RU2782066C2 - Pyrimidine compounds containing acid groups - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: present invention relates to a compound having a structure of the Formula (1) or to its pharmaceutically acceptable salt, having immunomodulating properties, which act through TLR, and which are useful in the treatment of viral infections and cancer diseases.

,

where R^1a is selected from a group consisting of H, C₁-C₄ alkyl, and A, where alkyl is optionally substituted with -COOH, -SO₂CH₃, -SCH₃, -OCH₃,

or A; R^1b is C₂-C₅ alkyl; X is C₁-C₄ alkyl, where alkyl is optionally substituted with A or -OH; L¹ is selected from a group consisting of a bond, -CH₂-, -O- and -CH₂CH₂-; Y is selected from a group consisting of C₁-C₃ alkyl and C₆ aryl, where C₆ aryl is optionally substituted with 1-5 substituents, which are independently selected from A, C₁-C₃ alkyl, and C₁-C₃ alkoxy; A is selected from a group consisting of

,

,

,

,

and

; L² is selected from a group consisting of a bond, -(CH₂)_n-, -C(O)NH(CH₂)_n-,

,

and

; m is an integer from zero to four; n is an integer from one to four; where the compound is substituted with at least one A. In this case, following conditions are satisfied: when X is -CH₃, L¹ is -CH₂-, Y is C₆ aryl substituted with A, and L² is -CH₂-, then A is not -L²-COOH, except for cases, when R^1a contains -COOH or -SO₂CH₃; and, when X is -CH₃, L¹ is -CH₂-, Y is C₆ aryl substituted with A, L² is -CH₂-, and A is

, then A and L¹ are not in a pair position relatively to each other.

EFFECT: obtaining a compound for the treatment of viral infections and cancer diseases.

55 cl, 1 tbl, 53 ex

Description

Cross-reference to related applications

This application claims the priority of U.S. Provisional Application No. 62/430,183, filed December 5, 2016, U.S. Provisional Application No. 62/532,230, filed July 13, 2017, the disclosures of which are incorporated herein by reference in their entirety.

Technical field

The present invention relates to a class of pyrimidine derivatives that have immunomodulatory properties that act through TLR7 and are useful in the treatment of viral or allergic diseases and cancers.

State of the art

The present invention relates to pyrimidine derivatives, methods for their preparation, pharmaceutical compositions containing them, and their use in therapy.

The immune system consists of innate and adaptive immunity, both of which work together to protect the host from microbial infections. It has been shown that innate immunity can recognize conserved pathogen-associated molecular precursors through toll-like receptors (TLRs) expressed on the cell surface of immune cells. Recognition of pathogens then triggers the production of cytokines (including interferon alpha (IFNα)) and the activation of costimulatory molecules on phagocytes, resulting in modulation of T cell function. Thus, innate immunity is closely related to acquired immunity and may influence the development and regulation of the acquired response.

TLRs are a family of type I transmembrane receptors characterized by an NH ₂ -terminal extracellular leucine-rich repeat domain (LRR) and a COOH-terminal intracellular tail containing a conserved region called the Toll/IL-1 receptor homology domain (TIR). The extracellular domain contains varying amounts of LRRs that are believed to be involved in ligand binding. To date, eleven TLRs have been described in humans and mice. They differ from each other in ligand specificity, expression profiles, and target genes that they can induce.

Ligands have been developed that act through TLRs (also known as immune response modifiers (IRMS)), such as the imidazoquinoline derivatives described in US Pat. 01448 and WO 99/28321.

Compounds with liver targeting properties are desirable. Some moieties that aid in liver targeting that have been described in the references include acid moieties. (Tu et al., Current Topics in Medicinal Chemistry, 2013, 13, 857–866; Oballa et al., J. Med. Chem., 2011, 54, 5082–5096; Pfefferkorn et al., J. Med. Chem. ., 2012, 55, 1318–1333, the contents of which are incorporated herein by reference in their entirety).

Brief description of the essence of the invention

The present invention relates to a compound having the structure of Formula (1) and pharmaceutically acceptable salts thereof,

(1)

(one)

where

; и A_, R ^1a is selected from the group consisting of H, C ₁ -C ₄ alkyl, -NH ₂ , -NHAc, -COOH, -SO ₂ CH _3, -SCH ₃ , -OCH ₃ ,

; _and A

, или A;where alkyl is optionally substituted with –OH, –NH ₂ , –NHAc, –COOH, –SO ₂ CH ₃ , –SCH ₃ , –OCH ₃ ,

, or A;

R ^1b is C ₂ -C ₅ alkyl;

X is selected from the group consisting of H and C ₁ -C ₄ alkyl, where alkyl is optionally substituted with A, -OH, or -C(CH ₃ ) ₂ OH;

,

, –O–, –S–, –SO₂–, –NH–, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, –O–, –S–, –SO ₂ –, –NH–, and –CH ₂ CH ₂ –;

Y is selected from the group consisting of C ₁ -C ₃ alkyl, aryl and heteroaryl, where alkyl, aryl and heteroaryl are optionally substituted with 1-5 substituents independently selected from A, C ₁ -C ₃ alkyl, and C ₁ -C ₃ alkoxy;

,

,

,

,

,

, и

;A is selected from the group consisting of

,

,

,

,

,

, and

;

,

,

, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилен)]–, –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–; –C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–; и –С(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–OCH₂CH₂CF₂–; L ² is selected from the group consisting of a bond, –(CH ₂ ) _n –, –C(O)NH(CH ₂ ) _n –,

,

,

, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –; –C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –; and –С(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –OCH ₂ CH ₂ CF ₂ –;

m is an integer from zero to four; and

n is an integer from one to four; and

where the compound is substituted with at least one A.

The present invention relates to a compound having the structure of Formula (1) and pharmaceutically acceptable salts thereof,

(1)

(one)

where

_, R ^1a is selected from the group consisting of H, C ₁ -C ₄ alkyl, -NH ₂ , -NHAc, -COOH, -SO ₂ CH _{3 ,} -SCH ₃ , -OCH ₃ , and

_,

;where alkyl is optionally substituted with –OH, –NH ₂ , –NHAc, –COOH, –SO ₂ CH ₃ , –SCH ₃ , –OCH ₃ , or

;

R ^1b is C ₂ -C ₅ alkyl;

X is selected from the group consisting of H and C ₁ -C ₄ alkyl, where alkyl is optionally substituted with A, -OH, or -C(CH ₃ ) ₂ OH;

,

, –O–, –S–, –SO₂–, –NH–, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, –O–, –S–, –SO ₂ –, –NH–, and –CH ₂ CH ₂ –;

Y is selected from the group consisting of C ₁ -C ₃ alkyl, aryl and heteroaryl, where alkyl, aryl and heteroaryl are optionally substituted with 1-5 substituents independently selected from A, C ₁ -C ₃ alkyl, and C ₁ -C ₃ alkoxy;

,

,

,

,

,

, и

;A is selected from the group consisting of

,

,

,

,

,

, and

;

,

,

, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилен)]–, –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–; –C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–; и –С(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–OCH₂CH₂CF₂–; L ² is selected from the group consisting of a bond, –(CH ₂ ) _n –, –C(O)NH(CH ₂ ) _n –,

,

,

, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –; –C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –; and –С(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –OCH ₂ CH ₂ CF ₂ –;

m is an integer from zero to four; and

n is an integer from one to four; and

where the compound is substituted with at least one A.

The present invention relates to a compound having the structure of Formula (1) and pharmaceutically acceptable salts thereof,

(1)

(one)

where

R ^1a is selected from the group consisting of H, C ₁ -C ₄ alkyl, -NH ₂ , -COOH, and -SO ₂ CH _3, where alkyl is optionally substituted with -OH, -NH ₂ , -COOH, or -SO ₂ CH ₃ ;

R ^1b is C ₂ -C ₅ alkyl;

X is selected from the group consisting of H and C ₁ -C ₄ alkyl, where alkyl is optionally substituted with A;

,

, –O–, –S–, –SO₂–, –NH–, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, –O–, –S–, –SO ₂ –, –NH–, and –CH ₂ CH ₂ –;

Y is selected from the group consisting of C ₁ -C ₃ alkyl, aryl and heteroaryl, where alkyl, aryl and heteroaryl are optionally substituted with 1-5 substituents independently selected from A, C ₁ -C ₃ alkyl, and C ₁ -C ₃ alkoxy;

,

,

,

,

, и

; A is selected from the group consisting of

,

,

,

,

, and

;

,

,

, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилeн)]–, и –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–;L ² is selected from the group consisting of a bond, –(CH ₂ ) _n –, –C(O)NH(CH ₂ ) _n –,

,

,

, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, and –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –;

m is an integer from zero to four; and

n is an integer from one to four; and

where the compound is substituted with at least one A.

In some embodiments, a compound having the structure of Formula (1) may have any one or more of the following:

when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A; and L ² is -CH ₂ -; then A is not -L ² -COOH;

when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A; and L ² is -CH ₂ -; then A is not -L ² -COOH, unless R ^1a contains -COOH;

when L ¹ represents -CH ₂ -; Y is aryl substituted with A; and A is -L ² -COOH; and L ² is -CH ₂ -; then X is not -CH ₃ ;

when L ¹ represents -CH ₂ -; Y is aryl substituted with A; and A is -L ² -COOH; and L ² is -CH ₂ -; then X is not -CH ₃ unless R ^1a contains -COOH;

when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A; and A is -L ² -COOH; then L ² is not -CH ₂ -;

when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A; and A is -L ² -COOH; then L ² is not -CH ₂ -, except when R ^1a contains -COOH;

when X is -CH ₃ ; Y is aryl substituted with A; and A is -L ² -COOH; and L ² is -CH ₂ -; then L ¹ is not -CH ₂ -;

when X is -CH ₃ ; Y is aryl substituted with A; and A is -L ² -COOH; and L ² is -CH ₂ -; then L ¹ is not -CH ₂ -, except when R ^1a contains -COOH;

when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A; and A is -L ² -COOH; and L ² is -CH ₂ -; then R ^1a contains COOH;

when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A and -OCH ₃ ; and L ² is -CH ₂ -; then A is not -L ² -COOH;

when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A and -OCH ₃ ; and L ² is -CH ₂ -; then A is not -L ² -COOH unless R ^1a contains -COOH;

when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A and -OCH ₃ ; and L ² is -CH ₂ -; and R ^1a does not contain COOH; then A is not -L ² -COOH.

In some embodiments, a compound having the structure of Formula (1) may have any one or more of the following:

when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A; and L ² is -CH ₂ -; then A is not -L ² -COOH;

when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A; and L ² is -CH ₂ -; then A is not -L ² -COOH unless R ^1a contains -COOH or -SO ₂ CH ₃ ;

when L ¹ represents -CH ₂ -; Y is aryl substituted with A; and A is -L ² -COOH; and L ² is -CH ₂ -; then X is not -CH ₃ ;

when L ¹ represents -CH ₂ -; Y is aryl substituted with A; and A is -L ² -COOH; and L ² is -CH ₂ -; then X is not -CH ₃ unless R ^1a contains -COOH or -SO ₂ CH ₃ ;

when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A; and A is -L ² -COOH; then L ² is not -CH ₂ -;

when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A; and A is -L ² -COOH; then L ² is not -CH ₂ - unless R ^1a contains -COOH or -SO ₂ CH ₃ ;

when X is -CH ₃ ; Y is aryl substituted with A; and A is -L ² -COOH; and L ² is -CH ₂ -; then L ¹ is not -CH ₂ -;

when X is -CH ₃ ; Y is aryl substituted with A; and A is -L ² -COOH; and L ² is -CH ₂ -; then L ¹ is not -CH ₂ - unless R ^1a contains -COOH or -SO ₂ CH ₃ ;

when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A; and A is -L ² -COOH; and L ² is -CH ₂ -; then R ^1a contains COOH or –SO ₂ CH ₃ ;

when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A and -OCH ₃ ; and L ² is -CH ₂ -; then A is not -L ² -COOH;

when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A and -OCH ₃ ; and L ² is -CH ₂ -; then A is not -L ² -COOH unless R ^1a contains -COOH or -SO ₂ CH ₃ ;

when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A and -OCH ₃ ; and L ² is -CH ₂ -; and R ^1a does not contain COOH or –SO ₂ CH ₃ ; then A is not -L ² -COOH;

when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A; and A is -L ² -COOH; and L ² is -CH ₂ -; then R ^1a is not H or alkyl substituted by –OH.

In some embodiments, a compound having the structure of Formula (1) may have any one or more of the following:

; тогда A и L¹ не находятся в пара–положении по отношению друг к другу;(aa) when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A; L ² is –CH ₂ –, –O–(CH ₂ ) ₂ –O(CH ₂ ) ₂ –, or –O–(CH ₂ ) ₂ –O(CH ₂ ) ₂ (CF ₂ )–; and A is

; then A and L ¹ are not in para-position with respect to each other;

; тогда A и L¹ не находятся в пара–положении по отношению друг к другу;(bb) when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A; L ² is -CH ₂ -; and A is

; then A and L ¹ are not in para-position with respect to each other;

; тогда A и L¹ не находятся в пара–положении по отношению друг к другу;(cc) when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A and -OCH ₃ ; L ² is -CH ₂ -; and A is

; then A and L ¹ are not in para-position with respect to each other;

; тогда A и L¹ не находятся в пара–положении по отношению друг к другу;(dd) when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A; L ² is -O-(CH ₂ ) ₂ -O(CH ₂ ) ₂ -; and A is

; then A and L ¹ are not in para-position with respect to each other;

; тогда A и L¹ не находятся в пара–положении по отношению друг к другу;(ee) when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A; L ² is -O-(CH ₂ ) ₂ -O(CH ₂ ) ₂ (CF ₂ )-; and A is

; then A and L ¹ are not in para-position with respect to each other;

;(ff) when X is -CH ₃ ; R ^1a is H; R ^1b is C ₄ alkyl; L ¹ is -CH ₂ -; Y is aryl substituted with A; and L ² is –CH ₂ –, –O–(CH ₂ ) ₂ –O(CH ₂ ) ₂ –, or –O–(CH ₂ ) ₂ –O(CH ₂ ) ₂ (CF ₂ )–; then A is not

;

;(gg) when X is -CH ₃ ; R ^1a is H; R ^1b is C ₄ alkyl; L ¹ is -CH ₂ -; Y is aryl substituted with A; and L ² is -CH ₂ -; then A is not

;

;(hh) when X is -CH ₃ ; R ^1a is H; R ^1b is C ₄ alkyl; L ¹ is -CH ₂ -; Y is aryl substituted with A and -OCH ₃ ; and L ² is -CH ₂ -; then A is not

;

;(ii) when X is -CH ₃ ; R ^1a is H; R ^1b is C ₄ alkyl; L ¹ is -CH ₂ -; Y is aryl substituted with A; and L ² is -O-(CH ₂ ) ₂ -O(CH ₂ ) ₂ -; then A is not

;

; (jj) when X is -CH ₃ ; R ^1a is H; R ^1b is C ₄ alkyl; L ¹ is -CH ₂ -; Y is aryl substituted with A; and L ² is -O-(CH ₂ ) ₂ -O(CH ₂ ) ₂ (CF ₂ )-; then A is not

;

;(kk) when X is -CH ₃ ; R ^1a is H; R ^1b is C ₄ alkyl; L ¹ is -CH ₂ -; Y is aryl substituted with A; L ² is –CH ₂ –, –O–(CH ₂ ) ₂ –O(CH ₂ ) ₂ –, or –O–(CH ₂ ) ₂ –O(CH ₂ ) ₂ (CF ₂ )–; and A and L ¹ are in para-position with respect to each other; then A is not

;

;(ll) when X is -CH ₃ ; R ^1a is H; R ^1b is C ₄ alkyl; L ¹ is -CH ₂ -; Y is aryl substituted with A; L ² is -CH ₂ -; and A and L ¹ are in para-position with respect to each other; then A is not

;

;(mm) when X is -CH ₃ ; R ^1a is H; R ^1b is C ₄ alkyl; L ¹ is -CH ₂ -; Y is aryl substituted with A and -OCH ₃ ; L ² is -CH ₂ -; and A and L ¹ are in para-position with respect to each other; then A is not

;

;(nn) when X is -CH ₃ ; R ^1a is H; R ^1b is C ₄ alkyl; L ¹ is -CH ₂ -; Y is aryl substituted with A; L ² is -O-(CH ₂ ) ₂ -O(CH ₂ ) ₂ -; and A and L ¹ are in para-position with respect to each other; then A is not

;

. (oo) when X is -CH ₃ ; R ^1a is H; R ^1b is C ₄ alkyl; L ¹ is -CH ₂ -; Y is aryl substituted with A; L ² is -O-(CH ₂ ) ₂ -O(CH ₂ ) ₂ (CF ₂ )-; and A and L ¹ are in para-position with respect to each other; then A is not

.

The present invention relates to a compound of Formula (1), which is a compound of Formula (1a),

where

X is H or CH ₃ ;

,

, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, –CH ₂ –, –O–, –S–, –CF ₂ –,

,

, and –CH ₂ CH ₂ –;

,

,

,

,

,

, и

; A is selected from the group consisting of

,

,

,

,

,

, and

;

,

, –C(O)NH(CH₂)_n–, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилен)]–, и –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–; –C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–; и C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–OCH₂CH₂CF₂–; иL ² is selected from the group consisting of a bond, -CH ₂ -, -CH ₂ CH ₂ -,

,

, –C(O)NH(CH ₂ ) _n –, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, and –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –; –C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –; and C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –OCH ₂ CH ₂ CF ₂ –; and

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

The present invention relates to a compound of Formula (1), which is a compound of Formula (1a),

where

X is H or CH ₃ ;

,

, и–CH₂CH₂–;L ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, and–CH ₂ CH ₂ –;

,

,

,

,

, и

; A is selected from the group consisting of

,

,

,

,

, and

;

,

, –C(O)NH(CH₂)_n–, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилен)]–, и –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–; иL ² is selected from the group consisting of a bond, -CH ₂ -, -CH ₂ CH ₂ -,

,

, –C(O)NH(CH ₂ ) _n –, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, and –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –; and

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

The present invention relates to a compound of Formula (1), which is a compound of Formula (1a),

where

X is -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ -A ^1a ;

,

,

,

,

,

, и

; A ^1a is selected from the group consisting of

,

,

,

,

,

, and

;

,

, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, –CH ₂ –, –O–, –S–, –CF ₂ –,

,

, and –CH ₂ CH ₂ –;

,

,

,

,

,

, и

; A is selected from the group consisting of

,

,

,

,

,

, and

;

,

, –C(O)NH(CH₂)_n–, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилен)]–, и –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–; –C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–; и C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–OCH₂CH₂CF₂–; иL ² is selected from the group consisting of a bond, -CH ₂ -, -CH ₂ CH ₂ -,

,

, –C(O)NH(CH ₂ ) _n –, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, and –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –; –C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –; and C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –OCH ₂ CH ₂ CF ₂ –; and

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

The present invention relates to a compound of Formula (1), which is a compound of Formula (1a),

where

X is -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ -A ^1a ;

,

,

,

,

, и

; A ^1a is selected from the group consisting of

,

,

,

,

, and

;

,

, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, and –CH ₂ CH ₂ –;

,

,

,

,

, и

; A is selected from the group consisting of

,

,

,

,

, and

;

,

, –C(O)NH(CH₂)_n–, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилен)]–, и –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–; иL ² is selected from the group consisting of a bond, -CH ₂ -, -CH ₂ CH ₂ -,

,

, –C(O)NH(CH ₂ ) _n –, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, and –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –; and

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

The present invention relates to a compound of Formula (1), which is a compound of Formula (1b),

where

X is H or CH ₃ ;

,

, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, –CH ₂ –, –O–, –S–, –CF ₂ –,

,

, and –CH ₂ CH ₂ –;

,

,

,

,

, и

, и

; A is selected from the group consisting of

,

,

,

,

, and

, and

;

,

, –C(O)NH(CH₂)_n–, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилен)]–, и –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–; –C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–; и C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–OCH₂CH₂CF₂–; иL ² is selected from the group consisting of a bond, -CH ₂ -, -CH ₂ CH ₂ -,

,

, –C(O)NH(CH ₂ ) _n –, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, and –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –; –C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –; and C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –OCH ₂ CH ₂ CF ₂ –; and

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

The present invention relates to a compound of Formula (1), which is a compound of Formula (1b),

where

X is H or CH ₃ ;

,

, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, and –CH ₂ CH ₂ –;

,

,

,

,

, и

; A is selected from the group consisting of

,

,

,

,

, and

;

,

, –C(O)NH(CH₂)_n–, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилен)]–, и –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–; иL ² is selected from the group consisting of a bond, -CH ₂ -, -CH ₂ CH ₂ -,

,

, –C(O)NH(CH ₂ ) _n –, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, and –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –; and

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

The present invention relates to a compound of Formula (1), which is a compound of Formula (1b),

where

X is -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ -A ^1a ;

,

,

,

,

,

, и

; A ^1a is selected from the group consisting of

,

,

,

,

,

, and

;

,

, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, –CH ₂ –, –O–, –S–, –CF ₂ –,

,

, and –CH ₂ CH ₂ –;

,

,

,

,

,

, и

; A is selected from the group consisting of

,

,

,

,

,

, and

;

,

, –C(O)NH(CH₂)_n–, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилен)]–, и –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–; –C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–; и C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–OCH₂CH₂CF₂–; иL ² is selected from the group consisting of a bond, -CH ₂ -, -CH ₂ CH ₂ -,

,

, –C(O)NH(CH ₂ ) _n –, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, and –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –; –C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –; and C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –OCH ₂ CH ₂ CF ₂ –; and

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

The present invention relates to a compound of Formula (1), which is a compound of Formula (1b),

where

X is -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ -A ^1a ;

,

,

,

,

, и

; A ^1a is selected from the group consisting of

,

,

,

,

, and

;

,

, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, and –CH ₂ CH ₂ –;

,

,

,

,

, и

; A is selected from the group consisting of

,

,

,

,

, and

;

,

, –C(O)NH(CH₂)_n–, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилен)]–, и –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–; иL ² is selected from the group consisting of a bond, -CH ₂ -, -CH ₂ CH ₂ -,

,

, –C(O)NH(CH ₂ ) _n –, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, and –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –; and

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

The present invention relates to a compound of Formula (1), which is a compound of Formula (1c),

where

X is -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ -A ^1a ;

,

,

,

,

,

, и

; A ^1a is selected from the group consisting of

,

,

,

,

,

, and

;

,

, и –CH₂CH₂–; L ¹ is selected from the group consisting of a bond, –CH ₂ –, –O–, –S–, –CF ₂ –,

,

, and –CH ₂ CH ₂ –;

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy; and

R ⁴ is H or C ₁ -C ₃ alkoxy.

