N; Latha G.; et al, WO 2005085242; Sugiyama, S.; Morishita, K.; Chiba, M.; Ishii, K., Heterocycles 2002, 57, 637-648; Meng, G., Guo, T., Ma, T. et al., Nature 2019, 574, 86-89].

Scheme 3

Compounds of formula (VI')

As shown in Scheme 4, a suitable alkylating agent, such as, but not limited to, Me ₂ SO ₄ , MeI, alkyl iodide, alkyl bromide, allyl bromide and a suitable base, such as, but not limited to, It can be prepared from a compound of formula (VI') by reaction in the presence of K ₂ CO ₃ , NaH, or KOt-Bu.

Scheme 4

Alternatively, compounds of formula (VI') can be prepared from compound 21 following similar chemistry described above for compound 9 . Compound 21 can be obtained from compound 18 through alkylation, subsequent functional group modification and removal of the PG ₃ protecting group as shown in Scheme 5.

Scheme 5

Compounds of formula (VI")

can be prepared from aldehyde intermediate 25 using standard functional group modifications, where X is as defined above. Compound 18 is converted to alcohol compound 22 through reduction of the ester. The reducing agent may be, but is not limited to, LiBH ₄ , DIBAL, or NaBH ₄ . Removal of the PG group of compound 22 affords intermediate 23 , which is then converted to compound 24 using similar chemistry described above. Preparation of aldehyde 25 from alcohol intermediate 24 via oxidation of the OH group using conditions such as, but not limited to, IBX oxidation, Swern oxidation, Dessmartin oxidation, or Albright-Goldman oxidation. do. Compound 26 of formula ( VI ") can then be synthesized from aldehyde intermediate 25 using appropriate chemistry depending on the nature of Chem. 2020, 63, 4562-4578], WO 2020/030143, and J. Med. Chem. 2015, 58, 3144-3155.

Scheme 6

Example

The compounds and processes of the invention will be better understood in conjunction with the following examples, which are intended to be illustrative only and are not intended to limit the scope of the invention. Starting materials are available from commercial vendors or were prepared by methods well known to those skilled in the art.

General conditions:

Mass spectra were performed on an LC-MS system using electrospray ionization. These were Agilent 1290 Infinity II systems with Agilent 6120 Quadrupole detectors. Spectra were obtained using a ZORBAX Eclipse XDB-C18 column (4.6 x 30 mm, 1.8 micron). Spectra were obtained at 298 K using mobile phases of 0.1% formic acid in water (A) and 0.1% formic acid in acetonitrile (B). Spectra were obtained with the following solvent gradients: 5% over 0-1.5 minutes (B), 5-95% over 1.5-4.5 minutes (B), and 95% over 4.5-6 minutes (B). The solvent flow rate was 1.2 mL/min. Compounds were detected at wavelengths of 210 nm and 254 nm. [M+H] ⁺ represents the monoisotopic molecular weight.

NMR spectra were performed on a Bruker 400 MHz spectrometer. The spectrum was measured at 298 K and referenced using the solvent peak. Chemical shifts for ¹ H NMR are reported in parts per million (ppm).

Compounds were purified via reverse-phase high-performance liquid chromatography (RPHPLC) using a Gilson GX-281 automated liquid management system. Unless otherwise specified, compounds were purified on a Phenomenex Kinetex EVO C18 column (250 x 21.2 mm, 5 micron). Unless otherwise specified, compounds were purified using mobile phases of water (A) and acetonitrile (B) at 298 K using gradient elution from 0% to 100% (B). The solvent flow rate was 20 mL/min, and compounds were detected at a wavelength of 254 nm.

Alternatively, compounds were purified via normal phase liquid chromatography (NPLC) using a Teledyne ISCO Combiflash purification system. Compounds were purified on REDISEP silica gel cartridges. The compound was purified at 298 K and detected at a wavelength of 254 nm.

Example 1 :

Step 1-3: Synthesis of (3R,5'S)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide hydrochloride

Stages 1 and 2: J. Med. Chem. Compound 1-2 was prepared according to the procedure reported in the literature as described in [2012, 55, 9069 ].

Step 3: Water (90 mL) was added in one portion to a clear solution of compound 1-2 (45.0 g, 136 mmol) in THF (720 mL) in a three-necked 2000 mL flask at 0°C. Acetic acid (54.6 mL, 953 mmol) was added at 0°C. The cloudy mixture was cooled to -30°C. A solution of NBS (24.24 g, 136 mmol) in THF/H ₂ O (8/1, 207 mL) was added dropwise over 30 min while maintaining the internal temperature below -30°C. The milky white mixture became a cloudy yellow solution, which was stirred at -30°C (internal temperature) for 1.0 hours. The cloudy yellow solution was allowed to heat to -20°C and added under stirring to a mixture of cold water (~300 mL), saturated NaHCO ₃ solution (~400 mL) and potassium carbonate (65.9 g, 477 mmol) in EtOAc (300 mL). Divided and poured. The mixture was further diluted with EtOAc (500 mL). The aqueous layer was extracted with EtOAc (1x). The combined organic layers were washed with brine (1x), dried over Na ₂ SO ₄ , filtered, and concentrated to give the crude product as a sticky pale yellow oil (56.0 g). The crude product was dissolved in DCM (60 mL) and filtered through a 330 g silica gel column (MTBE/cyclohexane) to give the desired product 1-3 as an off-white foam (48.20 g, 102%). ¹ H NMR (400 MHz, DMSO-d ₆ ) showed dr 10/1 ( 1-3a / 1-3b ).

Step 4: A clear, colorless solution of compound 1-3 (48.20 g, 139 mmol, dr 10/1) in 7 N ammonia in MeOH (400 mL) was stirred at 45°C in a sealed tube for 4 days. The mixture was allowed to cool and concentrated. The solid was dried under vacuum to yield the desired compound 1-4 as a yellow solid (42.80 g, 93%). ¹ H NMR (400 MHz, DMSO-d ₆ ) showed dr 10/1 ( 1-4a / 1-4b ).

Step 5: To a clear solution of compound 1-4 (42.80 g, 129 mmol, dr 10/1) in DMF (85 mL) at room temperature was added 4 M HCl (323 mL, 1292 mmol) in 1,4-dioxane. did. The obtained transparent, light yellow solution was stirred at room temperature for 2.5 hours and concentrated using a rotary evaporator. The obtained clear solution was poured into DCM (1700 mL) under stirring to form a slurry. The precipitated solid was collected by filtration and washed with DCM (x2). The solid was dried under vacuum to yield crude 1-5 as a pale yellow solid (35.20 g, 102%).

Recrystallization: 3 g of the crude compound 1-5 was mixed with DMF (9 mL) and heated to form an almost clear solution. During heating, solids began to appear. The mixture was allowed to cool to room temperature. The precipitated solid was collected by filtration and washed with DMF (1 mL) and DCM (2x). The solid was dried under vacuum to yield the desired product compound 1-5 as a white solid (2.14 g). ¹ H NMR (400 MHz, DMSO-d ₆ ) showed a clean product with ~0.9 equivalents of DMF and no minor diastereomers. ^1H NMR (400 MHz, DMSO- d ₆ ) δ 11.14(brs, 1H), 10.81(s, 1H), 9.08(brs, 1H), 8.07(s, 1H), 7.78(s, 1H), 7.66( d, J = 7.4 Hz, 1H), 7.27(td, J = 7.7, 1.2 Hz, 1H), 7.04(td, J = 7.6, 1.1 Hz, 1H), 6.92(d, J = 7.7 Hz, 1H), 4.65(dd, J = 11.2, 7.1 Hz, 1H), 3.59(d, J = 12.3 Hz, 1H), 3.45(d, J = 12.3 Hz, 1H), 2.50(dd, J = 12.9, 11.2 Hz, 1H ), 2.22(dd, J = 12.9, 11.2 Hz, 1H).

Step 6-9: Synthesis of Example 1

Step 6: Compound 1-5 (5 g, 14.90 mmol) and N-((benzyloxy)carbonyl)-N-methyl-L in anhydrous CH ₂ Cl ₂ (60 mL) and DMF (10 mL) at 0°C. -4-Methylmorpholine (4.92 mL, 44.7 mmol) and HATU (5.84 g, 15.35 mmol) were added to a mixture of leucine (4.29 g, 15.35 mmol). The resulting mixture was stirred at 0°C for 30 minutes and then at room temperature for 1 hour. The reaction mixture was diluted with DCM (100 mL) and washed sequentially with 5% NaHCO ₃ (100 mL), water (100 mL), and brine (100 mL). The collected organic layer was dried over Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by silica gel chromatography (0 - 10% MeOH/DCM) to give the desired compound 1-6 (5.33 g, 10.82 mmol, 72.6% yield) as a white solid. LC-MS, ES+: 493.14 [M+1].

Step 7: To a solution of compound 1-6 (4.0 g, 7.63 mmol) in MeOH (76 mL) was added 10% Pd-C (0.406 g, 0.382 mmol). The mixture was stirred under H ₂ balloon for 60 minutes. The mixture was then filtered through Celite and concentrated under vacuum to obtain compound 1-7 (2.7 g, 7.53 mmol, 99% yield), which was used in the next step without further purification.

Step 8: Compound 1-7 (300 mg, 0.837 mmol) and (S)-2-(((benzyloxy)carbonyl)amino in anhydrous CH ₂ Cl ₂ (7 mL) and DMF (1.4 mL) at 0°C. )-3-(4-Fluorophenyl)propanoic acid (279 mg, 0.879 mmol) was added to 4-methylmorpholine (184 μl, 1.674 mmol) and HATU (350 mg, 0.921 mmol). The resulting mixture was stirred at 0°C for 30 minutes and then at room temperature for several hours until LC-MS indicated the reaction was complete. The reaction mixture was diluted with DCM and washed with 5% NaHCO ₃ , water, and brine. The collected organic layer was dried over Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by silica gel chromatography (0 - 10% MeOH/DCM) to give the desired compound 1-8 (400 mg, 0.61 mmol, 73% yield) as a white solid. LC-MS, ES ⁺ : 658.26 [M+1].

Step 9: TFAA (17.75 μl, 0.128 mmol) was added to a solution of compound 1-8 (28 mg, 0.043 mmol) and triethylamine (35.6 μl, 0.255 mmol) in anhydrous CH ₂ Cl ₂ (1 mL) at 0°C. It was added dropwise. The mixture was then stirred at 0°C for 30 - 60 minutes until LC-MS indicated the reaction was complete. The reaction mixture was diluted with DCM, washed with 10% aqueous NaHCO ₃ , brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography (0 - 40% acetone/cyclohexane) to give Example 1 (18 mg, 0.028 mmol, 66.1% yield). LC-MS, ES ^- : 638.1 [MH]. ¹ H NMR (400 MHz, acetone- d ₆ ) δ 9.73 (s, 1H), 7.35 - 7.28 (m, 2H), 7.25 - 7.18 (m, 2H), 7.17 (dt, J = 7.9, 4.5 Hz, 1H ), 7.10 - 6.92(m, 3H), 6.40(d, J = 9.0 Hz, 1H), 5.45(dd, J = 9.3, 5.8 Hz, 1H), 5.21(t, J = 8.5 Hz, 1H), 4.95 (d, J = 2.2 Hz, 2H), 4.63(td, J = 9.7, 4.0 Hz, 1H), 4.04(d, J = 10.7 Hz, 1H), 3.96(d, J = 10.6 Hz, 1H), 3.15 (s, 3H), 2.82 - 2.63(m, 2H), 2.44(dd, J = 14.2, 10.3 Hz, 1H), 2.31(dd, J = 14.3, 4.1 Hz, 1H), 1.78(ddd, J = 14.2) , 9.3, 5.0 Hz, 1H), 1.66(ddd, J = 14.1, 8.8, 5.8 Hz, 1H), 1.53(dd, J = 13.3, 6.9 Hz, 1H), 0.95(d, J = 6.6 Hz, 3H) , 0.88(d, J = 6.5 Hz, 3H).