The present invention relates to a compound of Formula (1), which is a compound of Formula (1c),

where

X is -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ -A ^1a ;

,

,

,

,

, и

; A ^1a is selected from the group consisting of

,

,

,

,

, and

;

,

, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, and –CH ₂ CH ₂ –;

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy; and

R ⁴ is H or C ₁ -C ₃ alkoxy.

The present invention relates to a compound of Formula (1), which is a compound of Formula (1d),

X is -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ -A ^1a ;

,

,

,

,

,

, и

; A ^1a is selected from the group consisting of

,

,

,

,

,

, and

;

,

, –O–, –CH₂CH₂, и –S–; иL ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, –O–, –CH ₂ CH ₂ , and –S–; and

Y is H or C ₁ -C ₃ alkyl.

The present invention relates to a compound of Formula (1), which is a compound of Formula (1d),

X is -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ -A ^1a ;

,

,

,

,

, и

; A ^1a is selected from the group consisting of

,

,

,

,

, and

;

,

, –O–, и –CH₂CH₂–; иL ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, –O–, and –CH ₂ CH ₂ –; and

Y is H or C ₁ -C ₃ alkyl.

The present invention relates to a compound of Formula (1), which is a compound of Formula (1e),

where

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

The present invention relates to a compound of Formula (1), which is a compound of Formula (1f),

.

.

The present invention relates to a compound of Formula (1), which is a compound of Formula (1g),

where

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

The present invention relates to a compound of Formula (1), which is a compound of Formula (1h),

where

R ⁴ is H or C ₁ -C ₃ alkoxy.

The present invention relates to a compound of Formula (1), which is a compound of Formula (1i),

where

,

, –O–, –CH₂CH₂–, и –S–; иL ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, –O–, –CH ₂ CH ₂ –, and –S–; and

Y is H or C ₁ -C ₃ alkyl.

The present invention relates to a compound of Formula (1), which is a compound of Formula (1i),

where

,

, –O–, и –CH₂CH₂–; иL ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, –O–, and –CH ₂ CH ₂ –; and

Y is H or C ₁ -C ₃ alkyl.

The present invention relates to a compound of Formula (1), which is a compound of Formula (1j),

(1j).

(1j).

The present invention relates to a compound of Formula (1), which is a compound of Formula (1k),

(1k),

(1k),

The present description relates to pharmaceutical compositions containing a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The present disclosure relates to methods of treating a condition associated with TLR7 modulation in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof. In some embodiments, the condition is a viral infection or cancer.

The present disclosure relates to a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition associated with TLR7 modulation. In some embodiments, the condition is a viral infection or cancer.

The present disclosure relates to the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a condition associated with TLR7 modulation. In some embodiments, the condition is a viral infection or cancer.

Detailed Description of the Invention

Although specific embodiments of the essence of the present invention are illustrated and described in detail, the invention is not limited to them. The detailed description is given as an example of the present invention and should not be construed as constituting any limitation of the invention. Modifications will be apparent to those skilled in the art, and all modifications that do not depart from the spirit of the invention are intended to be included within the scope of the appended claims.

Definitions

The following definitions are intended to clarify, and not to limit, certain terms. If a particular term used in this document is not specifically defined, such term should not be considered indefinite. Rather, the terms are used in their accepted meanings.

As used herein, the term "alkyl" refers to a straight or branched chain saturated hydrocarbon. For example, an alkyl group may have 1 to 8 carbon atoms (i.e., (C ₁ -C ₈ )alkyl) or 1 to 6 carbon atoms (i.e., (C ₁ -C ₆ alkyl) or from 1 to 4 carbons.

As used herein, the term "alkylene" refers to a straight or branched chain saturated hydrocarbon radical having two monovalent radical centers obtained by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkane. For example, an alkylene group may have 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms.

Used in this document, the term "alkoxy" refers to an alkyl group attached to the original molecular fragment through an oxygen atom.

As used herein, the term "halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

As used herein, the term "aryl" refers to a single all-carbon aromatic ring or multiple fused all-carbon ring system, where at least one of the rings is aromatic. For example, an aryl group may have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl contains a phenyl radical. Aryl also contains multiple fused ring systems (e.g., ring systems containing 2, 3, or 4 rings) having from about 9 to about 20 carbon atoms, in which at least one ring is aromatic and where the other rings may be aromatic or non-aromatic (i.e. carbocycle). Such multiple fused ring systems may be optionally substituted with one or more (eg 1, 2 or 3) oxo groups on any carbocyclic portion of the multiple fused ring system. The rings of a multiple fused ring system may be connected to each other by fused, spiro, and bridged bonds if allowed by valence requirements. It should be understood that the point of attachment of the multiple fused ring system as defined above may be at any position on the ring system, including the aromatic or carbocyclic portion of the ring.

As used herein, the term "heteroaryl" refers to a single aromatic ring that has at least one atom other than carbon in the ring, where the atom is selected from the group consisting of oxygen, nitrogen and sulfur; the term also includes a plurality of fused ring systems that have at least one such aromatic ring, which for a plurality of fused ring systems is further described below. The term thus includes single aromatic rings with about 1–6 carbon atoms and about 1–4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in the rings. The sulfur and nitrogen atoms may also be present in oxidized form, provided the ring is aromatic. The term also includes multiple fused ring systems (e.g., ring systems containing 2, 3, or 4 rings) in which a heteroaryl group, as defined above, can be fused to one or more rings selected from heteroaryls (to form, for example, naphthyridinyl, such as 1,8-naphthyridinyl), heterocycles (to form, for example, 1,2,3,4-tetrahydronaphthyridinyl, such as for example, 5,6,7,8-tetrahydroquinolyl) and aryls (to form, for example, indazolyl), to form a polycondensed ring system. Thus, a heteroaryl (one aromatic ring or a system of polycondensed rings) has about 1–20 carbon atoms and about 1–6 heteroatoms in the heteroaryl ring. Such polyfused ring systems may be optionally substituted with one or more (eg 1, 2, 3 or 4) oxo groups on the carbocyclic or heterocyclic portions of the fused ring. The rings of a multiple fused ring system may be connected to each other by fused, spiro, and bridged bonds if allowed by valence requirements. It should be understood that the individual rings of the multiple fused ring system may be connected in any order relative to each other. It should also be understood that the point of attachment of the polyfused ring system (as defined above for heteroaryl) may be at any position of the polyfused ring system, including the heteroaryl, heterocyclic, aryl, or carbocyclic portion of the polyfused ring system, and at any suitable atom of the polyfused ring system, including the atom carbon and a heteroatom (eg nitrogen).

As used herein, the term "pharmaceutically acceptable" refers to forms of carriers, diluents, excipients, or salts that are compatible with the other ingredients of the composition and are not harmful to the recipient of the pharmaceutical composition.

As used herein, the term "pharmaceutical composition" refers to a compound of the present invention optionally admixed with one or more pharmaceutically acceptable carriers, diluents, excipients, or adjuvants. Pharmaceutical compositions preferably exhibit a degree of environmental stability to make them suitable for manufacturing and commercialization purposes.

As used herein, the term "effective amount", "therapeutic amount" or "effective dose" refers to an amount of the active ingredient sufficient to achieve the desired pharmacological or therapeutic effects, resulting in effective prevention or treatment of the disorder. Prevention of a disorder may be manifested by delaying or preventing the progression of the disorder, as well as delaying or preventing the onset of symptoms associated with the disorder. Treatment of a disorder may be manifested by the reduction or elimination of symptoms, the suppression or elimination of the progression of the disorder, or any other contribution to the patient's well-being.

The effective dose may vary depending on factors such as the condition of the patient, the severity of the symptoms of the disorder, and the route of administration of the pharmaceutical composition. Typically, to be administered at an effective dose, the compounds must be administered in an amount of less than 30 mg/kg of patient weight. Frequently, the compounds may be administered in amounts from less than about 1 mg/kg of patient weight to less than about 100 µg/kg of patient weight, and sometimes from about 10 µg/kg to less than 100 µg/kg of patient weight. The above effective doses are usually that amount administered as a single dose or as one or more doses administered over a 24 hour period. For human patients, an effective dose of the compounds may require administration of the compound in an amount of at least about 1 mg/24 hours/patient, but not more than about 2400 mg/24 hours/patient, and often not more than about 500 mg/24 hours/patient .

Connections

The present invention relates to a compound having the structure of Formula (1) and pharmaceutically acceptable salts thereof,

(1)

(one)

where

; и A_, R ^1a is selected from the group consisting of H, C ₁ -C ₄ alkyl, -NH ₂ , -NHAc, -COOH, -SO ₂ CH _3, -SCH ₃ , -OCH ₃ ,

; _and A

, или A;where alkyl is optionally substituted with –OH, –NH ₂ , –NHAc, –COOH, –SO ₂ CH ₃ , –SCH ₃ , –OCH ₃ ,

, or A;

R ^1b is C ₂ -C ₅ alkyl;

X is selected from the group consisting of H and C ₁ -C ₄ alkyl, where alkyl is optionally substituted with A, -OH, or -C(CH ₃ ) ₂ OH;

,

, –O–, –S–, –SO₂–, –NH–, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, –O–, –S–, –SO ₂ –, –NH–, and –CH ₂ CH ₂ –;

Y is selected from the group consisting of C ₁ -C ₃ alkyl, aryl and heteroaryl, where alkyl, aryl and heteroaryl are optionally substituted with 1-5 substituents independently selected from A, C ₁ -C ₃ alkyl, and C ₁ -C ₃ alkoxy;

,

,

,

,

,

, и

;A is selected from the group consisting of

,

,

,

,

,

, and

;

,

,

, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилен)]–, –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–; –C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–; и –С(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–OCH₂CH₂CF₂–; L ² is selected from the group consisting of a bond, –(CH ₂ ) _n –, –C(O)NH(CH ₂ ) _n –,

,

,

, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –; –C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –; and –С(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –OCH ₂ CH ₂ CF ₂ –;

m is an integer from zero to four; and

n is an integer from one to four; and

where the compound is substituted with at least one A.

The present invention relates to a compound having the structure of Formula (1) and pharmaceutically acceptable salts thereof,

(1)

(one)

where

_, R ^1a is selected from the group consisting of H, C ₁ -C ₄ alkyl, -NH ₂ , -NHAc, -COOH, -SO ₂ CH _{3 ,} -SCH ₃ , -OCH ₃ , and

_,

;where alkyl is optionally substituted with –OH, –NH ₂ , –NHAc, –COOH, –SO ₂ CH ₃ , –SCH ₃ , –OCH ₃ , or

;

R ^1b is C ₂ -C ₅ alkyl;

X is selected from the group consisting of H and C ₁ -C ₄ alkyl, where alkyl is optionally substituted with A, -OH, or -C(CH ₃ ) ₂ OH;

,

, –O–, –S–, –SO₂–, –NH–, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, –O–, –S–, –SO ₂ –, –NH–, and –CH ₂ CH ₂ –;

Y is selected from the group consisting of C ₁ -C ₃ alkyl, aryl and heteroaryl, where alkyl, aryl and heteroaryl are optionally substituted with 1-5 substituents independently selected from A, C ₁ -C ₃ alkyl, and C ₁ -C ₃ alkoxy;

,

,

,

,

,

, и

;A is selected from the group consisting of

,

,

,

,

,

, and

;

,

,

, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилен)]–, –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–; –C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–; и –С(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–OCH₂CH₂CF₂–; L ² is selected from the group consisting of a bond, –(CH ₂ ) _n –, –C(O)NH(CH ₂ ) _n –,

,

,

, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –; –C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –; and –С(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –OCH ₂ CH ₂ CF ₂ –;

m is an integer from zero to four; and

n is an integer from one to four; and

where the compound is substituted with at least one A.

, где алкил необязательно замещен –OH, –NH₂, –NHAc, –COOH, –SO₂CH₃, –SCH₃, –OCH₃, или

. В некоторых вариантах реализации, R^1a представляет собой –COOH, который является выбором среди заместителей А. В некоторых вариантах реализации, R^1a представляет собой

, который является выбором среди заместителей А. В некоторых вариантах реализации, R^1a представляет собой C₁–C₄ алкил, где алкил замещен –COOH, который является выбором среди заместителей A. В некоторых вариантах реализации, R^1a представляет собой C₁–C₄ алкил, где алкил замещен

, который является выбором среди заместителей А. As described above, R ^1a is selected from the group consisting of H, C ₁ -C ₄ alkyl, -NH ₂ , -NHAc, -COOH, -SO ₂ CH _{3 ,} -SCH ₃ , -OCH ₃ , and

where alkyl is optionally substituted with –OH, –NH ₂ , –NHAc, –COOH, –SO ₂ CH ₃ , –SCH ₃ , –OCH ₃ , or

. In some embodiments, R ^1a is -COOH, which is a choice of substituents A. In some embodiments, R ^1a is

, which is a choice of substituents A. In some embodiments, R ^1a is C ₁ -C ₄ alkyl, where alkyl is substituted by -COOH, which is a choice of substituents A. In some embodiments, R ^1a is C ₁ -C ₄ alkyl where alkyl is substituted

, which is a choice among substituents A.

The present invention relates to a compound having the structure of Formula (1) and pharmaceutically acceptable salts thereof,

(1)

(one)

where

R ^1a is selected from the group consisting of H, C ₁ -C ₄ alkyl, -NH ₂ , -COOH, and -SO ₂ CH _3, where alkyl is optionally substituted with -OH, -NH ₂ , -COOH, or -SO ₂ CH ₃ ;

R ^1b is C ₂ -C ₅ alkyl;

X is selected from the group consisting of H and C ₁ -C ₄ alkyl, where alkyl is optionally substituted with A;

,

, –O–, –S–, –SO₂–, –NH–, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, –O–, –S–, –SO ₂ –, –NH–, and –CH ₂ CH ₂ –;

Y is selected from the group consisting of C ₁ -C ₃ alkyl, aryl and heteroaryl, where alkyl, aryl and heteroaryl are optionally substituted with 1-5 substituents independently selected from A, C ₁ -C ₃ alkyl, and C ₁ -C ₃ alkoxy;

,

,

,

,

, и

; A is selected from the group consisting of

,

,

,

,

, and

;

,

,

, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилeн)]–, и–[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–;L ² is selected from the group consisting of a bond, –(CH ₂ ) _n –, –C(O)NH(CH ₂ ) _n –,

,

,

, -[O (CH ₂ CH ₂ )] _n -, - [O (C ₁ -C ₄ alkylene)] -, and - [O (CH ₂ CH ₂ )] _n -OCH ₂ CH ₂ CF ₂ -;

m is an integer from zero to four; and

n is an integer from one to four; and

where the compound is substituted with at least one A.

In some embodiments, R ^1b is C ₃ alkyl, C ₄ alkyl, or C ₅ alkyl. In some embodiments, R ^1b is -(CH ₂ ) ₂ CH ₃ . In some embodiments, R ^1b is -(CH ₂ ) ₃ CH ₃ .

представляет собой

или

. В некоторых вариантах реализации,

представляет собой

,

,

,

,

, или

. In some embodiments, R ^1a is H. In some embodiments, R ^1a is C ₁ -C ₄ alkyl optionally substituted with -OH. In some embodiments, R ^1a is C ₁ -C ₃ alkyl optionally substituted with -OH. In some embodiments, R ^1a is -CH ₂ C(CH ₃ ) ₂ OH. In some implementations,

represents

or

. In some implementations,

represents

,

,

,

,

, or

.

In some embodiments, the stereocenter of the carbon bearing R ^1A and R ^1B has the (S)-configuration. In some embodiments, the stereocenter of the carbon bearing R ^1A and R ^1B has the (R)-configuration.

представляет собой

. In some embodiments, R ^1a is C ₁ -C ₄ alkyl optionally substituted with -COOH. In some embodiments, R ^1a is C ₁ -C ₃ alkyl optionally substituted with -COOH. In some implementations,

represents

.

In some embodiments, R ^1a is C ₁ -C ₄ alkyl, where alkyl is optionally substituted with -OH, -NH ₂ , -COOH, or -SO ₂ CH ₃ . In some embodiments, R ^1a is -NH _2, -COOH, or -SO ₂ CH _3. In some embodiments, R ^1a is C ₁ -C ₄ alkyl optionally substituted with -OH, -OCH ₃ , -SCH ₃ , or -SO ₂ CH _3.

, где L² представляет собой связь. В некоторых вариантах реализации, X представляет собой CH_3. In some embodiments, X is C ₁ -C ₄ alkyl where alkyl is substituted by A. In some embodiments, X is C ₁ -C ₄ alkyl where alkyl is substituted

, where L ² is a bond. In some embodiments, X is CH _3.

In some embodiments, X is H. In some embodiments, X is C ₁ -C ₄ alkyl.

In some embodiments, L ¹ is -CH ₂ -, -CH ₂ CH ₂ -, or -O-. In some embodiments, L ¹ is -CH ₂ -. In some embodiments, L ¹ is -CH ₂ -, -CH ₂ CH ₂ -, -O-, or -S-.

,

, –S–, –SO₂–, или –NH–. In some embodiments, L ¹ is a bond, –CF ₂ –,

,

, -S-, -SO ₂ -, or -NH-.

In some embodiments, Y is C ₁ -C ₃ alkyl or aryl. In some embodiments, Y is aryl, where aryl is substituted with C ₁ -C ₃ alkoxy. In some embodiments, Y is aryl, where aryl is substituted by A. In some embodiments, Y is aryl, where aryl is substituted by C ₁ -C ₃ alkoxy and A.

In some embodiments, Y is heteroaryl, where heteroaryl is optionally substituted with 1-5 substituents that are independently selected from A, C ₁ -C ₃ alkyl, and C ₁ -C ₃ alkoxy. In some embodiments, Y is C ₁ -C ₃ alkyl, where alkyl is optionally substituted with 1-5 substituents independently selected from A, C ₁ -C ₃ alkyl, and C ₁ -C ₃ alkoxy. In some embodiments, is aryl, where the aryl is optionally substituted with 1-5 substituents that are independently selected from A, C ₁ -C ₃ alkyl, and C ₁ -C ₃ alkoxy.

. В некоторых вариантах реализации, A представляет собой

. В некоторых вариантах реализации, A представляет собой

. В некоторых вариантах реализации, A представляет собой

. В некоторых вариантах реализации, A представляет собой

. В некоторых вариантах реализации, A представляет собой

. In some implementations, A is

. In some implementations, A is

. In some implementations, A is

. In some implementations, A is

. In some implementations, A is

. In some implementations, A is

.

. В некоторых вариантах реализации, L² представляет собой

. В некоторых вариантах реализации, L² представляет собой –C(O)NH(CH₂)_n–. In some embodiments, L ² is -(CH ₂ ) _n -. In some embodiments, L ² is

. In some embodiments, L ² is

. In some embodiments, L ² is -C(O)NH(CH ₂ ) _n -.

, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилeн)]–, или –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–. In some embodiments, L ² is a bond,

, -[O (CH ₂ CH ₂ )] _n -, - [O (C ₁ -C ₄ alkylene)] -, or - [O (CH ₂ CH ₂ )] _n -OCH ₂ CH ₂ CF ₂ -.

In some embodiments, n is one or two. In some implementations, n is one. In some embodiments, n is two. In some embodiments, n is three. In some embodiments, n is four.

In some embodiments, m is zero. In some embodiments, m is one. In some embodiments, m is two. In some embodiments, m is three. In some embodiments, m is four.

The present invention relates to a compound of Formula (1) having the structure of Formula (1a) and pharmaceutically acceptable salts thereof,

.

.

In some embodiments of Formula (1a),

X is H or CH ₃ ;

,

, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, –CH ₂ –, –O–, –S–, –CF ₂ –,

,

, and –CH ₂ CH ₂ –;

,

,

,

,

,

, и

; A is selected from the group consisting of

,

,

,

,

,

, and

;

,

, –C(O)NH(CH₂)_n–, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилен)]–, и –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–; –C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–; и C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–OCH₂CH₂CF₂–; иL ² is selected from the group consisting of a bond, -CH ₂ -, -CH ₂ CH ₂ -,

,

, –C(O)NH(CH ₂ ) _n –, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, and –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –; –C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –; and C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –OCH ₂ CH ₂ CF ₂ –; and

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

In another embodiment of Formula (1a)

X is H or CH ₃ ;

,

, и–CH₂CH₂–;L ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, and–CH ₂ CH ₂ –;

,

,

,

,

, и

; A is selected from the group consisting of

,

,

,

,

, and

;

,

, –C(O)NH(CH₂)_n–, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилен)]–, и –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–; иL ² is selected from the group consisting of a bond, -CH ₂ -, -CH ₂ CH ₂ -,

,

, –C(O)NH(CH ₂ ) _n –, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, and –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –; and

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

,

,

,

,

,

, и

или A^1a выбирают из группы, состоящей из

,

,

,

,

, и

. В вышеупомянутом, X содержит A^1a, который выбирают среди заместителей А. As described above, in some embodiments, X may be -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ - A ^1a ; where A ^1a is selected from the group consisting of

,

,

,

,

,

, and

or A ^1a is selected from the group consisting of

,

,

,

,

, and

. In the above, X contains A ^1a which is chosen from the substituents of A.

Accordingly, in some embodiments, X may be -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ -A ^1a ; where A ^1a represents A;

,

,

,

,

,

, и

; иwhere A is selected from the group consisting of

,

,

,

,

,

, and

; and

L ² is a bond.

Accordingly, in some embodiments, X may be -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ -A ^1a ; where A ^1a represents A;

,

,

,

,

, и

; и where A is selected from the group consisting of

,

,

,

,

, and

; and

L ² is a bond.

In another embodiment of Formula (1a)

X is -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ -A ^1a ;

,

,

,

,

,

, и

; A ^1a is selected from the group consisting of

,

,

,

,

,

, and

;

,

, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, –CH ₂ –, –O–, –S–, –CF ₂ –,

,

, and –CH ₂ CH ₂ –;

,

,

,

,

,

, и

; A is selected from the group consisting of

,

,

,

,

,

, and

;

,

, –C(O)NH(CH₂)_n–, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилен)]–, и –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–; –C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–; и C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–OCH₂CH₂CF₂–; иL ² is selected from the group consisting of a bond, -CH ₂ -, -CH ₂ CH ₂ -,

,

, –C(O)NH(CH ₂ ) _n –, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, and –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –; –C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –; and C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –OCH ₂ CH ₂ CF ₂ –; and

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

In another embodiment of Formula (1a)

X is -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ -A ^1a ;

,

,

,

,

, и

; A ^1a is selected from the group consisting of

,

,

,

,

, and

;

,

, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, and –CH ₂ CH ₂ –;

,

,

,

,

, и

; A is selected from the group consisting of

,

,

,

,

, and

;

,

, –C(O)NH(CH₂)_n–, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилен)]–, и –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–; иL ² is selected from the group consisting of a bond, -CH ₂ -, -CH ₂ CH ₂ -,

,

, –C(O)NH(CH ₂ ) _n –, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, and –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –; and

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

The present invention relates to a compound of Formula (1) having the structure of formula (1b) and pharmaceutically acceptable salts thereof,

.

.

In some embodiments of Formula (1b),

X is H or CH ₃ ;

,

, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, –CH ₂ –, –O–, –S–, –CF ₂ –,

,

, and –CH ₂ CH ₂ –;

,

,

,

,

, и

, и

; A is selected from the group consisting of

,

,

,

,

, and

, and

;

,

, –C(O)NH(CH₂)_n–, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилен)]–, и –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–; –C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–; и C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–OCH₂CH₂CF₂–; иL ² is selected from the group consisting of a bond, -CH ₂ -, -CH ₂ CH ₂ -,

,

, –C(O)NH(CH ₂ ) _n –, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, and –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –; –C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –; and C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –OCH ₂ CH ₂ CF ₂ –; and

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

In another embodiment of Formula (1b)

X is H or CH ₃ ;

,

, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, and –CH ₂ CH ₂ –;

,

,

,

,

, и

; A is selected from the group consisting of

,

,

,

,

, and

;

,

, –C(O)NH(CH₂)_n–, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилен)]–, и –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–; иL ² is selected from the group consisting of a bond, -CH ₂ -, -CH ₂ CH ₂ -,

,

, –C(O)NH(CH ₂ ) _n –, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, and –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –; and

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

,

,

,

,

,

, и

или A^1a выбирают из группы, состоящей из

,

,

,

,

, и

. В вышеупомянутом, X содержит A^1a, который выбирают среди заместителей А. As described above, In some embodiments, X may be -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ - A ^1a ; where A ^1a is selected from the group consisting of

,

,

,

,

,

, and

or A ^1a is selected from the group consisting of

,

,

,

,

, and

. In the above, X contains A ^1a which is chosen from the substituents of A.

Accordingly, in some embodiments, X may be -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ -A ^1a ; where A ^1a represents A;

,

,

,

,

,

, и

; иwhere A is selected from the group consisting of

,

,

,

,

,

, and

; and

L ² is a bond.

Accordingly, in some embodiments, X may be -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ -A ^1a ; where A ^1a represents A;

,

,

,

,

, и

; и where A is selected from the group consisting of

,

,

,

,

, and

; and

L ² is a bond.

In another embodiment of Formula (1b)

X is -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ -A ^1a ;

,

,

,

,

,

, и

; A ^1a is selected from the group consisting of

,

,

,

,

,

, and

;

,

, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, –CH ₂ –, –O–, –S–, –CF ₂ –,

,

, and –CH ₂ CH ₂ –;

,

,

,

,

,

, и

; A is selected from the group consisting of

,

,

,

,

,

, and

;

,

, –C(O)NH(CH₂)_n–, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилен)]–, и –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–; –C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–; и C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–OCH₂CH₂CF₂–; иL ² is selected from the group consisting of a bond, -CH ₂ -, -CH ₂ CH ₂ -,

,

, –C(O)NH(CH ₂ ) _n –, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, and –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –; –C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –; and C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –OCH ₂ CH ₂ CF ₂ –; and

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

In another embodiment of Formula (1b)

X is -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ -A ^1a ;

,

,

,

,

, и

; A ^1a is selected from the group consisting of

,

,

,

,

, and

;

,

, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, and –CH ₂ CH ₂ –;

,

,

,

,

, и

; A is selected from the group consisting of

,

,

,

,

, and

;

,

, –C(O)NH(CH₂)_n–, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилен)]–, и –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–; иL ² is selected from the group consisting of a bond, -CH ₂ -, -CH ₂ CH ₂ -,

,

, –C(O)NH(CH ₂ ) _n –, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, and –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –; and

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

The present invention relates to a compound of Formula (1) having the structure of formula (1c) and pharmaceutically acceptable salts thereof,

.

.

,

,

,

,

,

, и

или A^1a выбирают из группы, состоящей из

,

,

,

,

, и

. В вышеупомянутом, X содержит A^1a, который выбирают среди заместителей А. As described above, In some embodiments, X may be -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ - A ^1a ; where A ^1a is selected from the group consisting of

,

,

,

,

,

, and

or A ^1a is selected from the group consisting of

,

,

,

,

, and

. In the above, X contains A ^1a which is chosen from the substituents of A.

Accordingly, in some embodiments, X may be -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ -A ^1a ; where A ^1a represents A;

,

,

,

,

,

, и

; иwhere A is selected from the group consisting of

,

,

,

,

,

, and

; and

L ² is a bond.

Accordingly, in some embodiments, X may be -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ -A ^1a ; where A ^1a represents A;

,

,

,

,

, и

; и where A is selected from the group consisting of

,

,

,

,

, and

; and

L ² is a bond.

In some embodiments of Formula (1c),

X is -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ -A ^1a ;

,

,

,

,

,

, и

; A ^1a is selected from the group consisting of

,

,

,

,

,

, and

;

,

, и –CH₂CH₂–; L ¹ is selected from the group consisting of a bond, –CH ₂ –, –O–, –S–, –CF ₂ –,

,

, and –CH ₂ CH ₂ –;

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy; and

R ⁴ is H or C ₁ -C ₃ alkoxy.

In another embodiment of Formula (1c)

X is -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ -A ^1a ;

,

,

,

,

, и

; A ^1a is selected from the group consisting of

,

,

,

,

, and

;

,

, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, and –CH ₂ CH ₂ –;

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy; and

R ⁴ is H or C ₁ -C ₃ alkoxy.

The present invention relates to a compound of Formula (1) having the structure of formula (1d) and pharmaceutically acceptable salts thereof,

,

,

,

,

,

, и

или A^1a выбирают из группы, состоящей из

,

,

,

,

, и

. В вышеупомянутом, X содержит A^1a, который выбирают среди заместителей А. As described above, In some embodiments, X may be -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ - A ^1a ; where A ^1a is selected from the group consisting of

,

,

,

,

,

, and

or A ^1a is selected from the group consisting of

,

,

,

,

, and

. In the above, X contains A ^1a which is chosen from the substituents of A.

Accordingly, in some embodiments, X may be -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ -A ^1a ; where A ^1a represents A;

,

,

,

,

,

, и

; иwhere A is selected from the group consisting of

,

,

,

,

,

, and

; and

L ² is a bond.

Accordingly, in some embodiments, X may be -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ -A ^1a ; where A ^1a represents A;

,

,

,

,

, и

; и where A is selected from the group consisting of

,

,

,

,

, and

; and

L ² is a bond.

In some embodiments of Formula (1d),

X is -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ -A ^1a ;

,

,

,

,

,

, и

; A ^1a is selected from the group consisting of

,

,

,

,

,

, and

;

,

, –O–, –CH₂CH₂, и –S–; иL ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, –O–, –CH ₂ CH ₂ , and –S–; and

Y is H or C ₁ -C ₃ alkyl.

In another embodiment of Formula (1d)

X is -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ -A ^1a ;

,

,

,

,

, и

; A ^1a is selected from the group consisting of

,

,

,

,

, and

;

,

, –O–, и –CH₂CH₂–; иL ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, –O–, and –CH ₂ CH ₂ –; and

Y is H or C ₁ -C ₃ alkyl.

The present invention relates to a compound of Formula (1) having the structure of formula (1e) and pharmaceutically acceptable salts thereof,

where R ³ represents H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

The present invention relates to a compound of Formula (1) having the structure of formula (1f) and pharmaceutically acceptable salts thereof,

.

.

The present invention relates to a compound of Formula (1) having the structure of formula (1g) and pharmaceutically acceptable salts thereof,

where R ³ represents H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

The present invention relates to a compound of Formula (1) having the structure of formula (1h) and pharmaceutically acceptable salts thereof,

where R ⁴ represents H or C ₁ -C ₃ alkoxy.

The present invention relates to a compound of Formula (1) having the structure of formula (1i) and pharmaceutically acceptable salts thereof,

where

,

, –O–, –CH₂CH₂–, и –S–; иL ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, –O–, –CH ₂ CH ₂ –, and –S–; and

Y is H or C ₁ -C ₃ alkyl.

In another embodiment of Formula (1i)

,

, –O–, и –CH₂CH₂–; иL ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, –O–, and –CH ₂ CH ₂ –; and

Y is H or C ₁ -C ₃ alkyl.

The present invention relates to a compound of Formula (1) having the structure of formula (1j) and pharmaceutically acceptable salts thereof,

(1j).

(1j).

In some embodiments of Formula (1j), X is H or CH ₃ .

. In some embodiments of Formula (1j), R ^1a is selected from the group consisting of H and C ₁ -C ₄ alkyl, where alkyl is optionally substituted with -OH, -NH ₂ , -NHAc, -COOH, -SO ₂ CH ₃ , - SCH ₃ , –OCH ₃ , or

.

In some embodiments of Formula (1j), R ^1a is selected from the group consisting of H and C ₁ -C ₄ alkyl, where alkyl is optionally substituted with -COOH.

The present invention relates to a compound of Formula (1) having the structure of formula (1k) and pharmaceutically acceptable salts thereof,

(1k),

(1k),

In some embodiments of Formula (1k), X is H or CH ₃ .

In some embodiments of Formula (1k), R ^1b is C ₄ alkyl.

In some implementations of Formula (1k),

Y is aryl or heteroaryl, where aryl and heteroaryl are optionally substituted with 1-5 substituents independently selected from A, C ₁ -C ₃ alkyl, and C ₁ -C ₃ alkoxy;

,

,

,

,

, и

; иA is selected from the group consisting of

,

,

,

,

, and

; and

,

,

, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилeн)]–, и–[O(CH₂CH₂)]_n–OCH₂CH₂CF₂. L ² is selected from the group consisting of a bond, –(CH ₂ ) _n –, –C(O)NH(CH ₂ ) _n –,

,

,

, -[O (CH ₂ CH ₂ )] _n -, - [O (C ₁ -C ₄ alkylene)] -, and - [O (CH ₂ CH ₂ )] _n -OCH ₂ CH ₂ CF ₂ .

In some implementations of Formula (1k),

Y is aryl, where aryl is optionally substituted with 1-5 substituents independently selected from A, C ₁ -C ₃ alkyl, and C ₁ -C ₃ alkoxy;

,

, и

; иA is selected from the group consisting of

,

, and

; and

,

,

, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилeн)]–, и–[O(CH₂CH₂)]_n–OCH₂CH₂CF₂. L ² is selected from the group consisting of a bond, –(CH ₂ ) _n –, –C(O)NH(CH ₂ ) _n –,

,

,

, -[O (CH ₂ CH ₂ )] _n -, - [O (C ₁ -C ₄ alkylene)] -, and - [O (CH ₂ CH ₂ )] _n -OCH ₂ CH ₂ CF ₂ .

In some implementations of Formula (1k),

Y is aryl, where aryl is optionally substituted with 1-5 substituents independently selected from A, C ₁ -C ₃ alkyl, and C ₁ -C ₃ alkoxy;

; иA represents

; and

,

, и

. L ² is selected from the group consisting of a bond, –(CH ₂ ) _n –,

,

, and

.

представляет собой

или

. In one embodiment of Formula (1), R ^1b is -(CH ₂ ) ₂ CH ₃ and R ^1a is H. In one embodiment of Formula (1), R ^1b is -(CH ₂ ) ₂ CH ₃ and R ^1a is C ₁ -C ₄ alkyl, optionally substituted with -OH. In one embodiment of Formula (1), R ^1b is -(CH ₂ ) ₂ CH ₃ and R ^1a is -CH ₂ C(CH ₃ ) ₂ OH. In one version of Formula (1),

represents

or

.

In one embodiment of Formula (1), Y is aryl, where aryl is substituted with C ₁ -C ₃ alkoxy and A. In one embodiment of Formula (1), is aryl, where aryl is substituted with -OCH ₃ and A.

In one embodiment of Formula (1), R ^1b is -(CH ₂ ) ₃ CH ₃ and R ^1a is C ₁ -C ₄ alkyl optionally substituted with -COOH. In one embodiment of Formula (1), R ^1b is -(CH ₂ ) ₂ CH ₃ and R ^1a is -CH ₂ COOH.

The present description relates to the compound of formula (1)

(1),

(one),

having one, two, three or more of the following:

R ^1b is -(CH ₂ ) ₂ CH ₃ ;

R ^1a is H;

X is -CH ₃ ;

L ¹ is -CH ₂ -; and

Y is aryl optionally substituted with 1-5 substituents independently selected from A, C ₁ -C ₃ alkyl, and C ₁ -C ₃ alkoxy.

The present description relates to the compound of formula (1)

(1),

(one),

having one, two, three or more of the following:

R ^1b is -(CH ₂ ) ₂ CH ₃ or -(CH ₂ ) ₃ CH ₃ ;

R ^1a is H; and

X is C ₁ -C ₄ alkyl, where alkyl is substituted by A.

The present description relates to the compound of formula (1)

(1),

(one),

having one, two, three or more of the following:

R ^1b is -(CH ₂ ) ₂ CH ₃ or -(CH ₂ ) ₃ CH ₃ ;

R ^1a is C ₁ -C ₄ alkyl substituted with -OH, -NH ₂ , -COOH, or -SO ₂ CH; and

X is C ₁ -C ₄ alkyl, where alkyl is substituted by A.

The present description relates to the compound of formula (1)

(1),

(one),

having one, two, three or more of the following:

R ^1b is -(CH ₂ ) ₂ CH ₃ or -(CH ₂ ) ₃ CH ₃ ;

R ^1a is C ₁ -C ₄ alkyl optionally substituted with -COOH;

X is -CH ₃ ;

L ¹ is -CH ₂ -; and

Y is aryl optionally substituted with 1-5 substituents independently selected from A, C ₁ -C ₃ alkyl, and C ₁ -C ₃ alkoxy.

The present description relates to the compound of formula (1)

(1),

(one),

having one, two, three or more of the following:

a) R ^1b is -(CH ₂ ) ₂ CH ₃ or -(CH ₂ ) ₃ CH ₃ ;

b) R ^1a is H or C ₁ -C ₄ alkyl optionally substituted with -COOH;

c) X is -CH ₃ ;

d) L ¹ is -CH ₂ -; and

и C₁–C₃ алкокси. e) Y is aryl optionally substituted with 1-5 substituents independently selected from

and C ₁ -C ₃ alkoxy.

The present invention relates to a compound having the structure of Formula (1) and pharmaceutically acceptable salts thereof,

(1)

(one)

where

R ^1a is selected from the group consisting of H, C ₁ -C ₄ alkyl, -NH ₂ , -COOH, and -SO ₂ CH _3, where alkyl is optionally substituted with -OH, -NH ₂ , -COOH, or -SO ₂ CH ₃ ;

R ^1b is C ₂ -C ₅ alkyl;

X is selected from the group consisting of H and C ₁ -C ₄ alkyl, where alkyl is optionally substituted by A or halogen;

,

, –O–, –S–, –SO₂–, –NH–, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, –O–, –S–, –SO ₂ –, –NH–, and –CH ₂ CH ₂ –;

Y is selected from the group consisting of C ₁ -C ₃ alkyl, aryl and heteroaryl, where alkyl, aryl and heteroaryl are optionally substituted with 1-5 substituents independently selected from A, C ₁ -C ₃ alkyl, and C ₁ -C ₃ alkoxy;

,

,

,

,

, и

; A is selected from the group consisting of

,

,

,

,

, and

;

,

,

, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилeн)]–, и –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–;L ² is selected from the group consisting of a bond, –(CH ₂ ) _n –, –C(O)NH(CH ₂ ) _n –,

,

,

, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, and –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –;

m is an integer from zero to four; and

n is an integer from one to four; and

where the compound is substituted with at least one A,

with one or more of the following symptoms,

(a) when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A; and L ² is -CH ₂ -; then A is not -L ² -COOH;

(b) when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A; and L ² is -CH ₂ -; then A is not -L ² -COOH unless R ^1a contains -COOH;

(c) when L ¹ is -CH ₂ -; Y is aryl substituted with A; and A is -L ² -COOH; and L ² is -CH ₂ -; then X is not -CH ₃ ;

(d) when L ¹ is -CH ₂ -; Y is aryl substituted with A; and A is -L ² -COOH; and L ² is -CH ₂ -; then X is not -CH ₃ unless R ^1a contains -COOH;

(e) when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A; and A is -L ² -COOH; then L ² is not –CH ₂ –;

(f) when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A; and A is -L ² -COOH; then L ² is not -CH ₂ -, except when R ^1a contains -COOH;

(g) when X is -CH ₃ ; Y is aryl substituted with A; and A is -L ² -COOH; and L ² is -CH ₂ -; then L ¹ is not -CH ₂ -;

(h) when X is -CH ₃ ; Y is aryl substituted with A; and A is -L ² -COOH; and L ² is -CH ₂ -; then L ¹ is not -CH ₂ -, except when R ^1a contains -COOH;

(i) when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A; and A is -L ² -COOH; and L ² is -CH ₂ -; then R ^1a contains COOH;

(j) when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A and -OCH ₃ ; and L ² is -CH ₂ -; then A is not -L ² -COOH;

(k) when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A and -OCH ₃ ; and L ² is -CH ₂ -; then A is not -L ² -COOH unless R ^1a contains -COOH;

(l) when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A and -OCH ₃ ; and L ² is -CH ₂ -; and R ^1a does not contain COOH; then A is not -L ² -COOH.