Example 2

Step 1: A mixture of compound 1-8 (370 mg, 0.563 mmol) and 10% Pd-C (29.9 mg, 0.028 mmol) in MeOH (5.63 mL) was stirred under H ₂ balloon for 60 min. The mixture was filtered through Celite and concentrated under vacuum to obtain compound 2-1 (290 mg, 98% yield), which was used directly without further purification. LC-MS, ES ⁺ : 524.13 [M+1].

Step 2: TFAA (31.9 μl, 0.229 mmol) was added dropwise to a solution of compound 2-1 (30 mg, 0.057 mmol) and triethylamine (63.9 μl, 0.458 mmol) in CH ₂ Cl ₂ (1.146 mL) at 0°C. did. The mixture was stirred at 0°C for ˜30 min and then at room temperature for ˜60 min. The reaction mixture was then diluted with DCM, washed with 10% aqueous NaHCO ₃ , brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography (0 - 50% acetone/cyclohexane) to give Example 2 (22 mg, 0.037 mmol, 63.8% yield). LC-MS, ES ^- : 600.0 [MH]. ¹ H NMR (400 MHz, acetone- d ₆ ) δ 9.77 (s, 1H), 8.41 (d, J = 8.4 Hz, 1H), 7.31 - 7.23 (m, 2H), 7.19 (ddd, J = 7.7, 6.9 , 2.0 Hz, 1H), 7.12 - 7.02(m, 4H), 6.97(dt, J = 7.8, 0.9 Hz, 1H), 5.45(dd, J = 9.3, 5.9 Hz, 1H), 5.22(t, J = 8.5 Hz, 1H), 4.96(td, J = 9.0, 4.8 Hz, 1H), 4.05(d, J = 10.6 Hz, 1H), 3.99(d, J = 10.5 Hz, 1H), 3.20(s, 3H) , 2.80 - 2.64(m, 2H), 2.64 - 2.47(m, 2H), 1.80(ddd, J = 14.4, 9.3, 5.2 Hz, 1H), 1.70(ddd, J = 14.2, 8.6, 5.9 Hz, 1H) , 1.58 - 1.43(m, 1H), 0.92(dd, J = 26.3, 6.6 Hz, 6H).

Example 3

Methyl chloroformate (4.43 μl, 0.057 mmol) was added to a solution of compound 2-1 (30 mg, 0.057 mmol) and triethylamine (63.9 μl, 0.458 mmol) in CH ₂ Cl ₂ (1.146 mL) at 0°C. did. After stirring at 0°C for 45 minutes, TFAA (31.9 μl, 0.229 mmol) was added dropwise. After stirring at 0°C for 30 min, the reaction was stirred at room temperature for -60 min.

Work-up: The reaction mixture was diluted with DCM, washed with 10% aqueous NaHCO ₃ , brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography (0 - 50% acetone/cyclohexane) to give Example 3 (5 mg, 15% yield). LC-MS, ES ^- : 562.0 [MH]. ¹ H NMR (400 MHz, acetone- d ₆ ) δ 9.60 (s, 1H), 7.08 (dt, J = 12.9, 4.8 Hz, 2H), 7.01 (td, J = 5.2, 2.6 Hz, 1H), 6.93 - 6.85(m, 4H), 6.80(d, J = 7.7 Hz, 1H), 6.11(d, J = 8.9 Hz, 1H), 5.29(dd, J = 9.2, 6.0 Hz, 1H), 5.06(t, J = 8.5 Hz, 1H), 4.45(td, J = 9.6, 4.1 Hz, 1H), 3.88(d, J = 10.7 Hz, 1H), 3.81(d, J = 10.6 Hz, 1H), 3.31(s, 3H) ), 3.00(s, 3H), 2.63 - 2.45(m, 2H), 2.27(dd, J = 14.3, 10.1 Hz, 1H), 2.16(dd, J = 14.2, 4.2 Hz, 1H), 1.61(dt, J = 8.8, 5.1 Hz, 1H), 1.57 - 1.47 (m, 1H), 1.43-1.36 (m, 1H), 0.78 (dd, J = 24.7, 6.5 Hz, 6H).

Example 4

Step 1: Compound 2-1 (25 mg, 0.048 mmol) and 5-methylisoxazole-3-carboxylic acid (6.37 mg, 0.050 mmol) were dissolved in CH ₂ Cl ₂ (0.40 mL) and DMF (0.10 mL) . 4-Methylmorpholine (10.50 μl, 0.095 mmol) and HATU (19.97 mg, 0.053 mmol) were added at 0°C. After stirring at 0° C. for 1 hour, the reaction mixture was diluted with DCM, washed with 5% NaHCO ₃ , brine, dried over Na ₂ SO ₄ and concentrated in vacuo. Crude compound 4-1 was used directly in the next step without further purification. LC-MS, ES ⁺ : 633.20 [M+H].

Step 2: Compound 4-1 (0.030 g, 0.048 mmol) was dissolved in CH ₂ Cl ₂ (0.96 mL). Triethylamine (0.040 mL, 0.288 mmol) and TFAA (0.020 mL, 0.144 mmol) were added at 0°C. The mixture was stirred at 0°C for ˜30 min and then at room temperature for ˜60 min. 28% ammonia in water (19 uL, 0.29 mmol) was added. After stirring at room temperature for a further 1 hour, the reaction mixture was diluted with CH ₂ Cl ₂ , washed with water, brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography (0 - 50% acetone/cyclohexane) to give Example 4 (22 mg, 75% yield over 2 steps). LC-MS, ES ⁺ : 615.2 [M+H]. ¹ H NMR (400 MHz, acetone-d ₆ ) δ 9.76 (s, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.30 - 7.22 (m, 2H), 7.18 (td, J = 7.3, 2.0 Hz, 1H), 7.11 - 6.91(m, 5H), 6.35(s, 1H), 5.45(dd, J = 9.2, 6.0 Hz, 1H), 5.24(t, J = 8.5 Hz, 1H), 5.10(td) , J = 8.9, 4.3 Hz, 1H), 4.07(d, J = 10.7 Hz, 1H), 4.00(d, J = 10.6 Hz, 1H), 3.23(s, 3H), 2.83 - 2.65(m, 3H) , 2.57(dd, J = 14.2, 4.3 Hz, 1H), 2.44(s, 3H), 1.87 - 1.63(m, 2H), 1.63 - 1.48(m, 1H), 0.91(dd, J = 25.8, 6.6 Hz) , 6H).

Example 5

Steps 1-4: Example 5 was prepared following a procedure similar to that described in Example 1 . ES ^- : 651.99 [MH].

Example 6

Step 1: Compound 5-4 (237 mg, 0.363 mmol) was dissolved in MeOH (4.53 mL). 10% Pd-C (19.29 mg, 0.018 mmol) was added. The mixture was stirred under H ₂ (balloon) for 60 minutes. The mixture was filtered through Celite and concentrated under vacuum to obtain compound 6-2 (187 mg, 0.360 mmol, 99% yield), which was used in the next step without further purification. LC-MS, ES ⁺ : 520.24 [M+H].

Step 2: Compound 6-2 (20 mg, 0.038 mmol) was dissolved in CH ₂ Cl ₂ (0.77 mL). Triethylamine (16.09 μl, 0.115 mmol) and TFAA (8.03 μl, 0.058 mmol) were added at 0°C. The mixture was stirred at 0°C for -45 minutes. The reaction mixture was diluted with DCM, washed with 10% aqueous NaHCO ₃ , brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography (0 - 50% acetone/cyclohexane) to give Example 6 . LC-MS, ES ^- : 614.06 [MH]. ¹ H NMR (400 MHz, acetone- d ₆ ) δ 9.78 (s, 1H), 8.41 (d, J = 8.9 Hz, 1H), 7.25 (ddd, J = 8.4, 5.3, 2.5 Hz, 2H), 7.18 ( ddd, J = 7.7, 5.1, 3.8 Hz, 1H), 7.11 - 7.01(m, 4H), 6.98(dt, J = 7.7, 0.9 Hz, 1H), 5.50(dd, J = 6.8, 5.7 Hz, 1H) , 5.22(t, J = 8.6 Hz, 1H), 4.94(td, J = 9.0, 5.6 Hz, 1H), 4.07(d, J = 10.5 Hz, 1H), 4.00(d, J = 10.5 Hz, 1H) , 3.21(s, 3H), 2.80 - 2.67(m, 2H), 2.49 - 2.42(m, 2H), 2.17 - 2.11(m, 1H), 1.56(dd, J = 14.2, 5.7 Hz, 1H), 0.94 (s, 9H).

Example 7

Compound 6-2 (20 mg, 0.038 mmol) and 4,6,7-trifluoro-1H-indole-2-carboxylic acid (9.11 mg, 0.042 mmol) were dissolved in CH ₂ Cl ₂ (0.321 mL) and DMF (0.064 mL). ) was dissolved in 4-Methylmorpholine (8.46 μl, 0.077 mmol) and HATU (16.83 mg, 0.044 mmol) were added at 0°C. The mixture was stirred at 0° C. to room temperature for 1 hour. The reaction mixture was diluted with DCM and washed with brine. The organic layer was dried over Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by silica gel chromatography (0 - 50% acetone/cyclohexane) to give Example 7 (20 mg, 0.028 mmol, 72.5% yield). LC-MS, ES ^- : 715.09 [MH]. ¹ H NMR (400 MHz, acetone- d ₆ ) δ 11.41 (s, 1H), 9.79 (s, 1H), 7.88 (d, J = 9.0 Hz, 1H), 7.28 (td, J = 5.6, 2.5 Hz, 3H), 7.20(ddd, J = 7.7, 5.9, 3.1 Hz, 1H), 7.13 - 7.08(m, 2H), 7.03 - 6.96(m, 3H), 6.90(ddd, J = 11.3, 9.6, 5.2 Hz, 1H), 5.53(dd, J = 7.0, 5.5 Hz, 1H), 5.23(t, J = 8.6 Hz, 1H), 5.12(ddd, J = 10.8, 9.0, 3.8 Hz, 1H), 4.11(d, J = 10.6 Hz, 1H), 4.01(d, J = 10.5 Hz, 1H), 3.24(s, 3H), 2.79 - 2.66(m, 2H), 2.50(dd, J = 14.2, 10.9 Hz, 1H), 2.39 (dd, J = 14.2, 3.9 Hz, 1H), 2.15(dd, J = 14.2, 7.0 Hz, 1H), 1.52(dd, J = 14.1, 5.5 Hz, 1H), 0.92(s, 9H).