In some embodiments, a compound having the structure of Formula (1) may have any one or more of the following:

(m) when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A; and L ² is -CH ₂ -; then A is not -L ² -COOH;

(n) when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A; and L ² is -CH ₂ -; then A is not -L ² -COOH unless R ^1a contains -COOH or -SO ₂ CH ₃ ;

(o) when L ¹ is -CH ₂ -; Y is aryl substituted with A; and A is -L ² -COOH; and L ² is -CH ₂ -; then X is not -CH ₃ ;

(p) when L ¹ represents -CH ₂ -; Y is aryl substituted with A; and A is -L ² -COOH; and L ² is -CH ₂ -; then X is not -CH ₃ unless R ^1a contains -COOH or -SO ₂ CH ₃ ;

(q) when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A; and A is -L ² -COOH; then L ² is not -CH ₂ -;

(r) when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A; and A is -L ² -COOH; then L ² is not -CH ₂ - unless R ^1a contains -COOH or -SO ₂ CH ₃ ;

(s) when X is -CH ₃ ; Y is aryl substituted with A; and A is -L ² -COOH; and L ² is -CH ₂ -; then L ¹ is not -CH ₂ -;

(t) when X is -CH ₃ ; Y is aryl substituted with A; and A is -L ² -COOH; and L ² is -CH ₂ -; then L ¹ is not -CH ₂ - unless R ^1a contains -COOH or -SO ₂ CH ₃ ;

(u) when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A; and A is -L ² -COOH; and L ² is -CH ₂ -; then R ^1a contains COOH or –SO ₂ CH ₃ ;

(v) when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A and -OCH ₃ ; and L ² is -CH ₂ -; then A is not -L ² -COOH;

(w) when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A and -OCH ₃ ; and L ² is -CH ₂ -; then A is not -L ² -COOH unless R ^1a contains -COOH or -SO ₂ CH ₃ ;

(x) when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A and -OCH ₃ ; and L ² is -CH ₂ -; and R ^1a does not contain COOH or –SO ₂ CH ₃ ; then A is not -L ² -COOH;

(y) when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A; and A is -L ² -COOH; and L ² is -CH ₂ -; then R ^1a is not H or alkyl substituted by –OH.

In some embodiments, a compound having the structure of Formula (1) may have any one or more of the following:

; тогда A и L¹ не находятся в пара–положении по отношению друг к другу;(aa) when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A; L ² is –CH ₂ –, –O–(CH ₂ ) ₂ –O(CH ₂ ) ₂ –, or –O–(CH ₂ ) ₂ –O(CH ₂ ) ₂ (CF ₂ )–; and A is

; then A and L ¹ are not in para-position with respect to each other;

; тогда A и L¹ не находятся в пара–положении по отношению друг к другу;(bb) when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A; L ² is -CH ₂ -; and A is

; then A and L ¹ are not in para-position with respect to each other;

; тогда A и L¹ не находятся в пара–положении по отношению друг к другу;(cc) when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A and -OCH ₃ ; L ² is -CH ₂ -; and A is

; then A and L ¹ are not in para-position with respect to each other;

; тогда A и L¹ не находятся в пара–положении по отношению друг к другу;(dd) when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A; L ² is -O-(CH ₂ ) ₂ -O(CH ₂ ) ₂ -; and A is

; then A and L ¹ are not in para-position with respect to each other;

; тогда A и L¹ не находятся в пара–положении по отношению друг к другу;(ee) when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A; L ² is -O-(CH ₂ ) ₂ -O(CH ₂ ) ₂ (CF ₂ )-; and A is

; then A and L ¹ are not in para-position with respect to each other;

;(ff) when X is -CH ₃ ; R ^1a is H; R ^1b is C ₄ alkyl; L ¹ is -CH ₂ -; Y is aryl substituted with A; and L ² is –CH ₂ –, –O–(CH ₂ ) ₂ –O(CH ₂ ) ₂ –, or –O–(CH ₂ ) ₂ –O(CH ₂ ) ₂ (CF ₂ )–; then A is not

;

;(gg) when X is -CH ₃ ; R ^1a is H; R ^1b is C ₄ alkyl; L ¹ is -CH ₂ -; Y is aryl substituted with A; and L ² is -CH ₂ -; then A is not

;

;(hh) when X is -CH ₃ ; R ^1a is H; R ^1b is C ₄ alkyl; L ¹ is -CH ₂ -; Y is aryl substituted with A and -OCH ₃ ; and L ² is -CH ₂ -; then A is not

;

;(ii) when X is -CH ₃ ; R ^1a is H; R ^1b is C ₄ alkyl; L ¹ is -CH ₂ -; Y is aryl substituted with A; and L ² is -O-(CH ₂ ) ₂ -O(CH ₂ ) ₂ -; then A is not

;

; (jj) when X is -CH ₃ ; R ^1a is H; R ^1b is C ₄ alkyl; L ¹ is -CH ₂ -; Y is aryl substituted with A; and L ² is -O-(CH ₂ ) ₂ -O(CH ₂ ) ₂ (CF ₂ )-; then A is not

;

;(kk) when X is -CH ₃ ; R ^1a is H; R ^1b is C ₄ alkyl; L ¹ is -CH ₂ -; Y is aryl substituted with A; L ² is –CH ₂ –, –O–(CH ₂ ) ₂ –O(CH ₂ ) ₂ –, or –O–(CH ₂ ) ₂ –O(CH ₂ ) ₂ (CF ₂ )–; and A and L ¹ are in para-position with respect to each other; then A is not

;

;(ll) when X is -CH ₃ ; R ^1a is H; R ^1b is C ₄ alkyl; L ¹ is -CH ₂ -; Y is aryl substituted with A; L ² is -CH ₂ -; and A and L ¹ are in para-position with respect to each other; then A is not

;

;(mm) when X is -CH ₃ ; R ^1a is H; R ^1b is C ₄ alkyl; L ¹ is -CH ₂ -; Y is aryl substituted with A and -OCH ₃ ; L ² is -CH ₂ -; and A and L ¹ are in para-position with respect to each other; then A is not

;

;(nn) when X is -CH ₃ ; R ^1a is H; R ^1b is C ₄ alkyl; L ¹ is -CH ₂ -; Y is aryl substituted with A; L ² is -O-(CH ₂ ) ₂ -O(CH ₂ ) ₂ -; and A and L ¹ are in para-position with respect to each other; then A is not

;

. (oo) when X is -CH ₃ ; R ^1a is H; R ^1b is C ₄ alkyl; L ¹ is -CH ₂ -; Y is aryl substituted with A; L ² is -O-(CH ₂ ) ₂ -O(CH ₂ ) ₂ (CF ₂ )-; and A and L ¹ are in para-position with respect to each other; then A is not

.

In some embodiments, the present disclosure relates to a compound of formula (1) that is not described in WO 2009/067081 (PCT/SE2008/051334). In some embodiments, the present disclosure relates to a compound of formula (1) that is not described in WO 2012/031140 (PCT/US2011/050231).

,

,

, или

. In some embodiments, the present disclosure relates to a compound of formula (1) that is not

,

,

, or

.

The present description relates to the following compounds and their pharmaceutically acceptable salts.

Compound -X –L ¹ –Y

Compound one _–CH3

–(CH ₂ ) ₃ CH ₃

2 _–CH3

–(CH ₂ ) ₃ CH ₃

3 _–CH3

–(CH ₂ ) ₃ CH ₃

four _–CH3

–(CH ₂ ) ₃ CH ₃

5 _–CH3

–(CH ₂ ) ₃ CH ₃

6 _–CH3

–(CH ₂ ) ₃ CH ₃

7 _–CH3

–(CH ₂ ) ₃ CH ₃

eight _–CH3

9 _–CH3

–(CH ₂ ) ₃ CH ₃

ten _–CH3

–(CH ₂ ) ₃ CH ₃

eleven _–CH3

–(CH ₂ ) ₃ CH ₃

12 _–CH3

–(CH ₂ ) ₃ CH ₃

13 _–CH3

–(CH ₂ ) ₃ CH ₃

fourteen _–CH3

–(CH ₂ ) ₃ CH ₃

fifteen

–(CH ₂ ) ₃ CH ₃

16 _–CH3

–(CH ₂ ) ₃ CH ₃

17 _–CH3

–(CH ₂ ) ₃ CH ₃

eighteen _–CH3

19

–(CH ₂ ) ₃ CH ₃

twenty _–CH3

20C _–CH3

21

–OCH ₃

The present description relates to the following compounds and their pharmaceutically acceptable salts.

Compound -X –L ¹ –Y

Compound 22 _–CH3

23 _–CH3

24 _–CH3

–(CH ₂ ) ₃ CH ₃

25 _–CH3

–(CH ₂ ) ₃ CH ₃

26 _–CH3

–(CH ₂ ) ₄ CH ₃

27

28 _–CH3

–(CH ₂ ) ₃ CH ₃

29

thirty _–CH3

–(CH ₂ ) ₃ CH ₃

31 _–CH3

–(CH ₂ ) ₃ CH ₃

32 _–CH3

33 _–CH3

34 _–CH3

35 _–CH3

36 _–CH3

37

–(CH ₂ ) ₃ CH ₃

38

39 _–CH3

40

–(CH ₂ ) ₃ CH ₃

41 _–CH3

42 _–CH3

43

–(CH ₂ ) ₃ CH ₃

44 _–CH3

45

46

47

–(CH ₂ ) ₃ CH ₃

48

49

fifty

51 _–CH3

Unless otherwise indicated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure, except for the replacement of a hydrogen atom with deuterium or tritium, or the replacement of a carbon atom with ¹³ C or ¹⁴ C, or the replacement of a nitrogen atom with ¹⁵ N, or the replacement of an oxygen atom with ¹⁷ O or ¹⁸ O, are within the scope of this inventions. Such isotopically labeled compounds are useful as research or diagnostic tools.

General synthesis methods

As noted in this document, the present description includes specific representative compounds that are identified in this document with a feature. The compounds of the present invention can be prepared in a variety of ways, including well-known standard synthetic methods. Illustrative general synthesis methods are set forth below, and then the specific compounds of the present invention are obtained in the working Examples.

In all the examples described below, protective groups for sensitive or reactive groups are used, if necessary, in accordance with the general principles of synthetic chemistry. Protecting groups are manipulated according to standard organic synthesis methods (TW Green and PGM Wuts , Protecting Groups in Organic Synthesis, 3rd ^Edition , John Wiley & Sons, New York (1999)). These groups are removed at a convenient stage in the synthesis of the compound using methods that are obvious to those skilled in the art. The choice of processes, as well as the reaction conditions and the order in which they are carried out, should be appropriate for obtaining the compounds of the present invention.

A typical synthesis for the compounds in question is shown in Scheme 1.

Scheme 1

In Scheme 1, a compound of formula (G) is an embodiment where L ¹ is -CH ₂ - and is aryl, which is suitably substituted. Also in Diagram 1, LG is the leaving group; and R is H or alkyl. Compounds of formula (A) and (B) are commercially available starting materials. Alternatively, the compounds of formula (A) and (B) can be synthesized by various synthetic methods using commercially available starting materials and/or starting materials obtained by conventional synthetic methods.

With reference to Scheme 1, compounds of formula (C) can be prepared by reacting a compound of formula (A) with a base such as sodium hydride in a suitable solvent such as tetrahydrofuran or N,N-dimethylformamide at a temperature of, for example, 0°C to room temperature (20°C), followed by the addition of a compound of formula (B). The reaction mixture is then preferably heated at a temperature of, for example, 50°C to 100°C, optionally in the presence of an additive such as potassium iodide.

Compounds of formula (D) can be prepared by reacting a compound of formula (C) with guanidine or guanidine carbonate in a suitable solvent such as methanol or ethanol at a temperature, for example in the range of 50°C to 150°C.

Compounds of formula (E) can be prepared by reacting a compound of formula (D) with phosphorus oxychloride at a temperature of, for example, 50°C to 110°C.

Compounds of formula (F) may be prepared by reacting a compound of formula (E) with an excess of an amine of formula R ^1a R ^1b NH, in a suitable solvent such as NMP, butanol or 1,2-dioxane, at a temperature of, for example, 50°C to 150 °C. Alternatively, the reaction can be carried out in a microwave oven at a temperature of, for example, 50°C to 200°C.

Compounds of formula (G) can be prepared by reacting a compound of formula (F) with a reducing agent such as lithium aluminum hydride in a suitable solvent such as tetrahydrofuran at a temperature of, for example, 0 °С to 60 °С.

A typical synthesis for the compounds in question is shown in Scheme 2.

Scheme 2

In Scheme 2, a compound of formula (G) is an embodiment in which L ¹ is -CH ₂ - and Y is aryl, which is suitably substituted. Also in Scheme 2, R is H or alkyl.

Continuing to refer to Scheme 2, compounds of formula (H) can be prepared by reacting a compound of formula (G) with an oxidizing agent such as manganese oxide in a suitable solvent such as tetrahydrofuran or N,N-dimethylformamide at a temperature of, for example, 40° C to 100 °C.

Compounds of formula (I) can be prepared by reacting a compound of formula (H) via a Wittig reaction with RO-C(O)-CH=PPh₃. The reaction may be carried out in a suitable solvent such as tetrahydrofuran at a temperature of, for example, 50°C to 150 °C.

Compounds of formula (J) can be prepared by reducing a compound of formula (I) under hydrogenation conditions. The reaction can be carried out with a catalyst such as palladium on carbon under a hydrogen atmosphere in a suitable solvent such as ethyl acetate at a temperature of, for example, 20°C to 100°C.

A typical synthesis for the compounds in question is shown in Scheme 3.

Scheme 3

In Scheme 3, a compound of formula (G) is an embodiment in which L ¹ is -CH ₂ - and Y is aryl, which is suitably substituted.

Continuing to refer to Scheme 3, compounds of formula (K) can be prepared by reacting a compound of formula (G) with a chlorinating agent such as thionyl chloride in a suitable solvent such as methylene chloride at a temperature, for example, from room temperature to 50°C.

Compounds of formula (L) can be prepared by reacting a compound of formula (K) with a cyanide salt such as potassium cyanide in a suitable solvent such as dimethyl sulfoxide or N,N-dimethylformamide (or a mixture of both solvents) at a temperature, for example from room temperature. up to 50 °С.

Compounds of formula (M) can be prepared by reacting a compound of formula (L) with an azide reagent such as trimethylsilyl azide in an azide-nitrile cycloaddition reaction. The reaction can be carried out in a suitable solvent such as NMP or dioxane at a temperature of, for example, 50°C to 150°C. The reaction may be carried out in the presence of a catalyst such as dibutyltin oxide.

Compounds of formula (N) may be prepared by reacting a compound of formula (M) with an alkylating agent such as 2-bromoacetate in a suitable solvent such as acetone at a temperature of, for example, 0°C to 60°C.

Scheme 4

In Scheme 4, a compound of formula (G) is an embodiment in which L ¹ is -CH ₂ - and Y is aryl, which is suitably substituted. The preparation of compounds of formula (K) and (L) is described above.

Continuing to refer to Scheme 4, compounds of formula (O) may be prepared by hydrolysis of a compound of formula (L), for example using a base such as potassium hydroxide, in a suitable solvent such as ethane-1,2-diol and water (or mixtures thereof). ) at a temperature, for example, from 50 °C to 200 °C.

A typical synthesis for the compounds in question is shown in Scheme 5.

Scheme 5

In Scheme 5, a compound of formula (G) is an embodiment in which L ¹ is -CH ₂ - and Y is aryl, which is suitably substituted. The preparation of the compound of formula (K) is described above.

Continuing to refer to Scheme 5, compounds of formula (P) can be prepared by reacting a compound of formula (K) with triethyl phosphite in a suitable solvent or without solvent at a temperature of, for example, 50°C to 150°C.

Compounds of formula (Q) can be prepared by reacting a compound of formula (P) with ethyl removers such as bromotrimethylsilane in a suitable solvent such as methylene chloride at a temperature of, for example, room temperature to 60°C.

A typical synthesis for the compounds in question is shown in Scheme 6.

Scheme 6

In Scheme 6, the compound of formula (F') is an embodiment in which L ¹ is -CH ₂ - and Y is aryl, which is suitably substituted. Also in Scheme 6, LG ¹ and LG ² by the outgoing group. Compounds of formula (A') and (B') are commercially available starting materials. Alternatively, the compounds of formula (A') and (B') can be synthesized by various synthetic methods using commercially available starting materials and/or starting materials obtained by conventional synthetic methods.

Continuing to refer to Scheme 6, compounds of formula (C') can be prepared by reacting a compound of formula (A') with a base such as sodium hydride in a suitable solvent such as tetrahydrofuran or N,N-dimethylformamide at a temperature of, for example, 0 °C to room temperature (20 °C), followed by the addition of the compound of formula (B). The reaction mixture is then preferably heated at a temperature of, for example, 50°C to 100°C, optionally in the presence of an additive such as potassium iodide.

Compounds of formula (D') can be prepared by reacting a compound of formula (C') with guanidine or guanidine carbonate in a suitable solvent such as methanol or ethanol at a temperature, for example, in the range of 50°C to 150°C.

Compounds of formula (E') can be prepared by reacting a compound of formula (D') with phosphorus oxychloride at a temperature of, for example, 50°C to 110°C.

Compounds of formula (F') can be prepared by reacting a compound of formula (E') with an excess of an amine of formula R ^1a R ^1b NH, in a suitable solvent such as NMP, butanol or 1,2-dioxane, at a temperature of, for example, 50° C to 150 °C. Alternatively, the reaction can be carried out in a microwave oven at a temperature of, for example, 50°C to 200°C.

A typical synthesis for the compounds in question is shown in Scheme 7.

Scheme 7

In Scheme 7, the compound of formula (F') is an embodiment in which L ¹ is -CH ₂ - and Y is aryl, which is suitably substituted. Also in Diagram 7, LG ² is the leaving group.

Continuing to refer to Chart 7, compounds of formula (G') can be prepared by reacting a compound of formula (F') with an azide reagent such as trimethylsilyl azide in an azide-nitrile cycloaddition reaction. The reaction can be carried out in a suitable solvent such as NMP or dioxane at a temperature of, for example, 50°C to 150°C. The reaction may be carried out in the presence of a catalyst such as dibutyltin oxide.

A typical synthesis for the compounds in question is shown in Scheme 8.

Scheme 8

In Scheme 8, the compound of formula (F') is an embodiment in which L ¹ is -CH ₂ - and Y is aryl, which is suitably substituted. Also in Diagram 8, LG ² is the leaving group.

Continuing to refer to Scheme 8, compounds of formula (I') can be prepared by reacting a compound of formula (F') with triethyl phosphite in a suitable solvent or without solvent at a temperature of, for example, 50°C to 150°C.

Compounds of formula (J') can be prepared by reacting a compound of formula (I') with ethyl removers such as bromotrimethylsilane in a suitable solvent such as methylene chloride at a temperature of, for example, room temperature to 60°C.

Method of treatment

The compounds of formula (1) and their pharmaceutically acceptable salts have activity as pharmaceuticals, in particular as modulators of toll-like receptor activity (especially TLR7), and thus can be used in the treatment of:

1. respiratory tract: obstructive airway diseases, including: asthma, including bronchial, allergic, internal, external, exercise-induced, drug (including aspirin and NSAIDs) and dust asthma, both intermittent and persistent, and all degrees severity and other causes of airway hypersensitivity; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and comorbidities; hypersensitivity pneumonitis; pulmonary fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonia, fibrosis is a complicating antineoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the vasculature of the lungs and pulmonary hypertension; antitussive activity, including the treatment of chronic cough associated with inflammatory and secretory conditions of the respiratory tract, and iatrogenic cough; acute and chronic rhinitis, including drug-induced rhinitis, and vasomotor rhinitis; perennial and seasonal allergic rhinitis, including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection, including the common cold, and infection caused by respiratory syncytial virus, influenza, coronavirus (including SARS), and adenovirus;

2. skin: psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrheic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus, pyoderma gangrenosum, skin sarcoidosis, discoid lupus erythematosus, pemphigus, pemphigoid, congenital epidermolysis bullosa, urticaria, angioedema, vasculitis, toxic erythema, cutaneous eosinophilia, alopecia areata type, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme; cellulitis, both infectious and non-infectious; panniculitis; cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions, non-malignant skin cancer, basal cell carcinoma; senile keratosis; drug-induced disorders, including persistent drug rash;

3. eye: blepharitis; conjunctivitis, including perennial and spring allergic conjunctivitis; iritis; anterior and posterior uveitis; choroiditis; autoimmune, degenerative or inflammatory disorders affecting the retina; ophthalmitis, including sympathetic ophthalmitis; sarcoidosis; infections, including viral, fungal and bacterial;

4. genitourinary system: nephritis, including interstitial and glomerulonephritis; nephrotic syndrome; cystitis, including acute and chronic (interstitial) cystitis and Hanner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvovaginitis; Peyronie's disease; erectile dysfunction (both in men and women);

5. allograft rejection: acute and chronic subsequent, for example, kidney, heart, liver, lung, bone marrow, skin or cornea transplantation or after blood transfusion; or chronic graft-versus-host disease;

6. other autoimmune and allergic disorders, including rheumatoid arthritis, irritable bowel syndrome, inflammatory bowel syndrome, colitis, Crohn's disease, systemic lupus erythematosus, multiple sclerosis, Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetes mellitus, idiopathic thrombocytophytic thrombocytopenitis, atonic fasciitis , hyper-IgE syndrome, antiphospholipid syndrome and Sazar syndrome;

7. Oncological diseases: treatment of common cancers, including liver, lung, bladder, gastrointestinal tract (including stomach, colorectal, esophageal and rectal), head and neck, prostate, breast, lung, ovary, pancreas, intestines and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including leukemias) and lymphoproliferative systems such as Hodgkin's lymphoma and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumor recurrence, and paraneoplastic syndromes; and

8. Infectious diseases: viral diseases such as genital warts, common warts, plantar warts, hepatitis B, hepatitis C, herpes simplex virus, molluscum contagiosum, smallpox, human immunodeficiency virus (HIV), human papillomavirus (HPV), cytomegalovirus (CMV), varicella-zoster virus (VVO), rhinovirus, adenovirus, coronavirus, influenza, parainfluenza; bacterial diseases such as tuberculosis and mycobacterium avium, leprosy; other infectious diseases such as fungal diseases, chlamydia, Candida, aspergillosis, cryptococcal meningitis, Carnii pneumocystis, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosomal infection and leishmaniasis.

The present description provides the use of a compound of formula (1) or a pharmaceutically acceptable salt thereof as a vaccine adjuvant used in conjunction with one or more antigens against the following diseases: HBV, HPV, meningitis, TDaP, influenza, rabies, tuberculosis, tuberculosis, malaria, Staphylococcus infection aureus and cancer (tumor-associated antigen or neo-antigen).

Thus, the present description relates to the compound of formula (1) or its pharmaceutically acceptable salt, as defined above, for use in therapy.

In an additional aspect, the present disclosure relates to the use of a compound of formula (1), or a pharmaceutically acceptable salt thereof, as defined above, in the manufacture of a medicament for use in therapy.

The present disclosure relates to methods of treating a condition associated with TLR7 modulation in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof. The present disclosure relates to a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition associated with TLR7 modulation. The present disclosure relates to the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a condition associated with TLR7 modulation. In some embodiments, the condition is a viral infection or cancer.

In the context of the present description, the term "therapy" also includes "prophylaxis", unless specifically indicated to the contrary. The terms "therapeutic" and "therapeutically" should be read as such.

It can be expected that prophylaxis is particularly important for the treatment of individuals who have experienced a previous episode of the disorder or condition or who are considered to be at increased risk for the disorder or condition. Patients at risk of developing a particular condition typically include those who have a family history of the condition or who have been found by genetic testing or screening to be particularly susceptible to developing the condition.

In particular, the compounds of the present invention (including pharmaceutically acceptable salts) can be used in the treatment of asthma, COPD, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, cancer, hepatitis B, hepatitis C, HIV, HPV, bacterial infections and dermatosis.

The present disclosure further provides a method for treating or reducing the risk of a disease or condition involving or resulting from abnormal cell growth (e.g., cancer), which method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (1) or a pharmaceutically effective amount thereof. acceptable salt as defined above.

The present description also relates to a method of treating or reducing the risk of an obstructive disease or condition of the respiratory tract (for example, asthma or COPD), which includes administering to a patient in need thereof, a therapeutically effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof, as defined above .

For the aforementioned therapeutic use, the dose administered may, of course, vary depending on the compound used, the route of administration, the desired treatment, and the disorder in question. For example, a daily dosage of a compound of the present invention when administered by inhalation may range from 0.05 micrograms per kilogram of body weight (μg/kg) to 100 micrograms per kilogram of body weight (μg/kg). Alternatively, if the compound is administered orally, the daily dosage of the compound of the present invention may range from 0.01 micrograms per kilogram of body weight (μg/kg) to 100 milligrams per kilogram of body weight (mg/kg).

Pharmaceutical compositions

The compounds of formula (1) and their pharmaceutically acceptable salts may be used alone, but are generally administered in the form of a pharmaceutical composition in which the compound/salt of formula (1) (active ingredient) is associated with a pharmaceutically acceptable adjuvant, diluent or carrier . Conventional methods for selecting and preparing suitable pharmaceutical formulations are described, for example, in "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.

In some embodiments, administration may be oral, intravenous, subcutaneous, intramuscular, intratumoral, intradermal, intranasal, inhalation, intravesical, topical, sublingual, buccal, intrarectal, intrathecal, intracranial, or other forms of local delivery.

Depending on the route of administration, the pharmaceutical composition will be from about 0.05 to about 99 wt. % (percent by weight), more specifically, from about 0.05 to about 80 wt. %, even more specifically, from about 0.10 to about 70 wt. %, and even more specifically from about 0.10 to about 50 wt. % active ingredient, all weight percentages based on total composition.

The present disclosure also provides a pharmaceutical composition comprising a compound of formula (1), or a pharmaceutically acceptable salt thereof, as defined above, in combination with a pharmaceutically acceptable adjuvant, diluent, or carrier.

The present description further provides a process for preparing a pharmaceutical composition of the present invention, which comprises mixing a compound of formula (1) or a pharmaceutically acceptable salt thereof, as defined above, with a pharmaceutically acceptable adjuvant, diluent, or carrier.

Pharmaceutical compositions may be administered topically (eg, to the skin or to the lungs and/or respiratory tract) in the form of, for example, creams, solutions, suspensions, heptafluorothorcan (HFA) aerosols, and dry powder formulations, such as formulations in an inhaler device known as a Turbuhaler. ^® ; or systemically, for example by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of a sterile injectable solution, suspension or emulsion (including intravenous, subcutaneous, intramuscular, intravascular or infusion); or by rectal administration in the form of suppositories.

Dry powder formulations and HFA aerosols of the compounds of the present invention (including pharmaceutically acceptable salts) may be administered by oral or nasal inhalation. For inhalation, the compound is desirably thinly divided. The finely divided compound preferably has a weight average diameter of less than 10 micrometers (µm) and can be suspended in the propellant mixture with a dispersant such as a C ₈ -C ₂₀ fatty acid or salt thereof (e.g. oleic acid), bile salt, phospholipid, alkyl saccharide, perfluorinated or polyethoxylated surfactant or other pharmaceutically acceptable dispersant.

The compounds of the present invention may also be administered via a dry powder inhaler. The inhaler may be a single or multiple dose inhaler and may be a breath-actuated dry powder inhaler.

One possibility is to mix the finely divided compound of the present invention with a carrier material, for example a mono-, di- or polysaccharide, sugar alcohol or other polyol. Suitable carriers are sugars, eg lactose, glucose, raffinose, melesitose, lactitol, maltitol, trehalose, sucrose, mannitol; and starch. Alternatively, the finely divided compound may be coated with another substance. The powder mixture may also be filled into hard gelatin capsules, each containing the desired dose of the active compound.

Another possibility is to process the fine powder into spheres which disintegrate during the inhalation procedure. This spheronized powder can be loaded into the drug reservoir of a multi-dose inhaler, such as the one known as the ^Turbuhaler® , in which the dosing device measures the desired dose, which is then inhaled by the patient. With this system, the active ingredient, with or without a carrier, is delivered to the patient.

For oral administration, the compound of the present invention may be mixed with an adjuvant or carrier, eg lactose, sucrose, sorbitol, mannitol; starch, for example potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatin or polyvinylpyrrolidone; and/or a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin and the like, and then compressed into tablets. If coated tablets are required, the cores prepared as described above may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatin, talc and titanium dioxide. Alternatively, the tablet may be coated with a suitable polymer dissolved in a highly volatile organic solvent.

To prepare soft gelatin capsules, the compound of the present invention may be mixed with, for example, vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the compound using the tablet excipients mentioned above. Also, liquid or semi-solid compositions of a compound of the present invention may be filled into hard gelatin capsules.

Liquid oral preparations may be in the form of syrups or suspensions, for example solutions containing a compound of the present invention, the residue of which is a sugar, and a mixture of ethanol, water, glycerol and propylene glycol. Optionally, such liquid preparations may contain colorants, flavors, saccharin and/or carboxymethyl cellulose as a thickener, or other excipients known to those skilled in the art.

Combination Therapy

The compounds of the present invention (ie, the compounds of formula (1) and their pharmaceutically acceptable salts) can also be administered in combination with other compounds used to treat the above conditions.

The present invention therefore further relates to combination therapy in which a compound of the present invention or a pharmaceutical composition or a composition containing a compound of the present invention is administered simultaneously or sequentially or as a combination preparation with another therapeutic agent or agents for the treatment of one or more of the listed conditions. .

The anti-cancer treatment as defined above may be used as the sole therapy or may include, in addition to the compound of the present invention, conventional surgery or radiation therapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anticancer agents:

(i) other antiproliferative/antineoplastic drugs and combinations thereof used in medical oncology, such as alkylating agents (eg, cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolomide, and nitrosoureas); antimetabolites (eg gemcitabine and antifolates such as fluoropyrimidines such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea); antitumor antibiotics (eg anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (eg vinca alkaloids such as vincristine, vinblastine, vindesine and vinorelbine and taxoids such as taxol, taxotere and polokinase inhibitors); and topoisomerase inhibitors (eg epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan and camptothecin);

(ii) cytostatic agents such as antiestrogens (eg tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxifene), antiandrogens (eg bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (eg goserelin, leuprorelin and buserelin), progestogens (megestrol acetate), aromatase inhibitors (eg anastrozole, letrozole, vorazole and exemestane) and 5α-reductase inhibitors such as finasteride;

(iii) anti-invasive agents (eg c-Src-kinase family inhibitors such as 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5 -tetrahydropyran-4-yloxyquinazoline (AZD0530; International Patent Application WO 01/94341) and N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl] -2-methylpyrimidine-4ylamino}thiazole-5-carboxylic acid (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661), and metalloproteinase inhibitors such as marimastat, inhibitors of plasminogen activator receptor function urokinase or heparanase antibodies);

(iv) growth factor function inhibitors: for example, such inhibitors include growth factor antibodies and growth factor receptor antibodies (e.g., anti-erbB2 antibody trastuzumab [Herceptin™], anti-EGFR antibody panitumumab, anti-erbBl antibody cetuximab [Erbitux, C225] and any growth factor antibodies or growth factor receptors described by Stern et al Critical reviews in oncology/hematology, 2005, Vol 54, ppl 1-29); such inhibitors also include tyrosine kinase inhibitors, for example epidermal growth factor family inhibitors (for example, EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4- amine(gefitinib, ZD 1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazoline-4-amine(erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro- 4-fluorophenyl)-7-(3-morpholinopropoxy)quinazoline-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib, hepatocyte growth factor family inhibitors, platelet growth factor family inhibitors such as imatinib, serine/threonine kinase inhibitors ( e.g. Ras/Raf signaling inhibitors such as farnesyl transferase inhibitors eg sorafenib (BAY 43-9006)), MEK and/or AKT kinase cellular signaling inhibitors, hepatocyte growth factor inhibitors, c-kit inhibitors, abl-kinase inhibitors , IGF receptor (insulin-like growth factor) kinase inhibitors; aurorakinase inhibitors s (eg, AZD1 152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX39459) and cyclin-dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors;

(v) anti-angiogenic agents, such as those that inhibit the action of vascular endothelial growth factor [eg, the vascular endothelial cell growth factor antibody bevacizumab (Avastin™) and VEGF receptor tyrosine kinase inhibitors, such as 4-(4-bromo-2-fluoroanilino) -6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (ZD6474; Example 2 in WO 01/32651), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7 -(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171; Example 240 in WO 00/47212), vatalanib (PTK787; WO 98/35985) and SUl 1248 (sunitinib; WO 01/60814), compounds such as those described in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms (eg linomide, inhibitors of αvβ3 integrin function and angiostatin)];

(vi) vascular damaging agents such as combretastatin A4 and the compounds described in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;

(vii) antisense therapies, for example those directed to the targets listed above, such as ISIS 2503, antisense antiras;

(viii) gene therapy approaches, including for example aberrant gene replacement approaches such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene directed enzyme drug therapy) approaches such as using cytosine deaminase, thymidine kinase, or the bacterial nitroreductase enzyme, and approaches for increasing patient tolerance to chemotherapy or radiotherapy, such as multidrug-resistant gene therapy;

(ix) immunotherapeutic approaches, including, for example, ex-vivo and in-vivo approaches to increase the immunogenicity of a patient's tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4, or granulocyte-macrophage colony-stimulating factor, approaches to reduce anergy T cells, transfected immune cell approaches such as cytokine-transfected dendritic cells, cytokine-transfected tumor cell line approaches, and anti-idiotypic antibody approaches;

(x) Checkpoint inhibitors, including but not limited to antibodies for PD-1/PD-L1, CTLA-4, TIM-3, LAG-3, OX-40, GITR, VISTA, 4-1BB, CD40, TIGIT .BTLA;

(xi) Kinase inhibitors, including, but not limited to, small molecule or monoclonal antibody inhibitors BRAF, EGFR, ALK, RAS, RAF, VEGF, HER, c-MET, MEK, FGFR, BCR-ABL, PI3K;

(xii) Inhibitors of cancer/immune metabolism, including, but not limited to, inhibitors of IDO, TDO, GLS, IDH, arginase, adenosine receptor, CD73, CD39;

(xiii) Epigenetic modulators including, but not limited to, HDAC inhibitors, bromodomain, methyltransferase;

(xiv) Development Path Modulator, including but not limited to Smo, Wnt, YAP;

(xv) Other anti-cancer or immuno-oncological biologics, including, but not limited to, oncolytic virus, BCG, CART, cytokines; and

(xv) Antibodies, including but not limited to anti-PD-1 antibody and anti-PD-L1 antibody.

In addition, for the treatment of inflammatory diseases, COPD, asthma, and allergic rhinitis, the compounds of the present invention can be combined with agents such as inhibitors of necrosis factor alpha (TNF-alpha), such as anti-TNF monoclonal antibodies (e.g., Remicade, CDP-870 and adalimumab) and TNF-immunoglobulin receptor (such as Enbrel); non-selective COX-1/COX-2 cyclooxygenase inhibitors applied topically or systemically (such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac azapropazone, pyrazolones , such as phenylbutazone, salicylates such as aspirin), COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib and etoricoxib); corticosteroids; glucocorticosteroids (administered locally, orally, intramuscularly, intravenously or intraarticularly); beta agonists; antihistamines; methotrexate, lefunomide; hydroxychloroquine, d-penicillamine, auranofin, or other parenteral or oral gold preparations.

For the treatment of infectious diseases, the compounds of the present invention can be combined with agents such as nucleoside antivirals; non-nucleoside antivirals, including but not limited to entry inhibitors, polymerase, reverse transcriptase, protease, integrase; monoclonal antibodies against specific viruses; miRNA therapy; antibiotics; and antifungal.

For the treatment of HBV, the compounds of the present invention may be combined with agents such as antiviral nucleosides.

The present invention also further relates to other innate immune agonists targeting the following classes of receptors including, but not limited to, TLR (Toll-like receptor); NLR (Nod-like receptor); CLR (C-type lectin receptor); RLR (RIG-I-like receptor); and STING (interferon gene stimulator).

The present invention also further relates to the combination of a compound of the present invention and a leukotriene biosynthesis inhibitor, a 5-lipoxygenase (5-LO) inhibitor, or a 5-lipoxygenase-activating protein (FLAP) antagonist such as; zileuton; AVT-761; fenleyton; tepoxalin; Ebbott-79175; Ebbott-85761; N-(5-substituted)thiophene-2-alkylsulfonamide; 2,6-di-tert-butylphenol hydrazones; methoxytetrahydropyran such as Zeneca ZD-2138; connection SB-210661; a pyridinyl-substituted 2-cyanonaphthalene compound such as L-739.010; a 2-cyanoquinoline compound such as L-746,530; or an indole or quinoline compound such as MK-591, MK-886 and BAY x 1005.

The present invention further relates to the combination of a compound of the present invention and a leukotriene receptor antagonist (LTB4, LTC4, LTD4 and LTE4) selected from the group consisting of phenothiazin-3-ones such as L-651,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamides such as BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A) and BAY x 7195.

The present invention also further relates to the combination of a compound of the present invention and a phosphodiesterase (PDE) inhibitor such as methylxanthanine, including theophylline and aminophylline; a selective inhibitor of the PDE isoenzyme, including a PDE4 inhibitor, a PDE4D isoform inhibitor, or a PDE5 inhibitor.

The present invention also relates to the combination of a compound of the present invention and a type 1 histamine receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine or mizolastine; applied orally, topically or parenterally.

The present invention also further relates to the combination of a compound of the present invention and a gastroprotective type 2 histamine receptor antagonist.

The present invention also relates to the combination of a compound of the present invention and a type 4 histamine receptor antagonist.

The present invention also further relates to the combination of a compound of the present invention and an alpha-1/alpha-2-adrenergic agonist of a vasoconstrictor sympathomimetic agent such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, hydrochloride tramazoline or ethylnorepinephrine hydrochloride.

The present invention further relates to the combination of a compound of the present invention and an anticholinergic agent, including muscarinic receptor (M1, M2 and M3) antagonists such as atropine, hyoscine, glycopyrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.

The present invention further relates to the combination of a compound of the present invention together with a beta-adrenergic agonist (including beta-receptor subtypes 1-4) such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate and pirbuterol.

The present invention further relates to the combination of a compound of the present invention and a chromone such as sodium chromoglycate or sodium nedocromil.

The present invention still further relates to the combination of a compound of the present invention with an insulin-like growth factor type I (IGF-I) mimetic.

The present invention further relates to the combination of a compound of the present invention and a glucocorticoid such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide, or mometasone furoate.

The present invention further relates to the combination of a compound of the present invention with an inhibitor of matrix metalloproteases (MMPs), ie stromelysins, collagenases and gelatinases, and aggrecanase; especially collagenase-1 (MMP-I), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-IO) and stromelysin-3 ( MMP-11) and MMP-9 and MMP-12.

The present invention further relates to the combination of a compound of the present invention together with modulators of chemokine receptor function such as CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR1O and CCR11 antagonists (for the CC family) ; CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for C-X-C family) and CX3CR1 for C-X3-C family.

The present invention further relates to the combination of a compound of the present invention together with a cytokine or cytokine function modulator, including interferon alpha, beta and gamma; interleukins (ILs), including IL1 up to 15; and interleukin antagonists or inhibitors, including agents that act on cytokine signaling pathways.

The present invention further relates to the combination of a compound of the present invention with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody that modulates Ig function, such as anti-IgE (omalizumab).

The present invention further relates to the combination of a compound of the present invention and another systemically or topically administered anti-inflammatory agent such as thalidomide or a derivative thereof, retinoid, dithranol or calcipotriol.

The present invention further relates to the combination of a compound of the present invention with an antibacterial agent such as a penicillin derivative, tetracycline, macrolide, beta-lactam, fluoroquinolone, metronidazole, inhaled aminoglycoside; an antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir, and oseltamavir; a protease inhibitor such as indinavir, nelfinavir, ritonavir and saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine, or zidovudine; or a non-nucleoside reverse transcriptase inhibitor such as nevirapine or efavirenz.

In a further aspect, the present invention provides a combination (eg, for the treatment of COPD, asthma, or allergic rhinitis) of a compound of formula (1), or a pharmaceutically acceptable salt thereof, as defined above, and one or more agents independently selected from:

• non-steroidal glucocorticoid receptor agonist (GR-receptor);

• a selective β2-adrenergic agonist (such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol or indacaterol);

• a phosphodiesterase inhibitor (such as a PDE4 inhibitor);

• a protease inhibitor (such as an inhibitor of neutrophil elastase or matrix metalloprotease MMP-12);

• glucocorticoid;

• anticholinergic agent;

• a chemokine receptor function modulator (such as a CCR1 receptor antagonist); and

• an inhibitor of kinase function (such as p38 or IKK kinases).

The present invention also provides a pharmaceutical product comprising in combination a preparation of a first active ingredient which is a compound of formula (1) or a pharmaceutically acceptable salt thereof as defined above and a preparation of a second active ingredient which is

• non-steroidal glucocorticoid receptor agonist (GR-receptor);

•selective agonist β2-adrenergic receptor;

• phosphodiesterase inhibitor;

• protease inhibitors;

• glucocorticoid;

• anticholinergic agent;

• modulator of chemokine receptor function; or

• kinase function inhibitor;

for simultaneous, sequential or separate use in therapy.

In another aspect, the present invention provides a kit comprising a formulation of a first active ingredient which is a compound of formula (1) or a pharmaceutically acceptable salt thereof as defined above and a formulation of a second active ingredient which is

• non-steroidal glucocorticoid receptor agonist (GR-receptor);

•selective agonist β2-adrenergic receptor;

• phosphodiesterase inhibitor; protease inhibitors;

• glucocorticoid;

• anticholinergic agent;

• modulator of chemokine receptor function; or

• kinase function inhibitor;

And instructions for the simultaneous, sequential or separate administration of drugs to a patient in need of it.

Exemplary Embodiments

Implementation variant I-1. A compound having the structure of Formula (1), or a pharmaceutically acceptable salt thereof,

(1)

(one)

where

R ^1a is selected from the group consisting of H, C ₁ -C ₄ alkyl, -NH ₂ , -COOH, and -SO ₂ CH _3, where alkyl is optionally substituted with -OH, -NH ₂ , -COOH, or -SO ₂ CH ₃ ;

R ^1b is C ₂ -C ₅ alkyl;

X is selected from the group consisting of H and C ₁ -C ₄ alkyl, where alkyl is optionally substituted with A;

,

, –O–, –S–, –SO₂–, –NH–, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, –O–, –S–, –SO ₂ –, –NH–, and –CH ₂ CH ₂ –;

Y is selected from the group consisting of C ₁ -C ₃ alkyl, aryl and heteroaryl, where alkyl, aryl and heteroaryl are optionally substituted with 1-5 substituents independently selected from A, C ₁ -C ₃ alkyl, and C ₁ -C ₃ alkoxy;

,

,

,

,

, и

; A is selected from the group consisting of

,

,

,

,

, and

;

,

,

, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилeн)]–, и–[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–;L ² is selected from the group consisting of a bond, –(CH ₂ ) _n –, –C(O)NH(CH ₂ ) _n –,

,

,

, -[O (CH ₂ CH ₂ )] _n -, - [O (C ₁ -C ₄ alkylene)] -, and - [O (CH ₂ CH ₂ )] _n -OCH ₂ CH ₂ CF ₂ -;

m is an integer from zero to four; and

n is an integer from one to four; and

where the compound is substituted with at least one A; and

when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A; and L ² is -CH ₂ -; then A is not -L ² -COOH unless R ^1a contains -COOH.