Example 8

To a solution of compound 6-2 (20 mg, 0.038 mmol) in anhydrous CH ₂ Cl ₂ (0.77 mL) at 0°C was added triethylamine (21.46 μl, 0.154 mmol), followed by isocyanatocyclopropane (3.49 μl). , 0.050 mmol) was added. The mixture was stirred at 0°C for 1 hour. The reaction mixture was diluted with DCM and washed with 5% NaHCO ₃ . The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel chromatography (0 - 50% acetone/cyclohexane) to give Example 8 (16 mg, 0.027 mmol, 69.0% yield). LC-MS, ES ^- : 601.13 [MH]. ¹ H NMR (400 MHz, acetone- d ₆ ) δ 9.79 (s, 1H), 7.20-7.12 (m, 3H), 7.08 - 6.92 (m, 5H), 5.63 (s, 1H), 5.56 (d, J = 9.1 Hz, 1H), 5.48(dd, J = 7.0, 5.5 Hz, 1H), 5.21(t, J = 8.6 Hz, 1H), 4.78(td, J = 9.1, 4.9 Hz, 1H), 4.06(dd , J = 10.5, 1.2 Hz, 1H), 3.98(d, J = 10.4 Hz, 1H), 3.17(s, 3H), 2.79 - 2.63(m, 2H), 2.39 - 2.24(m, 3H), 2.18 - 2.11(m, 1H), 1.51(dd, J = 14.2, 5.5 Hz, 1H), 0.94(s, 9H), 0.64 - 0.46(m, 2H), 0.29(ddt, J = 5.9, 3.8, 2.2 Hz, 2H).

Example 9

Step 1: N ₃ SO ₂ F solution was prepared as described in Meng, G., Guo, T., Ma, T. et al. It was prepared according to the process reported in Nature 574, 86-89 (2019). In a plastic tube, ACN (0.4 mL, 1/10 the amount of water) was added to a solution of sodium azide (100 mg, 1.538 mmol) in H ₂ O (4.05 mL) and MTBE (4.05 mL) at 0°C. Solid 1-(fluorosulfonyl)-2,3-dimethyl-1H-imidazole-3-ium trifluoromethanesulfonate (606 mg, 1.846 mmol) was added. The mixture was stirred vigorously at 0°C for 10-15 minutes. After standing at room temperature for ∼30 min, the organic phase was separated and kept in a loosely sealed plastic bottle at room temperature for at least 12 hours. After standing for >12 hours, the red aqueous layer was removed from the bottle. The desired product was diluted with MTBE to a total volume of 5.1 mL to prepare a 0.3 MN ₃ SO ₂ F solution and stored at 4°C away from light.

Step 2: Meng, G., Guo, T., Ma, T. et al. The amine was converted to an azide according to the procedure reported in Nature 574 , 86-89 (2019). To a solution of compound 6-2 (85 mg, 0.164 mmol) in DMF (0.61 mL) at room temperature was added a 0.3 M solution (1063 μl, 0.213 mmol) of the formed sulfurazidic fluorideine MTBE, followed by KHCO ₃ (water 3.0 M, 218 μl, 0.654 mmol) was added. The resulting suspension was stirred at room temperature for -30 minutes. The mixture was diluted with EtOAc, washed with saturated NaHCO ₃ , water, brine, dried and concentrated to give crude azide compound 9-1 (82 mg, 0.150 mmol, 92% yield), which was used in the next step. I used it directly. LC-MS, ES ^- ( m/z ): 544.1 [MH].

Step 3: Potassium carbonate (15.18 mg, 0.110 mmol) and sodium ascorbate (6.10 mg, 0.031 mmol), CuSO ₄ .5H ₂ O (3.84 mg, 0.015 mmol) in water (0.34 mL)/DMF (0.34 mL) and Compound 9-1 (24 mg, 0.044 mmol) was added to a mixture of cyclopropylacetylene (14.89 μl, 0.176 mmol). The reaction mixture was heated at 55° C. for 60 minutes and then cooled to room temperature. The reaction mixture was diluted with EtOAc, washed with saturated NaHCO ₃ , water, brine, dried and concentrated. The residue was purified by silica gel chromatography (0 - 70% EtoAc/cyclohexane) to give Example 9 (12 mg, 0.02 mmol, 45% yield). LC-MS, ES ^- : 610.19 [MH]. ¹ H NMR (400 MHz, acetone- d ₆ ) δ 9.79 (s, 1H), 7.63 (s, 1H), 7.23 (dtd, J = 24.0, 7.6, 1.2 Hz, 2H), 7.13 - 6.87 (m, 6H) ), 5.73(dd, J = 11.1, 4.4 Hz, 1H), 5.47(t, J = 6.3 Hz, 1H), 5.22(t, J = 8.6 Hz, 1H), 4.21(d, J = 10.6 Hz, 1H) ), 4.00(d, J = 10.5 Hz, 1H), 3.16(s, 3H), 3.12 - 3.00(m, 1H), 2.79 - 2.66(m, 2H), 2.64 - 2.53(m, 1H), 2.05 - 1.98(m, 1H), 1.87(ddd, J = 8.4, 6.8, 4.3 Hz, 1H), 1.48(dd, J = 14.3, 6.2 Hz, 1H), 0.87 - 0.83(m, 2H), 0.83(s, 9H), 0.70 - 0.60(m, 2H).

Example 10

Step 1. Compound 1-5 (400 mg, 1.192 mmol) and Boc-Freidinger lactam (394 mg, 1.252 mmol) were added in CH ₂ Cl ₂ (4.97 mL) and DMF (0.994 mL) at 0°C. did. At 0°C, 4-methylmorpholine (393 μl, 3.58 mmol) and HATU (499 mg, 1.312 mmol) were added. The reaction was stirred at 0°C for ~30 min and then heated to room temperature and stirred for 90 min. The mixture was diluted with DCM and washed with water and brine. The collected organic layer was dried over MgSO ₄ and concentrated under vacuum. The residue was purified by silica gel chromatography (0 - 10% MeOH in DCM) to give the desired compound 10-1 (600 mg, 1.137 mmol, 95% yield) as a white solid. LC-MS, ES ⁺ : 528.15 [M+H].

Step 2: To a solution of compound 10-1 (188 mg, 0.356 mmol) in CH ₂ Cl ₂ (3.56 mL) at 0° C. was added triethylamine (298 μl, 2.138 mmol), followed by TFAA (149 μl, 1.069 mmol). ) was added. The mixture was stirred at 0°C for -45 minutes. The reaction mixture was diluted with DCM, washed with 10% aqueous NaHCO ₃ , brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography (0-40% acetone/cyclohexane) to give the desired compound Example 10 (82 mg, 45% yield). LC-MS, ES ⁺ : 510.12 [M+H].

Example 55

Step 1: (S)-2-(((benzyloxy)carbonyl)amino)-3,3-dimethylbutanoic acid (305 mg, 1.150 mmol) and methyl L-prolinate hydrochloride (209 mg, 1.265 mmol) ) was dissolved in CH ₂ Cl ₂ (5.75 mL). DIPEA (531 μl, 2.87 mmol) and HATU (481 mg, 1.265 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM and washed sequentially with 1 M HCl, 5% NaHCO ₃ , and brine. The organic layer was dried over MgSO ₄ and concentrated under vacuum. The residue was purified by silica gel chromatography using 0-100% EtOAc/cyclohexane to give compound 55-1 (316 mg, 0.839 mmol, 73.0% yield).

Step 2: Compound 55-1 (316 mg, 0.839 mmol) was dissolved in THF (5.60 mL) and water (2.80 mL). Lithium hydroxide hydrate (88 mg, 2.099 mmol) was added at 0°C. The mixture was stirred at 0°C for 2 hours and at room temperature for 30 minutes. The reaction was quenched with 1 M HCl (2 mL) and extracted with MTBE. The organic layer was dried over Na ₂ SO ₄ and concentrated under vacuum to give compound 55-2 (308 mg, 0.850 mmol, quantitative yield).

Step 3: Compound 55-2 (250 mg, 0.690 mmol) and Compound 1-5 (231 mg, 0.690 mmol) were dissolved in DCM (5 mL) and DMF (2 mL). 4-Methylmorpholine (283 μl, 2.069 mmol) and HATU (262 mg, 0.690 mmol) were added, and the mixture was stirred at room temperature for 90 minutes. The reaction mixture was diluted with DCM and washed sequentially with 1 M HCl, 5% NaHCO ₃ , and brine. The collected organic layer was dried over MgSO ₄ and concentrated under vacuum. The residue was purified by silica gel chromatography using 0-100% acetone/cyclohexane to obtain compound 55-3 (308 mg, 0.535 mmol, 78% yield). LC-MS, ES ⁺ : 576.3 [M+H].

Step 4: Compound 55-3 (308 mg, 0.535 mmol) was dissolved in DCM (3 mL). Triethylamine (447 μl, 3.21 mmol) and TFAA (227 μl, 1.605 mmol) were added at 0°C. The mixture was stirred at 0° C. for 20 min and quenched with 5% NaHCO ₃ . The organic layer was loaded onto silica gel and eluted with 0-50% acetone/cyclohexane to give Example 55 (282 mg, 0.506 mmol, 95% yield). LC-MS, ES+: 580.26 [M+Na ⁺ ]; ¹ H NMR (400 MHz, acetone- d ₆ ) δ 9.67 (s, 1H), 7.51 - 7.34 (m, 2H), 7.34 (t, J = 0.9 Hz, 2H), 7.34 - 7.27 (m, 1H), 7.31 - 7.22 (m, 2H), 7.08 - 6.96 (m, 2H), 6.17 (d, J = 9.4 Hz, 1H), 5.09 (td, J = 9.7, 3.0 Hz, 2H), 5.03 - 4.93 (m, 1H), 4.63(t, J = 6.9 Hz, 1H), 4.39(d, J = 9.4 Hz, 1H), 4.29(d, J = 10.2 Hz, 1H), 4.02(m, 1H), 3.91(s, 1H), 3.82 - 3.74(m, 1H), 2.78 - 2.58(m, 2H), 2.32(s, 1H), 2.19(s, 1H), 2.01(m, 2H), 1.11(s, 9H).

Example 56

Example 55 (282 mg, 0.506 mmol) was dissolved in MeOH (5 mL). 10% Pd-C (26.9 mg, 0.025 mmol) was added. The mixture was stirred under hydrogen (balloon) for 1 hour. The mixture was filtered through Celite and concentrated under vacuum to give Example 56 (199 mg, 0.470 mmol, 93% yield) as a white solid. LC-MS, ES ⁺ : 424.29 [M+H]; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.68 (s, 1H), 7.30 - 7.17 (m, 2H), 7.01 - 6.86 (m, 2H), 5.07 (dd, J = 8.5, 6.9 Hz, 1H ), 4.53(dd, J = 8.3, 5.2 Hz, 1H), 4.09(d, J = 10.4 Hz, 1H), 3.89(d, J = 10.4 Hz, 1H), 3.83 - 3.66(m, 1H), 3.56 (dt, J = 9.8, 6.9 Hz, 1H), 3.17(m, 1 H), 2.67 - 2.57(m, 1H), 2.47(dd, J = 13.1, 6.9 Hz, 1H), 2.26 - 2.11(m, 1H), 2.00(dt, J = 12.7, 6.7 Hz, 1H), 1.81(dtd, J = 33.8, 12.2, 6.7 Hz, 2H), 0.95(s, 9H).

Example 57

Example 56 (20 mg, 0.047 mmol) was dissolved in DCM (0.472 mL). Hunigg's base (24.74 μl, 0.142 mmol) and benzenesulfonyl chloride (7.25 μl, 0.057 mmol) were added. The mixture was stirred at room temperature for 10 minutes, quenched with 5% NaHCO ₃ and extracted with DCM. The organic layer was loaded onto silica gel and eluted with 0-50% acetone/cyclohexane to give Example 57 (24 mg, 0.043 mmol, 90% yield). LC-MS, ES ⁺ : 586.23 [M+Na ⁺ ].

Example 58

Example 56 (20 mg, 0.047 mmol) was dissolved in DCM (0.472 mL). Hunigg's base (24.74 μl, 0.142 mmol) and 4-fluorobenzoyl chloride (6.70 μl, 0.057 mmol) were added. The mixture was stirred at room temperature for 10 minutes, quenched with 5% NaHCO ₃ and extracted with DCM. The organic layer was loaded onto silica gel and eluted with 0-50% acetone/cyclohexane to give Example 58 (22 mg, 0.040 mmol, 85% yield). LC-MS, ES ⁺ : 568.24 [M+Na].

Example 59

Example 56 (20 mg, 0.047 mmol) was dissolved in DCM (0.472 mL). Huunig's base (24.74 μl, 0.142 mmol) and a 1.0 M solution of isopropyl carbonochloridate in toluene (56.7 μl, 0.057 mmol) were added. The mixture was stirred at room temperature for 10 minutes, quenched with 5% NaHCO ₃ and extracted with DCM. The organic layer was loaded onto silica gel and eluted with 0-50% acetone/cyclohexane to give Example 59 (22 mg, 0.043 mmol, 91% yield). LC-MS, ES ⁺ : 532.25 [M+Na].

Example 60

Example 56 (22 mg, 0.052 mmol) was dissolved in DCM (0.519 mL). (Isocyanatomethyl)benzene (7.70 μl, 0.062 mmol) was added. The mixture was stirred at room temperature for 20 minutes, loaded on silica gel and eluted with 0-50% acetone/cyclohexane to give Example 60 (28 mg, 0.050 mmol, 97% yield). LC-MS, ES ⁺ : 579.27 [M+Na ⁺ ].

Example 61

Example 56 (22 mg, 0.052 mmol) was dissolved in DCM (0.519 mL). 2,4,5-trifluorobenzaldehyde (8.91 μl, 0.078 mmol) was added. The mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (1 M in THF) (51.9 μl, 0.052 mmol) was added. The mixture was stirred at room temperature for 30 minutes, quenched with 5% NaHCO ₃ and extracted with DCM. The organic layer was loaded onto silica gel and eluted with 0-50% acetone/cyclohexane to give Example 61 (8.6 mg, 0.015 mmol, 29.2% yield). LC-MS, ES ⁺ : 568.25 [M+H].

Example 62

Step 1: Compound 1-5 (1.7 g, 5.07 mmol) and (S)-2-((tert-butoxycarbonyl)amino in anhydrous CH ₂ Cl ₂ (17 mL) and DMF (3 mL) at 0°C. )-4-Methylmorpholine (1.67 mL, 15.2 mmol) and HATU (2.119 g, 5.57 mmol) were added to a mixture of -4,4-dimethylpentanoic acid (1.367 g, 5.57 mmol). The resulting mixture was stirred at 0°C for ~30 min and then at room temperature for several hours until LC-MS indicated the reaction was complete. The reaction mixture was diluted with DCM, washed with 5% NaHCO ₃ , water, brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel chromatography (0 - 10% MeOH/DCM) to give the desired compound 62-1 (1.7 g, 3.71 mmol, 73.2% yield) as a white solid. LC-MS, ES+: 456.3 [M+1].

Step 2: Compound 62-1 (1.0 g, 2.181 mmol) was added to 4 M HCl (10.90 ml, 43.6 mmol) at 0°C. After stirring for 15 minutes, the ice bath was removed and stirred at room temperature for 15 minutes. MTBE (60 mL) was added to the reaction mixture. The white precipitate obtained was collected by filtration under N ₂ and washed with MTBE (3x). The collected solid was further dried under high vacuum to obtain the desired compound 62-2 (860 mg, 2.15 mmol, 100% yield) as an excellent solid. LC-MS, ES+: 359.49 [M+H].

Step 3: (S)-2-(((benzyloxy)carbonyl)amino)-3-(4-fluorophenyl)propanoic acid (0.726 g, HATU (0.912 g, 2.398 mmol) was added to a solution of 2.289 mmol) and 4-methylmorpholine (0.959 ml, 8.72 mmol). The reaction mixture was stirred at room temperature for -20 minutes and then cooled to 0°C. Compound 62-2 (0.86 g, 2.18 mmol) was added, and the resulting mixture was stirred at 0°C for ~1 hour and then at room temperature for several hours until LC-MS indicated the reaction was complete. The reaction mixture was diluted with DCM, washed with 5% NaHCO ₃ , water, brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel chromatography (0 - 10% MeOH/DCM) to give the desired compound 62-3 (958 mg, 1.456 mmol, 66.8% yield) as a white solid. LC-MS, ES ⁺ : 658.26 [M+1].

Step 4: Compound 62-3 (473 mg, 0.719 mmol) was dissolved in DCM (7.2 mL). At 0°C, triethylamine (501 μl, 3.60 mmol) and TFAA (225 μl, 1.618 mmol) were added. The mixture was stirred at 0°C for ~30 min. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO ₃ , brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography (0 - 40% acetone/cyclohexane) to give Example 62 (400 mg, 0.719 mmol, 87% yield). LC-MS, ES-: 638.44 [MH].

Example 63

Step 1: Example 62 (372 mg, 0.581 mmol) was dissolved in MeOH (7.27 ml). 10% Pd-C (30.9 mg, 0.029 mmol) was added. The mixture was stirred under H ₂ (balloon) for 90 minutes. The mixture was filtered through Celite and concentrated under vacuum to give compound 63-1 (280 mg, 0.554 mmol, 95% yield) as a solid. LC-MS, ES-: 504.5 [MH].

Step 2: Compound 63-1 (30 mg, 0.059 mmol) was dissolved in DMF (0.2 mL) and ethyl 2,2,2-trifluoroacetate (0.2 mL, 1.661 mmol) at room temperature. Huunig's base (46.6 μl, 0.267 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and concentrated to dryness. The residue was purified by silica gel chromatography (0 - 40% acetone/cyclohexane) to give Example 63 (22 mg, 0.059 mmol, 62% yield). LC-MS, ES-: 600.4 [MH]. ¹ H NMR (400 MHz, acetone- d ₆ ) δ 9.78 (s, 1H), 8.34 (d, J = 8.3 Hz, 1H), 8.04 (s, 1H), 7.35 - 7.31 (m, 2H), 7.25 ( td, J = 7.7, 1.2 Hz, 1H), 7.11 - 7.03 (m, 3H), 7.02 - 6.94 (m, 2H), 5.18 (t, J = 8.4 Hz, 1H), 4.80 (dtd, J = 12.7, 8.7, 8.2, 4.4 Hz, 2H), 4.26(d, J = 10.2 Hz, 1H), 4.04(d, J = 10.2 Hz, 1H), 3.16(dd, J = 14.2, 4.4 Hz, 1H), 2.91- 2.88(m, 1H), 2.75 - 2.69(m, 2H), 1.96 - 1.88(m, 1H), 1.64(dd, J = 14.4, 8.3 Hz, 1H), 0.99(s, 9H).

Example 348

To a solution of compound 1-1 (15 mg, 0.026 mmol) in acetone (0.131 ml) was added K ₂ CO ₃ (5.44 mg, 0.039 mmol) and dimethyl sulfate (3.73 μl, 0.039 mmol) at room temperature. The reaction mixture was then heated at reflux for ~3 hours and monitored by LC-MS. The mixture was concentrated to remove acetone, then diluted with EtOAc, washed with water, brine, dried and concentrated. The crude material was purified by silica gel column eluting with 0 - 50% acetone/cyclohexane to give Example 348 (3.5 mg, 5.98 μmol) in 22.8% yield. LC-MS, ES-: 584.09 [M-1]. ¹ H NMR (400 MHz, Acetone-d ₆ ) ¹ H NMR (400 MHz, Acetone-d ₆ ) δ 8.22(s, 1H), 7.24(td, J = 7.7, 1.4 Hz, 1H), 7.01 - 6.89( m, 2H), 5.29 (dd, J = 7.5, 4.8 Hz, 1H), 5.04 (t, J = 8.5 Hz, 1H), 4.60 (t, J = 7.0 Hz, 1H), 3.88 - 3.75 (m, 2H) ), 3.11(s, 2H), 2.96(s, 2H), 2.85(s, 1H), 2.56(dd, J = 8.3, 6.1 Hz, 3H), 1.16(s, 3H), 0.77(d, J = 14.3 Hz, 8H).

Example 353

Step 1-1

Compound (1-1) (6.2 g) was dissolved in methanol (250 ml). Thionyl chloride (10 ml) was added and the mixture was stirred at room temperature overnight. Then, volatile substances were removed to obtain compound (1-2) (6 g), which was used directly in the next step without further purification.

Step 1-2

Compound (1-3) (1.5 g) was dissolved in DMF (15 ml) at 0°C, then 90% NaH powder (500 mg) was added under inert nitrogen atmosphere. After 1 hour, a solution of compound (1-2) (2 g) in DMF (30 ml) was added at 0°C. The mixture was allowed to reach room temperature and then heated to 80° C. for 20 hours. Volatiles were removed and the residue was purified on silica gel to give the product, compound (1-4) (50 mg).

Steps 1-3

Compound (1-4) (690 mg) was dissolved in MeOH (50 ml). 10% Pd/C (50 mg) was added and the mixture was stirred under hydrogen atmosphere at room temperature for 12 hours. The reaction was then opened to air and filtered over Celite. The filtrate was concentrated and purified on silica gel to obtain compound (1-5) (300 mg).

Steps 1-4

To a solution of compound (1-5) (190 mg) and Et ₃ N (161 mg) in DCM (3 mL) was added cyclopropanesulfonyl chloride (125 mg) at 0°C. The mixture was then stirred at room temperature for 2 hours. The mixture was poured into water (20 mL) and the aqueous layer was extracted with DCM (10 mL x 2). The combined organic phases were dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica column eluting with (0-40% EtOAc in petroleum ether) to give compound (1-6) (50 mg) as a yellow oil.

Steps 1-5

To a solution of compound (1-6) (110 mg) in THF (2 mL), MeOH (2 mL) and H ₂ O (2 mL) was added LiOH.H ₂ O (67 mg). The mixture was then stirred at 50°C for 3 hours. The mixture was poured into water (20 mL) and the aqueous phase was acidified to pH 2-3 with 2 N HCl. Extracted with EtOAc (10 mL x 3). The combined organic phases were dried over Na ₂ SO ₄ and concentrated to give compound (1-7) (130 mg), which was used directly without further purification.