Implementation option I–2. The compound of Embodiment I-1, or a pharmaceutically acceptable salt thereof, wherein R ^1b is -(CH ₂ ) ₂ CH ₃ .

Implementation variant I-3. The compound of Embodiment I-1, or a pharmaceutically acceptable salt thereof, wherein R ^1b is -(CH ₂ ) ₃ CH ₃ .

Implementation variant I-4. A compound according to any one of embodiments I-1-I-3, or a pharmaceutically acceptable salt thereof, wherein R ^1a is C ₁ -C ₄ alkyl optionally substituted with -OH.

Implementation variant I–5. A compound according to any one of embodiments I-1-I-4, or a pharmaceutically acceptable salt thereof, wherein R ^1a is -CH ₂ C(CH ₃ ) ₂ OH.

представляет собой

или

. Implementation variant I-6. A compound according to any one of embodiments I-1-I-4, or a pharmaceutically acceptable salt thereof, wherein

represents

or

.

Implementation variant I-7. A compound according to any one of embodiments I-1-I-3, or a pharmaceutically acceptable salt thereof, wherein R ^1a is C ₁ -C ₄ alkyl optionally substituted with -COOH.

представляет собой

. Implementation variant I-8. A compound according to any one of embodiments I-1-I-3 and I-7, or a pharmaceutically acceptable salt thereof, wherein

represents

.

Implementation variant I–9. A compound according to any one of embodiments I-1-I-3, or a pharmaceutically acceptable salt thereof, wherein R ^1a is H.

Implementation variant I–10. A compound according to any one of embodiments I-1-I-9, or a pharmaceutically acceptable salt thereof, wherein X is C ₁ -C ₄ alkyl, where alkyl is substituted by A.

, где L² представляет собой связь. Implementation variant I–11. A compound according to any one of embodiments I-1-I-10, or a pharmaceutically acceptable salt thereof, wherein X is C ₁ -C ₄ alkyl, where alkyl is substituted

, where L ² is a bond.

Implementation variant I-12. A compound according to any one of embodiments I-1-I-9, or a pharmaceutically acceptable salt thereof, wherein X is CH ₃ .

Implementation Option I–13. A compound according to any one of embodiments I-1-I-9, or a pharmaceutically acceptable salt thereof, wherein X is H.

Implementation Option I-14. A compound according to any one of embodiments I-1-I-13, or a pharmaceutically acceptable salt thereof, wherein L ¹ is -CH ₂ -, -CH ₂ CH ₂ -, or -O-.

Implementation Option I-15. A compound according to any one of embodiments I-1-I-14, or a pharmaceutically acceptable salt thereof, wherein L ¹ is -CH ₂ -.

Implementation Option I-16. A compound according to any one of embodiments I-1-I-15, or a pharmaceutically acceptable salt thereof, wherein Y is C ₁ -C ₃ alkyl or aryl.

Implementation Option I-17. A compound according to any one of embodiments I-1-I-16, or a pharmaceutically acceptable salt thereof, wherein Y is aryl, where aryl is substituted with C1-C3 alkoxy.

Implementation Option I-18. A compound according to any one of embodiments I-1-I-17, or a pharmaceutically acceptable salt thereof, wherein Y is aryl, where aryl is substituted by A.

. Implementation Option I–19. A compound according to any one of embodiments I-1-I-18, or a pharmaceutically acceptable salt thereof, wherein A is

.

. Implementation option I-20. A compound according to any one of embodiments I-1-I-18, or a pharmaceutically acceptable salt thereof, wherein A is

.

. Implementation variant I–21. A compound according to any one of embodiments I-1-I-18, or a pharmaceutically acceptable salt thereof, wherein A is

.

. Implementation variant I-22. A compound according to any one of embodiments I-1-I-18, or a pharmaceutically acceptable salt thereof, wherein A is

.

. Implementation variant I–23. A compound according to any one of embodiments I-1-I-18, or a pharmaceutically acceptable salt thereof, wherein A is

.

. Implementation variant I-24. A compound according to any one of embodiments I-1-I-18, or a pharmaceutically acceptable salt thereof, wherein A is

.

Implementation variant I-25. A compound according to any one of embodiments I-1-I-24, or a pharmaceutically acceptable salt thereof, wherein L ² is -(CH ₂ ) _n -.

Implementation variant I-26. A compound according to any one of embodiments I-1-I-25, or a pharmaceutically acceptable salt thereof, wherein n is one or two.

. Implementation variant I–27. A compound according to any one of embodiments I-1-I-24, or a pharmaceutically acceptable salt thereof, wherein L ² is

.

. Implementation variant I–28. A compound according to any one of embodiments I-1-I-24, or a pharmaceutically acceptable salt thereof, wherein L ² is

.

Implementation Option I–29. A compound according to any one of embodiments I-1-I-24, or a pharmaceutically acceptable salt thereof, wherein L ² is -C(O)NH(CH ₂ ) _n -.

Implementation variant I–30. The compound of embodiment I-1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (1a),

where

X is H or CH ₃

,

, и–CH₂CH₂–;L ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, and–CH ₂ CH ₂ –;

,

,

,

,

, и

; A is selected from the group consisting of

,

,

,

,

, and

;

,

, –C(O)NH(CH₂)_n–, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилен)]–, и –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–; иL ² is selected from the group consisting of a bond, -CH ₂ -, -CH ₂ CH ₂ -,

,

, –C(O)NH(CH ₂ ) _n –, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, and –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –; and

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

Implementation variant I–31. The compound of embodiment I-1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (1a),

where

X is -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ -A ^1a ;

,

,

,

,

, и

; A ^1a is selected from the group consisting of

,

,

,

,

, and

;

,

, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, and –CH ₂ CH ₂ –;

,

,

,

,

, и

; A is selected from the group consisting of

,

,

,

,

, and

;

,

, –C(O)NH(CH₂)_n–, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилен)]–, и –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–; иL ² is selected from the group consisting of a bond, -CH ₂ -, -CH ₂ CH ₂ -,

,

, –C(O)NH(CH ₂ ) _n –, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, and –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –; and

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

Implementation variant I-32. The compound of embodiment I-1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (1b),

where

X is H or CH ₃ ;

,

, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, and –CH ₂ CH ₂ –;

,

,

,

,

, и

; A is selected from the group consisting of

,

,

,

,

, and

;

,

, –C(O)NH(CH₂)_n–, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилен)]–, и –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–; иL ² is selected from the group consisting of a bond, -CH ₂ -, -CH ₂ CH ₂ -,

,

, –C(O)NH(CH ₂ ) _n –, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, and –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –; and

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

Implementation variant I–33. The compound of embodiment I-1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (1b),

where

X is -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ -A ^1a ;

,

,

,

,

, и

; A ^1a is selected from the group consisting of

,

,

,

,

, and

;

,

, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, and –CH ₂ CH ₂ –;

,

,

,

,

, и

; A is selected from the group consisting of

,

,

,

,

, and

;

,

, –C(O)NH(CH₂)_n–, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилен)]–, и –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–; иL ² is selected from the group consisting of a bond, -CH ₂ -, -CH ₂ CH ₂ -,

,

, –C(O)NH(CH ₂ ) _n –, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, and –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –; and

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

Implementation variant I–34. The compound of embodiment I-1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (1c),

where

X is -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ -A ^1a ;

,

,

,

,

, и

; A ^1a is selected from the group consisting of

,

,

,

,

, and

;

,

, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, and –CH ₂ CH ₂ –;

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy; and

R ⁴ is H or C ₁ -C ₃ alkoxy.

Implementation variant I–35. The compound of embodiment I-1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (1d),

X is -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ -A ^1a ;

,

,

,

,

, и

; A ^1a is selected from the group consisting of

,

,

,

,

, and

;

,

, –O–, и –CH₂CH₂–; иL ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, –O–, and –CH ₂ CH ₂ –; and

Y is H or C ₁ -C ₃ alkyl.

Implementation variant I-36. The compound of embodiment I-1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (1e),

where

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

Implementation variant I–37. The compound of embodiment I-1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (1f),

.

.

Implementation variant I–38. The compound of embodiment I-1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (1g),

where

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

Implementation variant I–39. The compound of embodiment I-1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (1h),

where

R ⁴ is H or C ₁ -C ₃ alkoxy.

Implementation variant I-40. The compound of embodiment I-1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (1i),

where

,

, –O–, и –CH₂CH₂–; иL ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, –O–, and –CH ₂ CH ₂ –; and

Y is H or C ₁ -C ₃ alkyl.

Implementation variant I-41. A compound or pharmaceutically acceptable salt selected from the group consisting of:

Compound -X –L ¹ –Y

one _–CH3

–(CH ₂ ) ₃ CH ₃ 2 _–CH3

–(CH ₂ ) ₃ CH ₃ 3 _–CH3

–(CH ₂ ) ₃ CH ₃ four _–CH3

–(CH ₂ ) ₃ CH ₃ 5 _–CH3

–(CH ₂ ) ₃ CH ₃ 6 _–CH3

–(CH ₂ ) ₃ CH ₃ 7 _–CH3

–(CH ₂ ) ₃ CH ₃ eight _–CH3

9 _–CH3

–(CH ₂ ) ₃ CH ₃ ten _–CH3

–(CH ₂ ) ₃ CH ₃ eleven _–CH3

–(CH ₂ ) ₃ CH ₃ 12 _–CH3

–(CH ₂ ) ₃ CH ₃ 13 _–CH3

–(CH ₂ ) ₃ CH ₃ fourteen _–CH3

–(CH ₂ ) ₃ CH ₃ fifteen

–(CH ₂ ) ₃ CH ₃ 16 _–CH3

–(CH ₂ ) ₃ CH ₃ 17 _–CH3

–(CH ₂ ) ₃ CH ₃ eighteen _–CH3

19

–(CH ₂ ) ₃ CH ₃ twenty _–CH3

21

–OCH ₃

Implementation variant I–42. A pharmaceutical composition containing a compound according to any of the embodiments of I-1-I-41, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Implementation variant I-43. A method of treating a condition associated with TLR7 modulation in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of embodiments I-1-I-41, or a pharmaceutically acceptable salt thereof.

Implementation variant I-44. The method of embodiment I-43, wherein the condition is a viral infection or cancer.

Implementation variant I-45. A compound according to any one of embodiments I-1-I-41, or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition associated with TLR7 modulation.

Implementation variant I–46. A compound of embodiment I-45 where the condition is a viral infection or cancer.

Implementation variant I-47. The use of a compound according to any one of embodiments I-1-I-41, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a condition associated with TLR7 modulation.

Implementation variant I–48. Application of implementation option I-47, where the condition is a viral infection or cancer.

Implementation variant II–1. A compound having the structure of Formula (1), or a pharmaceutically acceptable salt thereof,

(1)

(one)

where

_, R ^1a is selected from the group consisting of H, C ₁ -C ₄ alkyl, -NH ₂ , -NHAc, -COOH, -SO ₂ CH _{3 ,} -SCH ₃ , -OCH ₃ , and

_,

;where alkyl is optionally substituted with –OH, –NH ₂ , –NHAc, –COOH, –SO ₂ CH ₃ , –SCH ₃ , –OCH ₃ , or

;

R ^1b is C ₂ -C ₅ alkyl;

X is selected from the group consisting of H and C ₁ -C ₄ alkyl, where alkyl is optionally substituted with A, -OH, or -C(CH ₃ ) ₂ OH;

,

, –O–, –S–, –SO₂–, –NH–, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, –O–, –S–, –SO ₂ –, –NH–, and –CH ₂ CH ₂ –;

Y is selected from the group consisting of C ₁ -C ₃ alkyl, aryl and heteroaryl, where alkyl, aryl and heteroaryl are optionally substituted with 1-5 substituents independently selected from A, C ₁ -C ₃ alkyl, and C ₁ -C ₃ alkoxy;

,

,

,

,

,

, и

;A is selected from the group consisting of

,

,

,

,

,

, and

;

,

,

, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилена)]–, –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–; –C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–; и –С(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–OCH₂CH₂CF₂–; L ² is selected from the group consisting of a bond, –(CH ₂ ) _n –, –C(O)NH(CH ₂ ) _n –,

,

,

, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –; –C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –; and –С(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –OCH ₂ CH ₂ CF ₂ –;

m is an integer from zero to four; and

n is an integer from one to four; and

where the compound is substituted with at least one A; and

when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A; and L ² is -CH ₂ -; then A is not -L ² -COOH unless R ^1a contains -COOH.

Implementation variant II-2. The compound of embodiment II-1, or a pharmaceutically acceptable salt thereof, wherein R ^1b is -(CH ₂ ) ₂ CH ₃ .

Implementation variant II-3. The compound of embodiment II-1, or a pharmaceutically acceptable salt thereof, wherein R ^1b is -(CH ₂ ) ₃ CH ₃ .

Implementation variant II-4. A compound according to any one of embodiments II-1-II-3, or a pharmaceutically acceptable salt thereof, wherein R ^1a is C ₁ -C ₄ alkyl optionally substituted with -OH, -OCH ₃ , -SCH ₃ , -SO ₂ CH ₃

Implementation variant II–5. A compound according to any one of embodiments II-1-II-4, or a pharmaceutically acceptable salt thereof, wherein R ^1a is -CH ₂ C(CH ₃ ) ₂ OH.

представляет собой

,

,

,

,

, или

Implementation variant II-6. A compound according to any of the embodiments II-1-II-4, or a pharmaceutically acceptable salt thereof, wherein

represents

,

,

,

,

, or

Implementation variant II–7. A compound according to any one of embodiments II-1-II-3, or a pharmaceutically acceptable salt thereof, wherein R ^1a is C ₁ -C ₄ alkyl optionally substituted with -COOH.

представляет собой

. Implementation variant II-8. A compound according to any of the embodiments II-1-II 3 and II-7, or a pharmaceutically acceptable salt thereof, wherein

represents

.

Implementation variant II–9. A compound according to any one of embodiments II-1-II-3, or a pharmaceutically acceptable salt thereof, wherein R ^1a is H.

Implementation variant II–10. A compound according to any one of embodiments II-1-II-9, or a pharmaceutically acceptable salt thereof, wherein X is C ₁ -C ₄ alkyl, where alkyl is substituted by A.

, где L² представляет собой связь. Implementation variant II-11. A compound according to any one of embodiments II-1-II-10, or a pharmaceutically acceptable salt thereof, wherein X is C ₁ -C ₄ alkyl, where alkyl is substituted

, where L ² is a bond.

Implementation Option II–12. A compound according to any of the embodiments II-1-II-9, or a pharmaceutically acceptable salt thereof, wherein X is CH ₃ .

Implementation Option II–13. A compound according to any one of embodiments II-1-II-9, or a pharmaceutically acceptable salt thereof, wherein X is H.

Implementation Option II-14. A compound according to any one of embodiments II-1-II-13, or a pharmaceutically acceptable salt thereof, wherein L ¹ is -CH ₂ -, -CH ₂ CH ₂ -, -O-, or -S-.

Implementation Option II–15. A compound according to any one of embodiments II-1-II-14, or a pharmaceutically acceptable salt thereof, wherein L ¹ is -CH ₂ -.

Implementation Option II-16. A compound according to any one of embodiments II-1-II-15, or a pharmaceutically acceptable salt thereof, wherein Y is C ₁ -C ₃ alkyl or aryl.

Implementation Option II-17. A compound according to any one of embodiments II-1-II-16, or a pharmaceutically acceptable salt thereof, wherein Y is aryl, where aryl is substituted with C1-C3 alkoxy.

Implementation Option II–18. A compound according to any one of embodiments II-1-II-17, or a pharmaceutically acceptable salt thereof, wherein Y is aryl, where aryl is substituted by A.

. Implementation Option II-19. A compound according to any of the embodiments II-1-II-18, or a pharmaceutically acceptable salt thereof, wherein A is

.

. Implementation variant II–20. A compound according to any of the embodiments II-1-II-18, or a pharmaceutically acceptable salt thereof, wherein A is

.

. Implementation variant II–21. A compound according to any of the embodiments II-1-II-18, or a pharmaceutically acceptable salt thereof, wherein A is

.

. Implementation variant II–22. A compound according to any of the embodiments II-1-II-18, or a pharmaceutically acceptable salt thereof, wherein A is

.

. Implementation variant II–23. A compound according to any of the embodiments II-1-II-18, or a pharmaceutically acceptable salt thereof, wherein A is

.

. Implementation Option II–24. A compound according to any of the embodiments II-1-II-18, or a pharmaceutically acceptable salt thereof, wherein A is

.

. Implementation Option II–25. A compound according to any of the embodiments II-1-II-18, or a pharmaceutically acceptable salt thereof, wherein A is

.

Implementation variant II–26. A compound according to any of the embodiments II-1-II-25, or a pharmaceutically acceptable salt thereof, wherein L ² is -(CH ₂ ) _n -.

Implementation variant II–27. A compound according to any of the embodiments II-1-II-26, or a pharmaceutically acceptable salt thereof, wherein n is one or two.

. Implementation variant II–28. A compound according to any of the embodiments II-1-II-25, or a pharmaceutically acceptable salt thereof, wherein L ² is

.

. Implementation Option II–29. A compound according to any of the embodiments II-1-II-25, or a pharmaceutically acceptable salt thereof, wherein L ² is

.

Implementation variant II–30. A compound according to any one of embodiments II-1-II-25, or a pharmaceutically acceptable salt thereof, wherein L ² is -C(O)NH(CH ₂ ) _n -.

Implementation variant II–31. The compound of embodiment II-1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (1a),

where

X is H or CH ₃

,

, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, –CH ₂ –, –O–, –S–, –CF ₂ –,

,

, and –CH ₂ CH ₂ –;

,

,

,

,

,

, и

; A is selected from the group consisting of

,

,

,

,

,

, and

;

,

, –C(O)NH(CH₂)_n–, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилен)]–, и –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–; –C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–; C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–OCH₂CH₂CF₂–; иL ² is selected from the group consisting of a bond, -CH ₂ -, -CH ₂ CH ₂ -,

,

, –C(O)NH(CH ₂ ) _n –, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, and –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –; –C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –; C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –OCH ₂ CH ₂ CF ₂ –; and

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

Implementation variant II–32. The compound of embodiment II-1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (1a),

where

X is -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ -A ^1a ;

,

,

,

,

,

, и

; A ^1a is selected from the group consisting of

,

,

,

,

,

, and

;

,

, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, –CH ₂ –, –O–, –S–, –CF ₂ –,

,

, and –CH ₂ CH ₂ –;

,

,

,

,

,

, и

; A is selected from the group consisting of

,

,

,

,

,

, and

;

,

, –C(O)NH(CH₂)_n–, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилен)]–, и –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–; –C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–; C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–OCH₂CH₂CF₂–; иL ² is selected from the group consisting of a bond, -CH ₂ -, -CH ₂ CH ₂ -,

,

, –C(O)NH(CH ₂ ) _n –, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, and –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –; –C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –; C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –OCH ₂ CH ₂ CF ₂ –; and

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

Implementation variant II–33. The compound of embodiment II-1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (1b),

where

X is H or CH ₃ ;

,

, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, –CH ₂ –, –O–, –S–, –CF ₂ –,

,

, and –CH ₂ CH ₂ –;

,

,

,

,

, и

, и

; A is selected from the group consisting of

,

,

,

,

, and

, and

;

,

, –C(O)NH(CH₂)_n–, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилен)]–, и –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–; –C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–; C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–OCH₂CH₂CF₂–; иL ² is selected from the group consisting of a bond, -CH ₂ -, -CH ₂ CH ₂ -,

,

, –C(O)NH(CH ₂ ) _n –, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, and –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –; –C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –; C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –OCH ₂ CH ₂ CF ₂ –; and

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

Implementation variant II–34. The compound of embodiment II-1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (1b),

where

X is -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ -A ^1a ;

,

,

,

,

,

, и

; A ^1a is selected from the group consisting of

,

,

,

,

,

, and

;

,

, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, –CH ₂ –, –O–, –S–, –CF ₂ –,

,

, and –CH ₂ CH ₂ –;

,

,

,

,

,

, и

; A is selected from the group consisting of

,

,

,

,

,

, and

;

,

, –C(O)NH(CH₂)_n–, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилен)]–, и –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–; –C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–; C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–OCH₂CH₂CF₂–; иL ² is selected from the group consisting of a bond, -CH ₂ -, -CH ₂ CH ₂ -,

,

, –C(O)NH(CH ₂ ) _n –, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, and –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –; –C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –; C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –OCH ₂ CH ₂ CF ₂ –; and

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

Implementation variant II–35. The compound of embodiment II-1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (1c),

where

X is -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ -A ^1a ;

,

,

,

,

,

, и

; A ^1a is selected from the group consisting of

,

,

,

,

,

, and

;

,

, и –CH₂CH₂–; L ¹ is selected from the group consisting of a bond, –CH ₂ –, –O–, –S–, –CF ₂ –,

,

, and –CH ₂ CH ₂ –;

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy; and

R ⁴ is H or C ₁ -C ₃ alkoxy.

Implementation variant II–36. The compound of embodiment II-1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (1d),

X is -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ -A ^1a ;

,

,

,

,

,

, и

; A ^1a is selected from the group consisting of

,

,

,

,

,

, and

;

,

, –O–, и –CH₂CH₂, –S–; иL ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, –O–, and –CH ₂ CH ₂ , –S–; and

Y is H or C ₁ -C ₃ alkyl.