Steps 1-6

To a solution of compound (1-7) (130 mg) in DMF (3 mL) was added compound (1-8) (91 mg), EDCI (228 mg), HOBT (107 mg), and DIEA (102 mg). , the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (10 mL x 3). The organic layer was dried over Na ₂ SO ₄ and evaporated under vacuum. The residue was purified by silica column eluting with (0-5% MeOH in DCM) to give compound (1-9) (88 mg) as a yellow solid.

Steps 1-7

To a solution of compound (1-9) (88 mg) in THF (2 mL) was added TEA (49 mg) and TFAA (51 mg). The reaction was stirred at room temperature for 12 hours, then poured into water and extracted with EtOAc (10 mL x 2). The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by reverse phase HPLC to give Example 353 (7.9 mg) as a white solid along with the corresponding epimer (7.5 mg). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.75-7.53 (m, 2H), 7.46-7.30 (m, 2H), 7.22-6.88 (m, 4H), 6.37 (td, J = 7.2, 1.8 Hz , 1H), 6.08-4.98(m, 2H), 4.02-3.68(m, 2H), 3.00-2.47(m, 3H), 2.23-1.97(m, 2H), 1.65-1.43(m, 2H), 1.22 -1.09(m, 1H), 1.04-0.86(m, 8H). [MH] ^- m/z 521.8.

Example 361

Step 1

Methyl L-leucinate hydrochloride (1036 mg, 5.70 mmol) was dissolved in DCM (25 ml) and MeOH (5.00 ml). At 0°C, triethylamine (1590 μl, 11.41 mmol), sodium cyanotrihydroborate (287 mg, 4.56 mmol) and acetaldehyde (384 μl, 6.84 mmol) were added. The mixture was stirred at 0° C. for 2 hours, heated to room temperature, and stirred for 18 hours. The reaction was quenched with 5% NaHCO ₃ and extracted with DCM. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified on silica gel with 0-10% MeOH/DCM to give methyl ethyl-L-leucinate (787 mg, 4.54 mmol, 80% yield) as an oil. ¹ H NMR (400 MHz, chloroform- d ) δ 3.74 (s, 3H), 3.34 (td, J = 7.3, 1.3 Hz, 1H), 2.73 - 2.48 (m, 2H), 1.80 - 1.59 (m, 1H) , 1.59 - 1.42(m, 2H), 1.13(td, J = 7.2, 1.3 Hz, 3H), 0.94(ddd, J = 10.0, 6.6, 1.0 Hz, 6H).

Step 2

Methyl ethyl-L-leucinate (582 mg, 3.36 mmol) was dissolved in DMF (7 ml). ((benzyloxy)carbonyl)-L-alanine (750 mg, 3.36 mmol), Hunigg's base (587 μl, 3.36 mmol), and HATU (1277 mg, 3.36 mmol) were added. The mixture was stirred at room temperature for 5 minutes, heated to 80° C. and stirred for 70 minutes. The reaction mixture was cooled to room temperature, diluted with MTBE and quenched with 5% NaHCO ₃ . The organic layer was washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified on silica gel with 0-50% EtOAc/cyclohexane to give methyl N-(((benzyloxy)carbonyl)-L-alanyl)-N-ethyl-L-leucinate (774 mg, 2.045 mmol). , 60.9% yield) was obtained. ¹ H NMR (400 MHz, chloroform- d ) δ 7.43 - 7.28 (m, 5H), 5.68 (d, J = 8.4 Hz, 1H), 5.18 - 5.07 (m, 2H), 4.85 (dd, J = 9.7, 5.1 Hz, 1H), 4.67 (dt, J = 8.2, 6.7 Hz, 1H), 3.70 (s, 3H), 3.51 (dq, J = 14.5, 7.1 Hz, 1H), 3.35 - 3.21 (m, 1H), 1.88 (ddd, J = 14.2, 9.2, 5.1 Hz, 1H), 1.71 (ddd, J = 14.3, 9.8, 4.6 Hz, 1H), 1.42 - 1.24 (m, 6H), 1.05 - 0.91 (m, 6H).

Step 3

Methyl N-(((benzyloxy)carbonyl)-L-alanyl)-N-ethyl-L-leucinate (963 mg, 2.54 mmol) was dissolved in THF (13 ml) and water (13.00 ml). At 0°C, lithium hydroxide hydrate (214 mg, 5.09 mmol) was added. The mixture was stirred at 0°C for 2 hours and diluted with cyclohexane/water (10 mL each). The collected aqueous layer was quenched with 1 M HCl (6 mL) and extracted with DCM (2x) and EtOAc (2x). The combined organic layers were washed with brine, dried over MgSO ₄ and concentrated in vacuo. N-(((benzyloxy)carbonyl)-L-alanyl)-N-ethyl-L-leucine (649 mg, 1.781 mmol, 70.0% yield) was obtained as a colorless oil. ¹ H NMR (400 MHz, chloroform- d ) δ 7.42 - 7.28 (m, 5H), 5.81 (d, J = 8.3 Hz, 1H), 5.18 - 5.06 (m, 2H), 4.77 - 4.60 (m, 2H) , 3.54(dq, J = 14.4, 7.1 Hz, 1H), 3.30(dq, J = 14.8, 7.2 Hz, 1H), 1.92(ddd, J = 14.3, 8.9, 5.5 Hz, 1H), 1.75(ddd, J = 14.3, 9.4, 5.1 Hz, 1H), 1.62(m, 1H), 1.42 - 1.24(m, 6H), 1.04 - 0.92(m, 6H).

Step 4

Compound 1-5 (496 mg, 1.482 mmol) and N-(((benzyloxy)carbonyl)-L-alanyl)-N-ethyl-L-leucine (540 mg, 1.482 mmol) were dissolved in DMF (5 ml). dissolved in it. At 0°C, HOAt (0.6 M in DMF) (494 μl, 0.296 mmol), 2,4,6-trimethylpyridine (431 μl, 3.26 mmol), and HATU (620 mg, 1.630 mmol) were added. The mixture was stirred at 0° C. for 3.5 hours, heated to room temperature, and stirred for 1 hour. The reaction was quenched with 5% NaHCO ₃ at 0° C. and extracted with DCM (2x). The organic layer was washed with 1 M HCl, brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified on silica gel with 0-100% acetone/cyclohexane to give 361-1 (823 mg, 1.425 mmol, 96% yield). ¹ H NMR (400 MHz, acetone- d ₆ ) δ 9.67 (s, 1H), 7.37 - 7.23 (m, 5H), 7.08 (m, 2H), 7.08 - 6.92 (m, 3H), 6.40 (s, 1H) ), 6.27(d, J = 8.2 Hz, 1H), 5.44(t, J = 7.2 Hz, 1H), 5.03(s, 2H), 4.84 - 4.75(m, 1H), 4.40(p, J = 7.1 Hz) , 1H), 3.89(d, J = 10.1 Hz, 1H), 3.79(d, J = 10.2 Hz, 1H), 3.67(dq, J = 14.7, 7.4 Hz, 1H), 3.36(dt, J = 15.5, 7.2 Hz, 1H), 2.51(dd, J = 12.7, 9.9 Hz, 1H), 2.38(m, 1H), 1.82 - 1.73(m, 1H), 1.55(dq, J = 14.5, 6.5 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H), 0.92 (dd, J = 13.8, 6.3 Hz, 6H), 0.65 (d, J = 6.8 Hz, 3H). [M+H ⁺ ] 578.3.

Step 5

Compound 361-1 (823 mg, 1.425 mmol) was dissolved in CH ₂ Cl ₂ (7.12 ml). At 0°C, triethylamine (993 μl, 7.12 mmol) and TFAA (443 μl, 3.13 mmol) were added dropwise. The mixture was stirred at 0° C. for 15 min, quenched with 5% NaHCO ₃ and extracted with DCM. The organic layer was loaded onto silica gel and eluted with 0-50% acetone/cyclohexane to give 361-2 (530 mg, 0.947 mmol, 66.5% yield) ¹ H NMR (400 MHz, acetone- d ₆ ) δ 9.72(s, 1H), 7.37 - 7.24(m, 6H), 7.12 - 6.93(m, 3H), 6.33(d, J = 8.2 Hz, 1H), 5.46(t, J = 7.4 Hz, 1H), 5.16 (t, J = 8.4 Hz, 1H), 5.04(d, J = 2.1 Hz, 2H), 4.46(p, J = 7.1 Hz, 1H), 3.96(d, J = 10.5 Hz, 1H), 3.85(d , J = 10.5 Hz, 1H), 3.66(dq, J = 14.5, 7.1 Hz, 1H), 3.40(dq, J = 14.7, 7.1 Hz, 1H), 2.82 - 2.63(m, 2H), 1.80(dt, J = 14.2, 7.5 Hz, 1H), 1.61 (m, 2H), 1.33 (t, J = 7.2 Hz, 3H), 0.94 (dd, J = 10.7, 6.5 Hz, 6H), 0.79 (d, J = 6.9) Hz, 3H). [M+Na ⁺ ] 582.2.

Step 6

Compound 361-2 (530 mg, 0.947 mmol) was dissolved in MeOH (9.47 ml). 10% Pd/C (50.4 mg, 0.047 mmol) was added. The mixture was stirred under hydrogen (balloon) at room temperature for 90 minutes, filtered through Celite and concentrated in vacuo. 361-3 (430 mg, 1.010 mmol, quantitative yield) was obtained as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.72 (s, 1H), 7.23 (td, J = 7.6, 1.4 Hz, 1H), 7.00 (dd, J = 7.5, 1.4 Hz, 1H), 6.98 - 6.91(m, 1H), 6.88(d, J = 7.7 Hz, 1H), 5.26(t, J = 7.2 Hz, 1H), 5.15(t, J = 8.0 Hz, 1H), 3.76(d, J = 10.6 Hz, 1H), 3.55(d, J = 10.5 Hz, 1H), 3.42(m, 1H), 3.29 - 3.15(m, 1H), 2.63(m, 1H), 2.51 - 2.43(m, 1H), 1.71 (dt, J = 13.8, 7.3 Hz, 1H), 1.47(m, 2H), 1.14(t, J = 7.1 Hz, 3H), 0.89(dt, J = 9.4, 4.7 Hz, 6H), 0.55(d, J = 6.5 Hz, 3H). [M+H ⁺ ] 426.3.

Step 7

Compound 361-3 (16 mg, 0.038 mmol) was dissolved in CH ₂ Cl ₂ (0.313 ml) and DMF (0.063 ml). 4-(trifluoromethoxy)benzoic acid (7.75 mg, 0.038 mmol), 4-methylmorpholine (8.27 μl, 0.075 mmol), and HATU (14.30 mg, 0.038 mmol) were added. The mixture was stirred at room temperature for 1 hour, quenched with 5% NaHCO ₃ and extracted with DCM. The organic layer was loaded onto silica gel and eluted with 0-50% acetone to give Example 361 (20 mg, 0.033 mmol, 87% yield). ¹ H NMR (400 MHz, acetone- d ₆ ) δ 9.74 (s, 1H), 8.05 - 7.97 (m, 2H), 7.71 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 8.3 Hz, 2H), 7.31(td, J = 7.6, 1.6 Hz, 1H), 7.12(d, J = 7.2 Hz, 1H), 7.11 - 7.03(m, 1H), 7.03(d, J = 7.8 Hz, 1H), 5.48(t, J = 7.4 Hz, 1H), 5.18(t, J = 8.4 Hz, 1H), 4.88(p, J = 7.1 Hz, 1H), 3.98(d, J = 10.5 Hz, 1H), 3.89( d, J = 10.5 Hz, 1H), 3.74(dq, J = 14.4, 7.1 Hz, 1H), 3.46(dq, J = 14.6, 7.1 Hz, 1H), 2.75(d, J = 8.5 Hz, 1H), 2.69(dd, J = 13.2, 8.4 Hz, 1H), 1.82(dt, J = 14.7, 7.5 Hz, 1H), 1.72 - 1.53(m, 2H), 1.39(t, J = 7.2 Hz, 3H), 0.97 - 0.87(m, 9H). [M+Na ⁺ ] 636.2.

The following examples were prepared using procedures similar to those described above.

Example 373

Step 373-1:

A clear, colorless solution of the mixture of compounds from steps 1-3 (3.94 g, 11.4 mmol, dr 10/1) in acetonitrile (40 mL) was treated with NBS (2.23 g, 12.5 mmol) in three portions at room temperature. did. The reaction was stirred at room temperature for 3 hours. This became a pale yellow solution. LCMS did not show SM. The reaction was quenched with aqueous Na ₂ S ₂ O ₃ . The mixture was allowed to stir at room temperature for an additional 30 minutes. The cloudy mixture was further diluted with EtOAc (80 mL). The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product as an off-white solid. The crude material was dissolved in DCM (10 mL) and filtered through a 80 g pad of silica gel (MTBE) to give the desired product (dr 10/1) as a white solid. The product was treated with MTBE/hexane (2:1) (30 mL). The mixture was sonicated for 10 minutes to form a milky white suspension, which was filtered and washed with MTBE/hexane (2:1) to give the desired product as a white solid (4.23 g, 10.0 mmol, dr >100/1). . ESI MS m/z = 422.74, 424.64 [MH] ^- .

Step 373-2:

A clear, colorless solution of the compound from step 373-1 (4.2 g, 9.9 mmol) in n-PrOH (35 mL) was added to triethylamine (1.7 mL, 11.9 mmol), potassium vinyltrifluoroborate (1.6 g, 11.9 mmol). ) and PdCl ₂ (dppf) (290 mg, 0.4 mmol) under N ₂ . The mixture was degassed and backfilled with N ₂ (*3). N ₂ was foamed into the obtained orange suspension for 10 minutes. The reaction was heated to 100° C. and stirred for 20 hours. This resulted in a dark red/brown mixture. TLC (CH/EtOAc 2:1) showed no SM. The reaction was diluted with ethyl acetate (100 mL) and quenched with aqueous NaHCO ₃ . The aqueous layer was extracted with ethyl acetate (*2). The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude material was redissolved in ethyl acetate (20 mL) and treated with SiliaMetS DMT (8 g) as a metal scavenger. The mixture was stirred at room temperature for 16 hours, then filtered, washed with MTBE/CH (2:1) (200 mL) and concentrated in vacuo. The brown crude material was re-dissolved in ethyl acetate (20 mL), treated with activated carbon, and heated to 60° C. for 1 hour. After cooling, the mixture was filtered to give a pale yellow solution, which was further concentrated under vacuum to give the desired product (3.3 g, 8.7 mmol, 90%) as an off-white foam. ESI MS m/z = 370.79 [MH] ^- .

Step 373-3:

A clear pale yellow solution of the compound from step 373-2 (3.3 g, 8.9 mmol) in 7 N ammonia in MeOH (80 ml, 560 mmol) was stirred at 50° C. in a sealed pressure vessel over the weekend (3 days). LCMS did not show SM. The mixture was allowed to cool and concentrated under vacuum to give a yellow gel-like solid. The solid was redissolved in 30 mL MeOH/dioxane (1:10) and co-evaporated under vacuum to give a pale yellow solid. The crude material was dried under high pressure for 1 hour, then broken into small pieces and dried under high vacuum overnight to give a pale yellow powder. The powder was washed with 10 mL DCM/MTBE (1:2), sonicated, and filtered to yield the desired product (3.05 g, 8.5 mmol, 96%) as an off-white solid. ESI MS m/z = 355.79 [MH] ^- .

Step 373-4:

To a clear solution of compound from step 373-3 (1.15 g, 3.22 mmol) in DMF (2 ml) was added 4 M HCl in 1,4-dioxane (8 ml, 32 mmol) at room temperature. The obtained clear yellow solution was stirred at room temperature for 2 hours. The mixture was concentrated by rotary evaporator. The remaining clear DMF solution was poured into DCM (150 ml) under stirring to obtain a white slurry. The mixture was sonicated to form a cloudy suspension. The solid was washed with DCM, then MTBE and collected by filtration. The solid was dried under vacuum to give the desired product as an off-white powder (862 mg, 2.93 mmol, 91%). 1 g of the above product was mixed with DMF (2 ml) and heated with a heat gun to obtain an almost clear solution. During heating, solids began to appear. The mixture was allowed to cool to room temperature. The solid was washed with DMF (0.2 ml), DCM and MTBE and collected by filtration. The solid was dried under vacuum to give the desired product as a white solid (771 mg). ESI MS m/z = 257.77 [MH] ^- .

Step 373-5:

(S)-2-((tert-butoxycarbonyl)amino)hept-6-enoic acid (1 g, 4.11 mmol) and methyl methyl-L- in CH ₂ Cl ₂ (12 ml) and DMF (3 ml). A suspension of leucinate hydrochloride (0.81 g, 4.14 mmol) was treated with N-methylmorpholine (1.8 ml, 16.37 mmol) and HATU (1.71 g, 4.50 mmol) at room temperature. The reaction was stirred overnight at room temperature. The reaction was concentrated under vacuum and quenched with a saturated solution of sodium bicarbonate. The mixture was stirred at room temperature for an additional 30 minutes and diluted with ethyl acetate. The organic layer was washed three times with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was applied to a 40 g silica gel column and eluted with 0% to 25% ethyl acetate/cyclohexane to give the desired compound (1.12 g, 2.91 mmol, 71% yield) as a colorless syrup. ESI MS m / z = 384.95 [M+H] ⁺ .

Step 373-6:

A solution of compound from step 373-5 (1.1 g, 2.86 mmol) in THF (6 ml) and water (3 ml) was treated with lithium hydroxide (200 mg, 8.35 mmol) at 0°C. The reaction was stirred at 0°C for 5 hours and neutralized with 6 N HCl to pH = 2. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give the desired compound (1.05 g, 2.83 mmol, 99% yield) as a white solid. ESI MS m / z = 369.25 [MH] ^- .

Step 373-7:

A suspension of the compound from step 373-6 (285 mg, 0.77 mmol) and the compound from step 373-4 (221 mg, 0.75 mmol) in DMF (0.6 ml) and DCM (1.8 ml) was incubated with N-methylmorpholine ( 330 μl, 3.00 mmol) and HATU (318 mg, 0.836 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was quenched with a saturated solution of sodium bicarbonate and diluted with ethyl acetate. The organic layer was washed three times with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was applied to a 24 g silica gel column and eluted with 0% to 100% dichloromethane/methanol to give the desired product (77 mg, 0.126 mmol, 17% yield) as a white solid. ESI MS m / z = 608.33 [MH] ^- .

Step 373-8:

A solution of the compound from step 373-7 (77 mg, 0.126 mmol) in toluene (125 ml) was treated with Zhan 1B catalyst (17 mg, 0.023 mmol). The mixture was degassed by freeze-pump thawing at -78°C and backfilled with N ₂ . The reaction was heated to 90° C. and stirred overnight. The mixture was concentrated under vacuum. The crude material was applied to a 4 g silica gel column and eluted with 0% to 100% dichloromethane/methanol to give the desired product (7 mg, 0.012 mmol, 10% yield) as a black foam. ESI MS m / z = 580.19 [MH] ^- .

Step 373-9:

A solution of compound from step 373-8 (7 mg, 0.012 mmol) in MeOH (0.5 ml) was treated with Pd-C (2.7 mg, 2.54 μmol) under 1 atm H ₂ (0.024 mg, 0.012 mmol). The reaction was stirred overnight at room temperature. The mixture was filtered through Celite and washed with methanol. The filtrate was concentrated under vacuum to give the desired product (7 mg, 0.012 mmol, 100% yield) as a black foam. ESI MS m / z = 582.33 [MH] ^- .

Step 373-10:

A solution of compound from step 373-9 (7 mg, 0.012 mmol) in CH ₂ Cl ₂ (0.3 ml) was treated dropwise with TEA (15 μl, 0.108 mmol) and TFAA (6 μl, 0.042 mmol) at 0°C. . The reaction was stirred at 0° C. for 30 min and then quenched with ammonium hydroxide. The aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was added to a 4 g silica gel column and eluted with 0% to 100% ethyl acetate/cyclohexane to give Example 373 (1.7 mg, 3.01 μmol, 25% yield) as a white solid. ESI MS m / z = 564.22 [MH] ^- .

Example 374

Step 374-1. tert -butyl (2 S )-2-amino-4,4-dimethylpentanoate (0.974 g, 4.84 mmol) and pent-4-enoyl- L -alanine (0.753 g) in DCM (30 ml) at 0°C. , 4.40 mmol), 4-methylmorpholine (1.451 ml, 13.20 mmol) was added, and then HATU (1.840 g, 4.84 mmol) was added. The obtained yellow milky white solution was stirred at 0°C for 5 minutes and then at room temperature for 2 hours. The mixture was diluted with EtOAc and saturated NaHCO ₃ solution. The organic layer was washed with brine (*1), dried over Na ₂ SO ₄ (s), filtered and concentrated. The residue was purified by flash column chromatography (silica, cyclohexane/EtOAc) to afford the desired compound as a sticky, colorless oil (1.280 g, 82%). ESI MS m / z = 355.43 [M+H] ⁺ .

Step 374-2. To a solution of compound from step 374-1 (1.280 g, 3.61 mmol) in DCM (6 ml) at room temperature was added TFA (5.56 ml, 72.2 mmol). The solution was stirred at room temperature for 1 hour before being concentrated. The residue was co-evaporated with toluene (*2), DCM (*1) and dried under vacuum to give the desired compound as a sticky colorless oil (1.240 g, 100%), which was used directly in the next step. ESI MS m / z = 299.37 [M+H] ⁺ .

Step 374-3. 4-methylmor to a suspension of compound from 373-4 (1.060 g, 3.61 mmol) and compound from step 374-2 (1.077 g, 3.61 mmol) in DCM (10 ml) and DMF (2.000 ml) at 0°C. Folin (1.191 ml, 10.83 mmol) was added, followed by HATU (1.922 g, 5.05 mmol). The reaction mixture was stirred at 0° C. for 5 minutes and then at room temperature overnight. The mixture was diluted with saturated NaHCO ₃ solution and EtOAc. The aqueous layer was extracted with DCM (*1). The combined organic layers were washed with brine (*1), dried over Na ₂ SO ₄ (s), filtered and concentrated. The residue was purified by flash column chromatography (silica, cyclohexane/acetone) to give the desired compound as a white solid (0.290 g, 15%). ESI MS m / z = 538.31 [M+H] ⁺ .