Implementation variant II–37. The compound of embodiment II-1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (1e),

where R ³ represents H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

Implementation variant II–38. The compound of embodiment II-1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (1f),

.

.

Implementation variant II–39. The compound of embodiment II-1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (1g),

where R ³ represents H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

Implementation variant II–40. The compound of embodiment II-1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (1h),

where R ⁴ represents H or C ₁ -C ₃ alkoxy.

Implementation variant II–41. The compound of embodiment II-1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (1i),

where

,

, –O–, –CH₂CH₂–, и –S–; иL ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, –O–, –CH ₂ CH ₂ –, and –S–; and

Y is H or C ₁ -C ₃ alkyl.

Implementation variant II–42. A compound or pharmaceutically acceptable salt selected from the group consisting of:

Compound -X –L ¹ –Y

one _–CH3

–(CH ₂ ) ₃ CH ₃ 2 _–CH3

–(CH ₂ ) ₃ CH ₃ 3 _–CH3

–(CH ₂ ) ₃ CH ₃ four _–CH3

–(CH ₂ ) ₃ CH ₃ 5 _–CH3

–(CH ₂ ) ₃ CH ₃ 6 _–CH3

–(CH ₂ ) ₃ CH ₃ 7 _–CH3

–(CH ₂ ) ₃ CH ₃ eight _–CH3

9 _–CH3

–(CH ₂ ) ₃ CH ₃ ten _–CH3

–(CH ₂ ) ₃ CH ₃ eleven _–CH3

–(CH ₂ ) ₃ CH ₃ 12 _–CH3

–(CH ₂ ) ₃ CH ₃ 13 _–CH3

–(CH ₂ ) ₃ CH ₃ fourteen _–CH3

–(CH ₂ ) ₃ CH ₃ fifteen

–(CH ₂ ) ₃ CH ₃ 16 _–CH3

–(CH ₂ ) ₃ CH ₃ 17 _–CH3

–(CH ₂ ) ₃ CH ₃ eighteen _–CH3

19

–(CH ₂ ) ₃ CH ₃ twenty _–CH3

21

–OCH ₃

22 _–CH3

23 _–CH3

24 _–CH3

–(CH ₂ ) ₃ CH ₃ 25 _–CH3

–(CH ₂ ) ₃ CH ₃ 26 _–CH3

–(CH ₂ ) ₄ CH ₃ 27

28 _–CH3

–(CH ₂ ) ₃ CH ₃ 29

thirty _–CH3

–(CH ₂ ) ₃ CH ₃ 31 _–CH3

–(CH ₂ ) ₃ CH ₃ 32 _–CH3

33 _–CH3

34 _–CH3

35 _–CH3

36 _–CH3

37

–(CH ₂ ) ₃ CH ₃ 38

39 _–CH3

40

–(CH ₂ ) ₃ CH ₃ 41 _–CH3

42 _–CH3

43

–(CH ₂ ) ₃ CH ₃ 44 _–CH3

45

46

47

–(CH ₂ ) ₃ CH ₃ 48

49

fifty

51 _–CH3

Implementation variant II–43. A pharmaceutical composition containing a compound according to any of the embodiments of II-1-II-42, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Implementation variant II–44. A method of treating a condition associated with TLR7 modulation in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of II-1-II-42 or a pharmaceutically acceptable salt thereof.

Implementation variant II–45. The method of embodiment II-44, wherein the condition is a viral infection or cancer.

Implementation Option II–46. The method of embodiment II-45, wherein the administration is oral, intravenous, subcutaneous, intramuscular, intratumoral, intradermal, intranasal, inhalation, intravesical, topical, sublingual, buccal, intrarectal, intrathecal, intracranial or other forms of local delivery.

Implementation variant II–47. A compound according to any of the embodiments II-1-II-42, or a pharmaceutically acceptable salt thereof, for use as a drug.

Implementation variant II–48. A compound according to any one of embodiments II-1-II-42, or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition associated with TLR7 modulation.

Implementation Option II–49. A compound of embodiment II-48 wherein the condition is a viral infection or cancer.

Implementation variant II–50. The use of a compound according to any of the embodiments II-1-II-42, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a condition associated with TLR7 modulation.

Implementation variant II–51. Application of embodiment II-50, where the condition is a viral infection or cancer.

Implementation variant II–52. The pharmaceutical composition of embodiment II-43 further comprising at least one or more additional therapeutic agents.

Implementation variant II–53. The pharmaceutical composition of embodiment II-52, wherein at least one or more additional therapeutic agents is an antiviral nucleoside.

Implementation variant II–54. The pharmaceutical composition of embodiment II-52, wherein at least one or more additional therapeutic agents is an anti-PD-1 antibody or an anti-PD-L1 antibody.

Implementation variant II–55. A method of treating HBV in a subject in need thereof, comprising administering a compound according to any of the embodiments of II-1-II-42, or a pharmaceutically acceptable salt thereof, in combination with an antiviral nucleoside.

Implementation variant II–56. A method of treating cancer in a subject in need thereof, comprising administering a compound of any one of II-1-II-42, or a pharmaceutically acceptable salt thereof, in combination with an anti-PD-1 antibody or an anti-PD-L1 antibody.

Implementation variant III-1. A compound having the structure of Formula (1), or a pharmaceutically acceptable salt thereof,

(1)

(one)

where

; и A_, R ^1a is selected from the group consisting of H, C ₁ -C ₄ alkyl, -NH ₂ , -NHAc, -COOH, -SO ₂ CH _3, -SCH ₃ , -OCH ₃ ,

; _and A

, или A;where alkyl is optionally substituted with –OH, –NH ₂ , –NHAc, –COOH, –SO ₂ CH ₃ , –SCH ₃ , –OCH ₃ ,

, or A;

R ^1b is C ₂ -C ₅ alkyl;

X is selected from the group consisting of H and C ₁ -C ₄ alkyl, where alkyl is optionally substituted with A, -OH, or -C(CH ₃ ) ₂ OH;

,

, –O–, –S–, –SO₂–, –NH–, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, –O–, –S–, –SO ₂ –, –NH–, and –CH ₂ CH ₂ –;

Y is selected from the group consisting of C ₁ -C ₃ alkyl, aryl and heteroaryl, where alkyl, aryl and heteroaryl are optionally substituted with 1-5 substituents independently selected from A, C ₁ -C ₃ alkyl, and C ₁ -C ₃ alkoxy;

,

,

,

,

,

, и

;A is selected from the group consisting of

,

,

,

,

,

, and

;

,

,

, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилен)]–, –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–; –C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–; и –С(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–OCH₂CH₂CF₂–; L ² is selected from the group consisting of a bond, –(CH ₂ ) _n –, –C(O)NH(CH ₂ ) _n –,

,

,

, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –; –C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –; and –С(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –OCH ₂ CH ₂ CF ₂ –;

m is an integer from zero to four;

n is an integer from one to four;

where the compound is substituted with at least one A; and

when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A; and L ² is -CH ₂ -; then A is not -L ² -COOH unless R ^1a contains -COOH or -SO ₂ CH _3; and

; тогда A и L¹ не находятся в пара–положении по отношению друг к другу. when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A; L ² is –CH ₂ –, –O–(CH ₂ ) ₂ –O(CH ₂ ) ₂ –, or –O–(CH ₂ ) ₂ –O(CH ₂ ) ₂ (CF ₂ )–; and A is

; then A and L ¹ are not in para-position with respect to each other.

Implementation option III-2. A compound having the structure of Formula (1), or a pharmaceutically acceptable salt thereof,

(1)

(one)

where

_, R ^1a is selected from the group consisting of H, C ₁ -C ₄ alkyl, -NH ₂ , -NHAc, -COOH, -SO ₂ CH _{3 ,} -SCH ₃ , -OCH ₃ , and

_,

;where alkyl is optionally substituted with –OH, –NH ₂ , –NHAc, –COOH, –SO ₂ CH ₃ , –SCH ₃ , –OCH ₃ , or

;

R ^1b is C ₂ -C ₅ alkyl;

X is selected from the group consisting of H and C ₁ -C ₄ alkyl, where alkyl is optionally substituted with A, -OH, or -C(CH ₃ ) ₂ OH;

,

, –O–, –S–, –SO₂–, –NH–, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, –O–, –S–, –SO ₂ –, –NH–, and –CH ₂ CH ₂ –;

Y is selected from the group consisting of C ₁ -C ₃ alkyl, aryl and heteroaryl, where alkyl, aryl and heteroaryl are optionally substituted with 1-5 substituents independently selected from A, C ₁ -C ₃ alkyl, and C ₁ -C ₃ alkoxy;

,

,

,

,

,

, и

;A is selected from the group consisting of

,

,

,

,

,

, and

;

,

,

, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилен)]–, –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–; –C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–; и –С(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–OCH₂CH₂CF₂–; L ² is selected from the group consisting of a bond, –(CH ₂ ) _n –, –C(O)NH(CH ₂ ) _n –,

,

,

, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –; –C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –; and –С(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –OCH ₂ CH ₂ CF ₂ –;

m is an integer from zero to four; and

n is an integer from one to four; and

where the compound is substituted with at least one A; and

when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A; and L ² is -CH ₂ -; then A is not -L ² -COOH unless R ^1a contains -COOH or -SO ₂ CH ₃ ; and

; тогда A и L¹ не находятся в пара–положении по отношению друг к другу. when X is -CH ₃ ; L ¹ is -CH ₂ -; Y is aryl substituted with A; L ² is –CH ₂ –, –O–(CH ₂ ) ₂ –O(CH ₂ ) ₂ –, or –O–(CH ₂ ) ₂ –O(CH ₂ ) ₂ (CF ₂ )–; and A is

; then A and L ¹ are not in para-position with respect to each other.

Implementation variant III-3. A compound of embodiment III-1 or III-2, or a pharmaceutically acceptable salt thereof, wherein R ^1b is -(CH ₂ ) ₂ CH ₃ .

Implementation option III–4. A compound of embodiment III-1 or III-2, or a pharmaceutically acceptable salt thereof, wherein R ^1b is -(CH ₂ ) ₃ CH ₃ .

Implementation variant III-5. A compound according to any one of embodiments III-1-III-4, or a pharmaceutically acceptable salt thereof, wherein R ^1a is C ₁ -C ₄ alkyl optionally substituted with -OH, -OCH ₃ , -SCH ₃ , or -SO ₂ CH _3.

Implementation variant III–6. A compound according to any one of embodiments III-1-III-5, or a pharmaceutically acceptable salt thereof, wherein R ^1a is -CH ₂ C(CH ₃ ) ₂ OH.

представляет собой

,

,

,

,

, или

. Implementation variant III–7. A compound according to any of the embodiments III-1-III-6, or a pharmaceutically acceptable salt thereof, wherein

represents

,

,

,

,

, or

.

Implementation variant III–8. A compound according to any one of embodiments III-1-III-4, or a pharmaceutically acceptable salt thereof, wherein R ^1a is C ₁ -C ₄ alkyl optionally substituted with -COOH.

представляет собой

. Implementation variant III-9. A compound according to any of the embodiments III-1-III-4 and III-8, or a pharmaceutically acceptable salt thereof, wherein

represents

.

Implementation variant III–10. A compound according to any one of embodiments III-1-IIII-4, or a pharmaceutically acceptable salt thereof, wherein R ^1a is H.

Implementation variant III-11. A compound according to any one of embodiments III-1-III-10, or a pharmaceutically acceptable salt thereof, wherein X is C ₁ -C ₄ alkyl, where alkyl is substituted by A.

, где L² представляет собой связь. Implementation variant III-12. A compound according to any one of embodiments III-1-III-11, or a pharmaceutically acceptable salt thereof, wherein X is C ₁ -C ₄ alkyl, where alkyl is substituted

, where L ² is a bond.

Implementation variant III–13. A compound according to any of the embodiments III-1-III-10, or a pharmaceutically acceptable salt thereof, wherein X is CH ₃ .

Implementation variant III-14. A compound according to any one of embodiments III-1-III-10, or a pharmaceutically acceptable salt thereof, wherein X is H.

Implementation Option III-15. A compound according to any one of embodiments III-1-III-14, or a pharmaceutically acceptable salt thereof, wherein L ¹ is -CH ₂ -, -CH ₂ CH ₂ -, -O-, or -S-.

Implementation variant III–16. A compound according to any one of embodiments III-1-III-15, or a pharmaceutically acceptable salt thereof, wherein L ¹ is -CH ₂ -.

Implementation variant III–17. A compound according to any one of embodiments III-1-III-16, or a pharmaceutically acceptable salt thereof, wherein Y is C ₁ -C ₃ alkyl or aryl.

Implementation variant III-18. A compound according to any one of embodiments III-1-III-17, or a pharmaceutically acceptable salt thereof, wherein Y is aryl, where aryl is substituted with C1-C3 alkoxy.

Implementation Option III–19. A compound according to any one of embodiments III-1-III-18, or a pharmaceutically acceptable salt thereof, wherein Y is aryl, where aryl is substituted by A.

. Implementation variant III–20. A compound according to any one of embodiments III-1-III-19, or a pharmaceutically acceptable salt thereof, wherein A is

.

. Implementation variant III-21. A compound according to any one of embodiments III-1-III-19, or a pharmaceutically acceptable salt thereof, wherein A is

.

. Implementation variant III–22. A compound according to any one of embodiments III-1-III-19, or a pharmaceutically acceptable salt thereof, wherein A is

.

. Implementation variant III–23. A compound according to any one of embodiments III-1-III-19, or a pharmaceutically acceptable salt thereof, wherein A is

.

. Implementation variant III–24. A compound according to any one of embodiments III-1-III-19, or a pharmaceutically acceptable salt thereof, wherein A is

.

. Implementation variant III–25. A compound according to any one of embodiments III-1-III-19, or a pharmaceutically acceptable salt thereof, wherein A is

.

. Implementation variant III–26. A compound according to any one of embodiments III-1-III-19, or a pharmaceutically acceptable salt thereof, wherein A is

.

Implementation variant III-27. A compound according to any one of embodiments III-1-III-26, or a pharmaceutically acceptable salt thereof, wherein L ² is -(CH ₂ ) _n -.

Implementation variant III–28. A compound according to any one of embodiments III-1-III-27, or a pharmaceutically acceptable salt thereof, wherein n is one or two.

. Implementation variant III–29. A compound according to any one of embodiments III-1-III-26, or a pharmaceutically acceptable salt thereof, wherein L ² is

.

. Implementation variant III–30. A compound according to any one of embodiments III-1-III-26, or a pharmaceutically acceptable salt thereof, wherein L ² is

.

Implementation variant III-31. A compound according to any one of embodiments III-1-III-26, or a pharmaceutically acceptable salt thereof, wherein L ² is -C(O)NH(CH ₂ ) _n -.

Implementation variant III–32. The compound of embodiment III-1 or III-2, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (1a),

where

X is H or CH ₃

,

, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, –CH ₂ –, –O–, –S–, –CF ₂ –,

,

, and –CH ₂ CH ₂ –;

,

,

,

,

,

, и

; A is selected from the group consisting of

,

,

,

,

,

, and

;

,

, –C(O)NH(CH₂)_n–, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилен)]–, и –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–; –C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–; C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–OCH₂CH₂CF₂–; иL ² is selected from the group consisting of a bond, -CH ₂ -, -CH ₂ CH ₂ -,

,

, –C(O)NH(CH ₂ ) _n –, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, and –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –; –C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –; C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –OCH ₂ CH ₂ CF ₂ –; and

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

Implementation variant III-33. The compound of embodiment III-1 or III-2, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (1a),

where

X is -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ -A ^1a ;

,

,

,

,

,

, и

; A ^1a is selected from the group consisting of

,

,

,

,

,

, and

;

,

, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, –CH ₂ –, –O–, –S–, –CF ₂ –,

,

, and –CH ₂ CH ₂ –;

,

,

,

,

,

, и

; A is selected from the group consisting of

,

,

,

,

,

, and

;

,

, –C(O)NH(CH₂)_n–, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилен)]–, и –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–; –C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–; C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–OCH₂CH₂CF₂–; иL ² is selected from the group consisting of a bond, -CH ₂ -, -CH ₂ CH ₂ -,

,

, –C(O)NH(CH ₂ ) _n –, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, and –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –; –C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –; C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –OCH ₂ CH ₂ CF ₂ –; and

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

Implementation variant III-34. The compound of embodiment III-1 or III-2, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (1b),

where

X is H or CH ₃ ;

,

, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, –CH ₂ –, –O–, –S–, –CF ₂ –,

,

, and –CH ₂ CH ₂ –;

,

,

,

,

, и

, и

; A is selected from the group consisting of

,

,

,

,

, and

, and

;

,

, –C(O)NH(CH₂)_n–, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилен)]–, и –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–; –C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–; C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–OCH₂CH₂CF₂–; иL ² is selected from the group consisting of a bond, -CH ₂ -, -CH ₂ CH ₂ -,

,

, –C(O)NH(CH ₂ ) _n –, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, and –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –; –C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –; C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –OCH ₂ CH ₂ CF ₂ –; and

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

Implementation variant III–35. The compound of embodiment III-1 or III-2, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (1b),

where

X is -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ -A ^1a ;

,

,

,

,

,

, и

; A ^1a is selected from the group consisting of

,

,

,

,

,

, and

;

,

, и –CH₂CH₂–;L ¹ is selected from the group consisting of a bond, –CH ₂ –, –O–, –S–, –CF ₂ –,

,

, and –CH ₂ CH ₂ –;

,

,

,

,

,

, и

; A is selected from the group consisting of

,

,

,

,

,

, and

;

,

, –C(O)NH(CH₂)_n–, –[O(CH₂CH₂)]_n–, –[O(C₁–C₄ алкилен)]–, и –[O(CH₂CH₂)]_n–OCH₂CH₂CF₂–; –C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–; C(O)NHCH₂CH₂–[O(CH₂CH₂)]_m–OCH₂CH₂CF₂–; иL ² is selected from the group consisting of a bond, -CH ₂ -, -CH ₂ CH ₂ -,

,

, –C(O)NH(CH ₂ ) _n –, –[O(CH ₂ CH ₂ )] _n –, –[O(C ₁ –C ₄ alkylene)]–, and –[O(CH ₂ CH ₂ )] _n –OCH ₂ CH ₂ CF ₂ –; –C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –; C(O)NHCH ₂ CH ₂ –[O(CH ₂ CH ₂ )] _m –OCH ₂ CH ₂ CF ₂ –; and

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

Implementation variant III–36. The compound of embodiment III-1 or III-2, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (1c),

where

X is -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ -A ^1a ;

,

,

,

,

,

, и

; A ^1a is selected from the group consisting of

,

,

,

,

,

, and

;

,

, и –CH₂CH₂–; L ¹ is selected from the group consisting of a bond, –CH ₂ –, –O–, –S–, –CF ₂ –,

,

, and –CH ₂ CH ₂ –;

R ³ is H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy; and

R ⁴ is H or C ₁ -C ₃ alkoxy.

Implementation variant III-37. The compound of embodiment III-1 or III-2, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (1d),

X is -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a , or -CH ₂ C(CH ₃ ) ₂ -A ^1a ;

,

,

,

,

,

, и

; A ^1a is selected from the group consisting of

,

,

,

,

,

, and

;

,

, –O–, и –CH₂CH₂, –S–; иL ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, –O–, and –CH ₂ CH ₂ , –S–; and

Y is H or C ₁ -C ₃ alkyl.

Implementation variant III-38. The compound of embodiment III-1 or III-2, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (1e),

where R ³ represents H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

Implementation variant III–39. The compound of embodiment III-1 or III-22, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (1f),

.

.

Implementation variant III-40. The compound of embodiment III-1 or III-22, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (1g),

where R ³ represents H, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy.

Implementation variant III-41. The compound of embodiment III-1 or III-2, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (1h),

where R ⁴ represents H or C ₁ -C ₃ alkoxy.

Implementation variant III–42. The compound of embodiment III-1 or III-2, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (1i),

where

,

, –O–, –CH₂CH₂–, и –S–; иL ¹ is selected from the group consisting of a bond, -CH ₂ -, -CF ₂ -,

,

, –O–, –CH ₂ CH ₂ –, and –S–; and

Y is H or C ₁ -C ₃ alkyl.

Implementation variant III–43. The compound of embodiment III-1 or III-2, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (1j),

(1j).

(1j).

Implementation variant III-44. The compound of embodiment III-1 or III-2, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (1) is a compound of Formula (1k),

(1k).

(1k).