Step 374-4. To a solution of the compound from step 374-3 (0.120 g, 0.223 mmol) in CH ₂ Cl ₂ (5 ml) and DMF (1.000 ml) at room temperature was added Burgess reagent (0.067 g, 0.268 mmol). The obtained clear solution was stirred at room temperature for 1.5 hours. Additional Burgess reagent (0.067 g, 0.268 mmol) was added. The mixture was stirred at room temperature for 2 hours. It was quenched with water and extracted with DCM (*2). The combined organic layers were dried over Na ₂ SO ₄ (s), filtered and concentrated. The residue was purified by flash column chromatography (silica, cyclohexane/acetone) to give the desired compound as a yellow solid (40.0 mg, 35%). ESI MS m / z = 520.29 [M+H] ⁺ .

Step 374-5. To a solution of the compound from step 374-4 (0.0400 g, 0.077 mmol) in toluene (77 ml) was added Zhan 1B catalyst (0.011 g, 0.015 mmol). The mixture was purged with N ₂ and heated at 85° C. overnight. The mixture was allowed to cool and concentrated. The residue was dissolved in DCM (10 ml) at room temperature. 2-Mercaptonicotinic acid (0.024 g, 0.154 mmol) and Et ₃ N (0.021 ml, 0.154 mmol) were added. The mixture was stirred at 40° C. for 30 minutes before evaporating most of the DCM. The residue was filtered through a 1 g silica column and washed with acetone. The filtrate was concentrated. The residue was purified by flash column chromatography (silica, cyclohexane/acetone) to give the desired compound as a yellow solid (19.0 mg, 50%). ESI MS m / z = 492.47 [M+H] ⁺ .

Step 374-6. To a solution of the compound from step 374-5 (19.0 mg, 0.039 mmol) in MeOH (2.0 ml) at room temperature was added 10% Pd/C (4.11 mg, 3.86 μmol). The mixture was purified with H ₂ and then stirred with a hydrogen balloon for 2 hours at room temperature. LC-MS showed mostly SM, trace amounts of DP. The mixture was diluted with DCM (4 ml), filtered through a short pad of Celite and washed with DCM/MeOH (2/1). The filtrate was concentrated. The residue was again placed under the above hydrogenation conditions at 60 psi overnight. The mixture was diluted with DCM (4 ml), filtered through a short pad of Celite and washed with DCM/MeOH (2/1). The filtrate was concentrated. The residue was purified by flash column chromatography (silica, cyclohexane/acetone) to give Example 374 as a white solid (6.0 mg, 31%). ESI MS m / z = 494.28 [M+H] ⁺ .

The following compounds were prepared following a procedure similar to Example 374.

Example 375

, ESI MS m/z = 508.43 [M+H]⁺.

, ESI MS m / z = 508.43 [M+H] ⁺ .

Example 376

, ESI MS m/z = 536.44 [M+H]⁺.

, ESI MS m / z = 536.44 [M+H] ⁺ .

Example 377

, ESI MS m/z = 508.37 [M+H]⁺.

, ESI MS m / z = 508.37 [M+H] ⁺ .

Example 378

, ESI MS m/z = 494.35 [M+H]⁺.

, ESI MS m / z = 494.35 [M+H] ⁺ .

Example 379

, ESI MS m/z = 522.40 [M+H]⁺.

, ESI MS m / z = 522.40 [M+H] ⁺ .

biological activity

SARS-CoV-2 3C-like (3CL) protease fluorescence assay (FRET): Recombinant SARS-CoV-2 3CL-protease was expressed and purified. The TAMRA-SITSAVLQSGFRKMK-Dabcyl-OH peptide 3CLpro substrate was synthesized. A black, low-volume, round-bottom, 384-well microplate was used. In a typical assay, 0.85 μL of test compound was dissolved in DMSO and then incubated with SARS-CoV-2 3CL in 10 μL assay buffer (50 mM HEPES [pH 7.5], 1 mM DTT, 0.01% BSA, 0.01% Triton-X 100). -Incubated with protease (10 nM). Then, 10 μL of 3CL-protease substrate (40 μM) in assay buffer was added and the assay was run on an Envision multimode plate reader operating in fluorescence kinetic mode with excitation at 540 nm and emission at 580 nm at room temperature. Monitoring continued for 1 hour. Compound-free (DMSO only) and enzyme-free controls were routinely included in each plate. All experiments were performed in duplicate.

Data analysis: SARS-CoV-2 3CL-protease enzyme activity was measured as the initial rate of linear phase (RFU/s) and normalized to control samples DMSO (100% activity) and no enzyme (0% activity) to test compounds. Percent residual activity was determined at various concentrations (0 - 10 μM). IC ₅₀ was determined by fitting the data to a normalized activity (variable slope) versus concentration fit in GraphPad Prism 7. All experiments were performed in duplicate and the IC ₅₀ ranges are reported as follows: A < 0.1 μM; B 0.1-1 μM; C > 1 μM.

229E Assay Protocol

Virus stock preparation : MRC-5 cells (a diploid cell line composed of fibroblasts, originally developed from the lung tissue of an aborted Caucasian male fetus at 14 weeks of age) were used for culture of 229E human coronavirus (hCoV). Flasks were inoculated with hCoV-229E, and virus stocks were collected when cytopathic effect (CPE) exceeded 70%. Virus stocks were snap frozen using liquid nitrogen in growth medium (EMEM, 1% Penn/Strep, 1% non-essential amino acids, 10% heat-inactivated FBS) containing 5% glycerol and stored at -80°C. . Viral stock titers were quantified by the TCID ₅₀ (50% median tissue culture infectious dose) assay as described elsewhere.

229E Live Virus Assay : 384-well black cell culture treated plastic clear bottom plates are used in this assay. Using an ECHO liquid dispenser, three-fold serial dilutions of control and test compounds suspended in DMSO are added to plate wells in duplicate in a total volume of 125 nL per well. MRC-5 cells with passage number 17 or less are seeded into the inner 240 wells of a 384-well plate at 1,500 cells per well in a volume of 12.5 μL using growth medium. Virus stock is then added to the wells at a multiplicity of infection (MOI) of 0.05 in a volume of 12.5 μL per well, resulting in a total volume of ~25 μL in each well. Each plate consisted of a control row of 20 wells with cells and DMSO and virus but no compound (positive control, maximum CPE, minimum ATPlite signal), and a row with cells and DMSO but no compound or virus (negative control). , minimum CPE, maximum ATPlite signal), and rows containing no cells or viruses or compounds (background plate/reagent control). Control wells containing cells but no virus are given an additional 12.5 μL of growth medium containing the same amount of glycerol as those wells receiving the virus stock to keep media and volume conditions constant. Fill the outer 2 rows/columns of wells with 30 μL of moat medium (DMEM, 1% Penn/Strep) to act as a thermal and evaporation barrier surrounding the test wells. After addition of all ingredients, gently tap the sides of the plate by hand to promote even cell distribution in the wells. After confirmation of cell distribution, the plates are incubated for 6 days in a CO ₂ humidity controlled incubator at 34°C. After a 6-day culture period, the plates are read using ATPlite (12.5 μL added per well), which quantifies the amount of ATP present in each well (a measure of cell health). Read the assay plate using an Envision photometer. These data are used to calculate percent cell health per well relative to negative control wells and the EC ₅₀ for each compound using ExcelFit software and 4-parameter logistic curve fitting analysis.

All experiments were performed in duplicate and the EC ₅₀ ranges are reported as follows: A < 0.1 μM; B 0.1-1 μM; C > 1 μM.

Although the present invention has been particularly presented and described with reference to preferred embodiments thereof, it is understood that various changes in form and detail may be made therein without departing from the scope of the invention as encompassed by the appended claims. It will be understood by those skilled in the art.

Claims (18)

A compound represented by the following formula ( I ) or a pharmaceutically acceptable salt thereof:

In the above equation,
R ₁ , R ₂ , R ₃ , R ₂₁ , R ₂₂ , and R ₂₃ are each independently
1) hydrogen;
2) optionally substituted -C ₁ -C ₈ alkyl;
3) optionally substituted -C ₂ -C ₈ alkenyl;
4) optionally substituted -C ₂ -C ₈ alkynyl;
5) optionally substituted -C ₃ -C ₈ cycloalkyl;
6) optionally substituted 3 to 8 membered heterocycloalkyl;
7) optionally substituted aryl;
8) optionally substituted arylalkyl;
9) optionally substituted heteroaryl; and
10) optionally substituted heteroarylalkyl;
Alternatively, R ₁ and R ₂ together with the carbon atom to which they are attached form an optionally substituted 3 to 8 membered carbocyclic ring or an optionally substituted 3 to 8 membered heterocyclic ring;
Alternatively, R ₁ and R ₃ together with the atoms to which they are attached form an optionally substituted 3 to 8 membered heterocyclic ring;
Alternatively, R ₂₁ and R ₃ taken together with the intervening atoms form an optionally substituted 4 to 8 membered heterocyclic ring;
Alternatively, R ₂₂ is absent and R ₂₁ and R ₃ together with the intervening atoms form an optionally substituted 4-8 membered partially unsaturated heterocyclic ring or an optionally substituted 5-6 membered heteroaryl ring;
Alternatively, R ₂₁ and R ₂₂ together with the carbon atom to which they are attached form an optionally substituted 3 to 8 membered carbocyclic ring or an optionally substituted 3 to 8 membered heterocyclic ring;
R ₂₄ is
1) -C(O)R ₂₅ ;
2) -C(O)OR ₂₅ ;
3) -C(O)NR ₁₃ R ₁₄ ;
4) -S(O) ₂ R ₂₅ ;
5) hydrogen;
6) optionally substituted -C ₁ -C ₈ alkyl;
7) optionally substituted -C ₂ -C ₈ alkenyl;
8) optionally substituted -C ₂ -C ₈ alkynyl;
9) optionally substituted -C ₃ -C ₁₂ cycloalkyl;
10) optionally substituted 3 to 12 membered heterocycloalkyl;
11) optionally substituted aryl;
12) optionally substituted arylalkyl;
13) optionally substituted heteroaryl;
14) optionally substituted heteroarylalkyl;
15) -(CO)(CO)NR ₁₃ R ₁₄ ;
16) -(CO)(CO)R ₂₅ ;
17) -S(O) ₂ NR ₁₃ R ₁₄ ;
18) -C(S)R ₂₅ ; and
19) -C(S)NR ₁₃ R ₁₄ ;
Alternatively, R ₂₃ and R ₂₄ together with the nitrogen atom to which they are attached form an optionally substituted 3 to 12 membered heterocyclic ring or an optionally substituted 5 to 12 membered heteroaryl ring;
R ₂₅ is
1) optionally substituted -C ₁ -C ₈ alkyl;
2) optionally substituted -C ₂ -C ₈ alkenyl;
3) optionally substituted -C ₂ -C ₈ alkynyl;
4) optionally substituted -C ₃ -C ₁₂ cycloalkyl;
5) optionally substituted 3 to 12 membered heterocycloalkyl;
6) optionally substituted aryl;
7) optionally substituted arylalkyl;
8) optionally substituted heteroaryl; and
9) optionally substituted heteroarylalkyl;
R ₄ is hydrogen, optionally substituted -C ₁ -C ₄ alkyl, optionally substituted -C ₂ -C ₄ alkenyl, optionally substituted -C ₃ -C ₆ cycloalkyl, optionally substituted arylalkyl, optionally substituted hetero is an arylalkyl, halogen, -CN, -OH, or prodrug moiety;
B is optionally substituted aryl or optionally substituted heteroaryl;
Alternatively, one of R ₂₁ and R ₂₄ is L-, where L is a saturated or unsaturated linking group of 4 to 20 atoms in length that is attached to B;
X is
1) -CN;
2) -C(O)R ₁₅ ;
3) -CH(OH)SO ₃ R ₁₆ ;
4) -C(O)NR ₁₃ R ₁₄ ;
5) -C(O)C(O)NR ₁₃ R ₁₄ ;
6) -CH=CH-C(O)OR ₂₅ ,
7) -CH=CH-C(O)NR ₁₃ R ₁₄ ,
8) -CH=CH-S(O) ₂ NR ₁₃ R ₁₄ ,
9) -B(OR ₁₃ ) ₂ ;
10) -C≡CR ₁₃ ;
11) -C≡CC(O)OR ₂₅ ;
12) -C≡CC(O)NR ₁₃ R ₁₄ ;
13) -C≡CS(O) ₂ NR ₁₃ R ₁₄ ;
14) -(CR ₁₃ R ₁₄ ) _w -CN; and
15) -(CR ₁₃ R ₁₄ ) _w -(C=O)-R ₂₅ ;
w is 1, 2, 3, 4, or 5;
R ₁₃ and R ₁₄ are each independently
1) hydrogen;
2) optionally substituted -C ₁ -C ₈ alkyl;
3) optionally substituted -C ₂ -C ₈ alkenyl;
4) optionally substituted -C ₂ -C ₈ alkynyl;
5) optionally substituted -C ₃ -C ₈ cycloalkyl;
6) optionally substituted 3 to 8 membered heterocycloalkyl;
7) optionally substituted aryl;
8) optionally substituted arylalkyl;
9) optionally substituted heteroaryl; and
10) optionally substituted heteroarylalkyl;
Alternatively, R ₁₃ and R ₁₄ together with the nitrogen atom to which they are attached form an optionally substituted 3 to 8 membered heterocyclic ring;
R ₁₅ is hydrogen, hydroxy, optionally substituted -C ₁ -C ₈ alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl or heteroarylalkyl;
R ₁₆ is hydrogen or Na ⁺ . The compound according to claim 1, represented by one of the following formulas ( IV-1 ) to ( IV-4 ) or a pharmaceutically acceptable salt thereof:

_{In the} above _{formula , B ,} According to claim 1, a compound represented by one of the following formula ( V ) or a pharmaceutically acceptable salt thereof:

In the above equation,
Each R ₉ is independently
1) Halogen;
2) -CN;
3) -OR ₁₃ ;
4) -SR ₁₃ ;
5) -NR ₁₃ R ₁₄ ;
6) -OC(O)NR ₁₃ R ₁₄ ;
7) optionally substituted -C ₁ -C ₆ alkyl;
8) optionally substituted -C ₃ -C ₈ cycloalkyl;
9) optionally substituted 3-8 membered heterocycloalkyl;
10) optionally substituted aryl;
11) optionally substituted heteroaryl;
12) -OC(O)R ₂₅ ;
13) -C(O)NR ₁₃ R ₁₄ ;
14) -S(O)R ₂₅ ;
15) -S(O) ₂ -R ₂₅ ;
16) -S(O)(NH)R ₂₅ ;
17) -S(O) ₂ -NR ₁₃ R ₁₄ ;
18) -NR ₁₃ (C=O)R ₂₅ ;
19) -NR ₁₃ (C=O)OR ₂₅ ;
20) -NR ₁₃ (C=O)NR ₁₃ R ₁₄ ;
21) -NR ₁₃ -S(O) ₂ -R ₂₅ ; and
22) -NR ₁₃ -S(O) ₂ -NR ₁₃ R ₁₄ ;
n is 0, 1, 2, 3, or 4;
R ₁ , R ₂ , R ₃ , R ₄ , R ₁₃ , R ₁₄ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , R ₂₅ and X are as defined in clause 1. The compound according to claim 1, represented by the following formula ( XIX ) or a pharmaceutically acceptable salt thereof:

In the above equation,
Each R ₉ is independently
1) Halogen;
2) -CN;
3) -OR ₁₃ ;
4) -SR ₁₃ ;
5) -NR ₁₃ R ₁₄ ;
6) -OC(O)NR ₁₃ R ₁₄ ;
7) optionally substituted -C ₁ -C ₆ alkyl;
8) optionally substituted -C ₃ -C ₈ cycloalkyl;
9) optionally substituted 3-8 membered heterocycloalkyl;
10) optionally substituted aryl;
11) optionally substituted heteroaryl;
12) -OC(O)R ₂₅ ;
13) -C(O)NR ₁₃ R ₁₄ ;
14) -S(O)R ₂₅ ;
15) -S(O) ₂ -R ₂₅ ;
16) -S(O)(NH)R ₂₅ ;
17) -S(O) ₂ -NR ₁₃ R ₁₄ ;
18) -NR ₁₃ (C=O)R ₂₅ ;
19) -NR ₁₃ (C=O)OR ₂₅ ;
20) -NR ₁₃ (C=O)NR ₁₃ R ₁₄ ;
21) -NR ₁₃ -S(O) ₂ R ₂₅ ; and
22) -NR ₁₃ -S(O) ₂ NR ₁₃ R ₁₄ ;
n is 0, 1, 2, 3, or 4;
R ₁ , R ₃ , R ₄ , R ₂₁ , R ₂₂ , R ₂₃ , and R ₂₄ are as defined in clause 1. The compound according to claim 1, represented by one of the following formulas ( VII-1 ) to ( VII-5 ) or a pharmaceutically acceptable salt thereof:

In the above formula, R ₁ , R ₃ , R ₂₁ , R ₂₃ , R ₂₅ , R ₁₃ , and R ₁₄ are as defined in claim 1. The compound according to claim 1, represented by one of the following formulas ( XI-1 ) to ( XI-3 ), or a pharmaceutically acceptable salt thereof:

where A1 is an optionally substituted 4-8 membered lactam or an optionally substituted 2-pyridone; A2 is an optionally substituted 3-12 membered heterocyclic ring or an optionally substituted 5-12 membered heteroaryl ring; A3 is a 3 to 8 membered heterocyclic ring; R ₁ , R ₃ , R ₂₁ , R ₂₃ , and R ₂₄ are as defined in claim 1. The compound according to claim 1, represented by one of the following formulas ( XVII-1 ) to ( XVII-2 ):

In the above equation,
Each R ₉ is independently
1) Halogen;
2) -CN;
3) -OR ₁₃ ;
4) -SR ₁₃ ;
5) -NR ₁₃ R ₁₄ ;
6) -OC(O)NR ₁₃ R ₁₄ ;
7) optionally substituted -C ₁ -C ₆ alkyl;
8) optionally substituted -C ₃ -C ₈ cycloalkyl;
9) optionally substituted 3-8 membered heterocycloalkyl;
10) optionally substituted aryl;
11) optionally substituted heteroaryl;
12) -OC(O)R ₂₅ ;
13) -C(O)NR ₁₃ R ₁₄ ;
14) -S(O)R ₂₅ ;
15) -S(O) ₂ -R ₂₅ ;
16) -S(O)(NH)R ₂₅ ;
17) -S(O) ₂ -NR ₁₃ R ₁₄ ;
18) -NR ₁₃ (C=O)R ₂₅ ;
19) -NR ₁₃ (C=O)OR ₂₅ ;
20) -NR ₁₃ (C=O)NR ₁₃ R ₁₄ ;
21) -NR ₁₃ -S(O) ₂ R ₂₅ ; and
22) -NR ₁₃ -S(O) ₂ NR ₁₃ R ₁₄ ;
n is 0, 1, 2, 3, or 4;
r is 1, 2, 3, or 4,
R ₁ , R ₃ , R ₄ , and R ₂₁ are as defined in clause 1. The compound according to claim 1, represented by one of the following formulas ( XVIII-1 ) to ( XVIII-4 ):

In the above equation,
Each R ₉ is independently
1) Halogen;
2) -CN;
3) -OR ₁₃ ;
4) -SR ₁₃ ;
5) -NR ₁₃ R ₁₄ ;
6) -OC(O)NR ₁₃ R ₁₄ ;
7) optionally substituted -C ₁ -C ₆ alkyl;
8) optionally substituted -C ₃ -C ₈ cycloalkyl;
9) optionally substituted 3-8 membered heterocycloalkyl;
10) optionally substituted aryl;
11) optionally substituted heteroaryl;
12) -OC(O)R ₂₅ ;
13) -C(O)NR ₁₃ R ₁₄ ;
14) -S(O)R ₂₅ ;
15) -S(O) ₂ -R ₂₅ ;
16) -S(O)(NH)R ₂₅ ;
17) -S(O) ₂ -NR ₁₃ R ₁₄ ;
18) -NR ₁₃ (C=O)R ₂₅ ;
19) -NR ₁₃ (C=O)OR ₂₅ ;
20) -NR ₁₃ (C=O)NR ₁₃ R ₁₄ ;
21) -NR ₁₃ -S(O) ₂ R ₂₅ ; and
22) -NR ₁₃ -S(O) ₂ NR ₁₃ R ₁₄ ;
n is 0, 1, 2, 3, or 4;
R ₁ , R ₃ , R ₁₃ , R ₁₄ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ and R ₂₅ are as defined in clause 1. The compound according to claim 1, selected from the compounds described below or pharmaceutically acceptable salts thereof:

A pharmaceutical composition comprising the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. A method for treating or preventing viral infections from RNA-based viruses, coronaviruses, rhinoviruses and noroviruses in a subject susceptible to or suffering from such viral infections, comprising administering to the subject any of claims 1 to 9. A method comprising administering an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof. A method of treating or preventing a coronavirus infection in a subject in need of treatment or prevention of the coronavirus infection, wherein the subject is provided with a compound or combination of compounds according to any one of claims 1 to 9, or a pharmaceutically acceptable combination thereof. A method comprising administering a therapeutically effective amount of a salt. 13. The method of claim 12, wherein the coronavirus is 229E, NL63, OC43, HKU1, SARS-CoV or MERS coronavirus. A method for treating or preventing a viral infection in a subject susceptible to or suffering from a viral infection, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof. A method comprising administering. A method of inhibiting viral 3C protease or viral 3CL protease in a subject, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof. 1. A method of treating a respiratory disorder, including acute asthma, lung disease secondary to environmental exposure, acute lung infection, chronic lung infection, in a subject in need of treatment, comprising administering to the subject any one of claims 1 to 9: A method comprising administering a therapeutically effective amount of the compound according to or a pharmaceutically acceptable salt thereof. The method of claim 17, wherein the compound or a pharmaceutically acceptable salt thereof is administered orally, subcutaneously, intravenously, or by inhalation. 18. The method of any one of claims 11-17, wherein the subject is a human.