Implementation variant III-45. A compound or pharmaceutically acceptable salt selected from the group consisting of:

Compound -X –L ¹ –Y

Compound one _–CH3

–(CH ₂ ) ₃ CH ₃

2 _–CH3

–(CH ₂ ) ₃ CH ₃

3 _–CH3

–(CH ₂ ) ₃ CH ₃

four _–CH3

–(CH ₂ ) ₃ CH ₃

5 _–CH3

–(CH ₂ ) ₃ CH ₃

6 _–CH3

–(CH ₂ ) ₃ CH ₃

7 _–CH3

–(CH ₂ ) ₃ CH ₃

eight _–CH3

9 _–CH3

–(CH ₂ ) ₃ CH ₃

ten _–CH3

–(CH ₂ ) ₃ CH ₃

eleven _–CH3

–(CH ₂ ) ₃ CH ₃

12 _–CH3

–(CH ₂ ) ₃ CH ₃

13 _–CH3

–(CH ₂ ) ₃ CH ₃

fourteen _–CH3

–(CH ₂ ) ₃ CH ₃

fifteen

–(CH ₂ ) ₃ CH ₃

16 _–CH3

–(CH ₂ ) ₃ CH ₃

17 _–CH3

–(CH ₂ ) ₃ CH ₃

eighteen _–CH3

19

–(CH ₂ ) ₃ CH ₃

twenty _–CH3

20C _–CH3

21

–OCH ₃

22 _–CH3

23 _–CH3

24 _–CH3

–(CH ₂ ) ₃ CH ₃

25 _–CH3

–(CH ₂ ) ₃ CH ₃

26 _–CH3

–(CH ₂ ) ₄ CH ₃

27

28 _–CH3

–(CH ₂ ) ₃ CH ₃

29

thirty _–CH3

–(CH ₂ ) ₃ CH ₃

31 _–CH3

–(CH ₂ ) ₃ CH ₃

32 _–CH3

33 _–CH3

34 _–CH3

35 _–CH3

36 _–CH3

37

–(CH ₂ ) ₃ CH ₃

38

39 _–CH3

40

–(CH ₂ ) ₃ CH ₃

41 _–CH3

42 _–CH3

43

–(CH ₂ ) ₃ CH ₃

44 _–CH3

45

46

47

–(CH ₂ ) ₃ CH ₃

48

49

fifty

51 _–CH3

Implementation variant III–46. A pharmaceutical composition containing a compound according to any of the embodiments III-1-III-45 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Implementation variant III–47. A method of treating a condition associated with TLR7 modulation in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of III-1-III-45 or a pharmaceutically acceptable salt thereof.

Implementation variant III–48. The method of embodiment III-47, where the condition is a viral infection or cancer.

Implementation variant III–49. The method of embodiment III-47 or III-48, where the administration is oral, intravenous, subcutaneous, intramuscular, intratumoral, intradermal, intranasal, inhalation, intravesical, topical, sublingual, buccal, intrarectal, intrathecal, intracranial, or other forms of local delivery.

Implementation variant III-50. A compound according to any one of embodiments III-1-III-45, or a pharmaceutically acceptable salt thereof, for use as a drug.

Implementation variant III–51. A compound according to any one of embodiments III-1-III-45, or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition associated with TLR7 modulation.

Implementation variant III–52. A compound of embodiment III-51 wherein the condition is a viral infection or cancer.

Implementation variant III–53. The use of a compound according to any of the embodiments III-1-III-45 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of a condition associated with TLR7 modulation.

Implementation variant III–54. Application of embodiment III-53, where the condition is a viral infection or cancer.

Implementation variant III-55. The pharmaceutical composition of embodiment III-46 further comprising at least one or more additional therapeutic agents.

Implementation variant III-56. The pharmaceutical composition of embodiment III-55, wherein at least one or more additional therapeutic agents is an antiviral nucleoside.

Implementation variant III–57. The pharmaceutical composition of Embodiment III-55, wherein at least one or more additional therapeutic agents is an anti-PD-1 antibody or an anti-PD-L1 antibody.

Implementation variant III-58. A method of treating HBV in a subject in need thereof, comprising administering a compound of any one of III-1-III-45 embodiments, or a pharmaceutically acceptable salt thereof, in combination with an antiviral nucleoside.

Implementation variant III–59. A method of treating cancer in a subject in need thereof, comprising administering a compound of any one of III-1-III-45 embodiments, or a pharmaceutically acceptable salt thereof, in combination with an anti-PD-1 antibody or an anti-PD-L1 antibody.

Examples

The following examples are provided to illustrate the present description and should not be construed as limiting it. In these examples, all parts and percentages are by weight unless otherwise noted. Abbreviations in the examples are shown below.

Abbreviations

AIBN azobisisobutyronitrile aq. water solution DCM dichloromethane DMAP 4-dimethylaminopyridine EA ethyl acetate equiv. equivalent h hour HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazole[4,5-b]pyridinium-3-oxide hexafluorophosphate) HPLC high performance liquid chromatography LC-MS: liquid chromatography - mass spectrometry min minutes NBS N-bromosuccinimide NMP N-methylpyrrolidine NMR nuclear magnetic resonance PE petroleum ether kt or kt room temperature sat. saturated TBAF tetrabutylammonium fluoride TBDPS tert-butyldiphenylsilyl TEA triethylamine THF tetrahydrofuran TX thin layer chromatography

Example 1: 3-(4-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-3-methoxyphenyl)propanoic acid (Compound 1)

Stage 1: methyl 4–(2–(ethoxycarbonyl)–3–oxobutyl)–3–methoxybenzoate

Sodium hydride (60% in mineral oil, 1.25 eq.) was added portionwise over 10 min to a solution of ethyl 3-oxobutanoate (1.2 eq.) in THF (0.8 M) at 0 ^° C. The resulting suspension was stirred at 0°C for 10 minutes and a solution of methyl 4-(bromomethyl)-3-methoxybenzoate (1.0 eq.) in THF (0.5 M) was added dropwise over 10 minutes. The mixture was heated to 70°C and stirred for 3 hours. The mixture was allowed to cool and then poured into ice water and stirred for 30 minutes. The mixture was partitioned between EA/water. The organic layer was dried over Na ₂ SO ₄ , filtered, concentrated and purified by flash chromatography on silica (eluent PE/EA=100/1 to 5/1) to give the title compound.

Stage 2: methyl 4-((2-amino-4-hydroxy-6-methylpyrimidin-5-yl)methyl)-3-methoxybenzoate

A mixture of methyl 4-(2-(ethoxycarbonyl)-3-oxobutyl)-3-methoxybenzoate (1.0 eq.) and guanidine carbonate (1.0 eq.) in MeOH (0.2 M) was stirred overnight at 65° C and allowed to cool to room temperature. The precipitate was collected by filtration and suspended in water. The solid was collected by filtration and washed with MeOH and EA to give the title compound as a white solid.

Stage 3: methyl 4-((2-amino-4-chloro-6-methylpyrimidin-5-yl)methyl)-3-methoxybenzoate

Methyl 4–((2–amino–4–hydroxy–6–methylpyrimidin–5–yl)methyl)–3–methoxybenzoate (1.0 eq.) in POCl ₃ (0.5 M) was stirred overnight at 100°C under N ₂ atmosphere. The mixture was cooled to room temperature and the solvent was removed. Water was added to the residue and the pH of the mixture was adjusted to 7 with solid NaHCO ₃ . The resulting mixture was heated at 50°C for 1 hour and then left to cool to room temperature. The solid was collected, washed with water, EA and dried in vacuo to give the title compounds.

Stage 4: methyl 4-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-3-methoxybenzoate

Butan-1-amine (4.5 eq.). The resulting mixture was stirred overnight at 125°C and the mixture was cooled to room temperature. The mixture was partitioned between EA/water. The organic layer was dried over Na ₂ SO ₄ , concentrated and purified by flash chromatography on silica (eluent PE/EA=20:1 to 1:5) to give the title compound.

Stage 5: (4-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-3-methoxyphenyl)methanol

To a stirred solution of methyl 4–((2–amino–4– (butylamino)–6–methylpyrimidin–5–yl)methyl)–3methoxybenzoate (1.0 eq.) in THF (0.1 M) was added dropwise LiAlH_four(1 M in THF, 2.0 eq.). The resulting mixture was stirred at 0°C for 10 minutes and at room temperature for 1 hour. The mixture was diluted with EA and quenched with 2N. NaOH. The mixture was partitioned between EA/water. The organic layer was dried over Na₂SO_four, filtered and concentrated to give the title compound as a white solid.

Stage 6: 4–((2–amino–4–(butylamino)–6–methylpyrimidin–5–yl)methyl)–3–methoxybenzaldehyde

To a stirred solution of (4–((2–amino–4–(butylamino)–6–methylpyrimidin–5–yl)methyl)–3–methoxyphenyl)methanol (1.0 equiv.) in THF (0.06 M) was added MnO₂(5.0 eq.). The resulting mixture was stirred overnight at 50^oC. The mixture was filtered. The filtrate was concentrated to give the title compound.

Stage 7: ethyl (E)-3-(4-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-3-methoxyphenyl)acrylate

A mixture of 4-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-3-methoxybenzaldehyde (1.0 eq.) and ethyl 2–(triphenyl–λ⁵-phosphanylidene)acetate (1.2 eq.) in THF (0.1 M) was stirred at 70°C for 5 h. The mixture was concentrated and purified by flash chromatography on silica (eluent 0-5% MeOH in DCM) to give the title compounds as a white solid.

Stage 8: ethyl 3–(4–((2–amino–4–(butylamino)–6–methylpyrimidin–5–yl)methyl)–3–methoxyphenyl)propanoate

To a stirred solution of ethyl (E)–3–(4–((2–amino–4–(butylamino)–6–methylpyrimidin–5–yl)methyl)–3–methoxyphenyl)acrylate (1.0 eq.) in EA (0.02 M) was added Pd/C (20 wt.%). The resulting mixture was stirred overnight at 50°C under H₂. The mixture was filtered. The filtrate was concentrated and purified by flash chromatography on silica (eluent 0-5% MeOH in DCM) to give the title compound.

Step 9: 3-(4-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-3-methoxyphenyl)propanoic acid

To a stirred solution of ethyl 3-(4-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-3-methoxyphenyl)propanoate (1.0 eq.) in MeOH (0.03 M) added 1 n. NaOH (5.0 eq.). The resulting mixture was stirred overnight at 45 ^° C. The solvent was removed. The residue was neutralized with 2N. HCl to pH 7. The suspension was filtered. The solid was collected and dissolved in HCl/dioxane. The solution was concentrated to give the title compound as a white solid (HCl salt).

LC-MS: [M+H] = 373.4

¹ H NMR (400 MHz, DMSO– d ₆ ) δ 12.32 (br s, 1H), 12.11 (br s, 1H), 7.83 (br s, 1H), 7.41 (br s, 2H), 6.90 (s, 1H), 6.70 (s, 2H), 3.83 (s, 3H), 3.64 (s, 2H), 3.36–3.30 (m, 2H ), 2.82–2.77 (m, 2H), 2.54–2.50 (m, 2H), 2.11 (s, 3H), 1.50–1.43 (m, 2H), 1.23–1.15 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H).

Example 2: 5-(4-((2H-tetrazol-5-yl)methyl)-2-methoxybenzyl)-N4-butyl-6-methylpyrimidine-2,4-diamine (Compound 2)

Stage 1: N4-butyl-5-(4-(chloromethyl)-2-methoxybenzyl)-6-methylpyrimidine-2,4-diamine

To a stirred solution of (4-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-3-methoxyphenyl)methanol (1.0 eq., Example 1 - Step 5) in DCM ( 0.14 M) was added SOCl ₂ (1.8 eq.) at room temperature under N ₂ . The mixture was stirred at room temperature for 1 hour. The mixture was partitioned between DCM/sat. aq. _NaHC03 . The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound.

Stage 2: 2–(4–((2–amino–4–(butylamino)–6–methylpyrimidin–5–yl)methyl)–3–methoxyphenyl)acetonitrile

MixtureN ^four-butyl-5-(4-(chloromethyl)-2-methoxybenzyl)-6-methylpyrimidine-2,4-diamine (1.0 eq.) in 1:1 DMSO/DMF (0.14 M) and NaCN (2.8 eq.) was stirred overnight at room temperature. The mixture was partitioned between EA/water. The organic layer was dried over Na₂SO_four, filtered, concentrated and purified by flash chromatography on silica (eluent 0-5% MeOH in DCM) to give the title compound.

Step 3: 5-(4-((2H-tetrazol-5-yl)methyl)-2-methoxybenzyl)-N4-butyl-6-methylpyrimidine-2,4-diamine

To a stirred mixture of 2–(4–((2–amino–4–(butylamino)–6–methylpyrimidin–5–yl)methyl)–3–methoxyphenyl)acetonitrile (1.0 eq.), Bu ₂ SnO (2, 0 eq.) in NMP (0.06 M) was added TMSN ₃ (10.0 eq.). The resulting mixture was stirred overnight at 125°C under N ₂ . The mixture was cooled to room temperature. The mixture was filtered to give the title compound as a white powder.

LC-MS: [M+H] = 383.5

¹ H NMR (400 MHz, DMSO– d ₆ ) δ 12.19 (s, 1H), 7.85 (br s, 1H), 7.34 (br s, 2H), 7.01 (s, 1H) , 6.74 (s, 2H), 4.24 (s, 2H), 3.84 (s, 3H), 3.65 (s, 2H), 3.37–3.34 (m, 2H), 2.09 (s, 3H), 1.48-1.41 (m, 2H), 1.23-1.16 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H) .

Example 3A: 5-(5-((2H-tetrazol-5-yl)methyl)-2-methoxybenzyl)-N4-butyl-6-methylpyrimidine-2,4-diamine (Compound 3)

Stage A: methyl 3-(bromomethyl)-4-methoxybenzoate

To a mixture of methyl 4-methoxy-3-methylbenzoate (1.0 eq.) in CCl_four (0.37 M), NBS (1.1 eq.) and AIBN (0.2 eq.) were stirred overnight at 95°C under nitrogen atmosphere. The resulting mixture was concentrated and partitioned between DCM and water, the organic layer was dried over Na₂SO_four, concentrated and purified by flash chromatography on silica (eluent PE/EA=100:1 to 20:1) to give the title compound as a white solid.

Obtaining (3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxyphenyl)methanol

In the preparation of (3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxyphenyl)methanol, Example 1 - Steps 1-5 was followed, but using methyl 3-(bromomethyl )-4-methoxybenzoate instead of methyl 4-(bromomethyl)-3-methoxybenzoate in Stage 1.

Obtaining 5-(5-((2H-tetrazol-5-yl)methyl)-2-methoxybenzyl)-N4-butyl-6-methylpyrimidine-2,4-diamine

In the preparation of 5-(5-((2 H -tetrazol-5-yl)methyl)-2-methoxybenzyl) -N ⁴ -butyl-6-methylpyrimidine-2,4-diamine Example 2 - Steps 1-3 was followed, but using (3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxyphenyl)methanol instead of 4-((2-amino-4-(butylamino)-6- methylpyrimidin-5-yl)methyl)-3-methoxyphenyl)methanol in Step 1. The title compound was purified by preparative HPLC using acetonitrile/water as eluent to give a white solid.

LC-MS: [M+H] = 383.3

¹ H NMR (400 MHz, DMSO– d ₆ ) δ 7.03 (d, J = 7.6 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.73 (s , 1H), 6.60 (br s, 1H), 6.31 (s, 2H), 3.97 (s, 2H), 3.80 (s, 3H), 3.60 (s, 2H), 3.29–3.24 (m, 2H), 2.02 (s, 3H), 1.43–1.37 (m, 2H), 1.22–1.17 (m, 2H), 0, 84 (t, J =7.2 Hz, 3H).

Example 3B: 5-(5-((2H-tetrazol-5-yl)methyl)-2-methoxybenzyl)-N4-butyl-6-methylpyrimidine-2,4-diamine (Compound 3)

Stage 1: methyl 3-(bromomethyl)-4-methoxybenzoate

A mixture of methyl 4-methoxy-3-methylbenzoate (1.0 eq) in CCl ₄ (0.37 M), NBS (1.1 eq) and AIBN (0.2 eq) was stirred overnight at 95° C in a nitrogen atmosphere. The resulting mixture was concentrated and partitioned between DCM and water, the organic layer was dried over Na ₂ SO ₄ , concentrated and purified by flash chromatography on silica (eluent PE/EA=100:1 to 20:1) to give the title compound in form of a white solid.

Stage 2: methyl 3–(2–(ethoxycarbonyl)–3–oxobutyl)–4–methoxybenzoate

To a mixture of ethyl 3-oxobutanoate (1.2 equiv.) in THF (0.35 M) at 0°C was added portionwise 60% NaH (1.25 equiv.) in N ₂ . The resulting suspension was stirred at 0°C for 10 min, then a solution of methyl 3-(bromomethyl)-4-methoxybenzoate (1.0 eq.) in THF (2 M) was added dropwise over 10 min. The resulting mixture was stirred overnight at 70 ^° C. The mixture was cooled to room temperature and ice water was added. The mixture was extracted with ethyl acetate. The organic layer was separated and dried over Na ₂ SO ₄ , concentrated and purified by flash chromatography on silica (eluent PE/EA=50:1-5:1) to give the title compound as a yellow oil.

Stage 3: methyl 3-((2-amino-4-hydroxy-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzoate

To a solution of methyl 3–(2–(ethoxycarbonyl)–3–oxobutyl)–4–methoxybenzoate (1.0 eq.) in MeOH (0.2 M) was added guanidine carbonate (1.0 eq.). The resulting mixture was stirred at 65°C for 16 h and then cooled to room temperature. The precipitate was collected by filtration, the solid was triturated with water and filtered. The filter cake was washed with MeOH and EtOAc, dried in vacuo to give the title compound as a white solid.

Stage 4: methyl 3-((2-amino-4-chloro-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzoate

Suspension of methyl 3-((2-amino-4-hydroxy-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzoate (1.0 eq.) in POCl₃ (0.55 M) was stirred at 100°C for 15 h. The reaction mixture was allowed to cool to room temperature and POCl₃ evaporated to dryness under reduced pressure. The residue was diluted with water and adjusted to pH 7 with saturated NaHCO₃. Then the mixture was heated at 50°C for 1 h, cooled to room temperature. The precipitate was collected by filtration and the filter cake was washed with water and EtOAc, dried in vacuo to give the title compound.

Step 5: methyl 3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzoate

A mixture of butan-1-amine (4.5 eq.) and methyl 3-((2-amino-4-chloro-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzoate (1.0 eq.) in NMP (0.3 M) stirred overnight at 150^oC. The reaction mixture was allowed to cool, diluted with EtOAc, washed with water and brine. The organic phase was dried and evaporated under reduced pressure. The residue was suspended in diethyl ether and the solid was collected by filtration to give the title compound as a solid.

Stage 6: (3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxyphenyl)methanol

2, 5M LiAlH ₄ (2.0 eq.) in THF at 0° C. under N ₂ atmosphere. The resulting mixture was stirred at 0° C. for 30 minutes and then at room temperature for 2 hours. The mixture was diluted with EtOAc and quenched with 2N. NaOH. The suspension was filtered and the filtrate was divided between EA/water. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound as a white solid.

Stage 7: N ^four -butyl-5-(5-(chloromethyl)-2-methoxybenzyl)-6-methylpyrimidine-2,4-diamine

To a stirred solution of (3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxyphenyl)methanol (1.0 eq.) in DCM (0.34 M) was added SOCl ₂ (1.3 eq.) at room temperature under N ₂ atmosphere. The mixture was stirred at room temperature for 1 h. The mixture was partitioned between DCM and saturated aqueous NaHCO ₃ . The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound.

Step 8: 2-(3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxyphenyl)acetonitrile

MixtureN ^four-butyl-5-(5-(chloromethyl)-2-methoxybenzyl)-6-methylpyrimidine-2,4-diamine (1.0 eq.) in 1:1 DMSO/DMF (0.34 M) and NaCN (2.8 eq.) was stirred overnight at room temperature. The mixture was partitioned between EA/water. The organic layer was dried over Na₂SO_four, filtered, concentrated and purified by flash chromatography on silica (eluent 0-5% MeOH in DCM) to give the title compound.

Stage 9: 5–(5–((2 H -tetrazol-5-yl)methyl)-2-methoxybenzyl)- N ^four -butyl-6-methylpyrimidine-2,4-diamine

To a stirred mixture of 2–(3–((2–amino–4–(butylamino)–6–methylpyrimidin–5–yl)methyl)–4–methoxyphenyl)acetonitrile (1.0 equiv.) in NMP (0.06 M) and Bu₂SnO (2.0 equiv.) was added TMSN₃(10.0 eq.). The resulting mixture was stirred overnight at 125°C under N₂. The mixture was cooled to room temperature and the mixture was concentrated and purified by preparative HPLC to give the title compound as a solid.

LC-MS: [M+H] ⁺ = 383.3

¹ H NMR (400 MHz, DMSO– d ₆ ) δ 7.03 (d, J = 7.6 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.73 (s , 1H), 6.60 (br s, 1H), 6.31 (s, 2H), 3.97 (s, 2H), 3.80 (s, 3H), 3.60 (s, 2H), 3.29–3.24 (m, 2H), 2.02 (s, 3H), 1.43–1.37 (m, 2H), 1.22–1.17 (m, 2H), 0, 84 (t, J =7.2 Hz, 3H).

Example 4: 3-(3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxyphenyl)propanoic acid (Compound 4)

The title compound was prepared according to the procedures described in Example 1 - Steps 1-9, but using methyl 3-(bromomethyl)-4-methoxybenzoate instead of methyl 4-(bromomethyl)-3-methoxybenzoate in Step 1.

LC-MS: [M+H] = 373.2

¹ H NMR (400 MHz, DMSO– d ₆ ) δ 12.47 (s, 1H), 7.81 (t, J =4.8 Hz, 1H), 7.46 (br s, 2H), 7, 06 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.72 (s, 1H), 3.81 (s, 3H), 3, 76 (s, 2H), 3.40–3.36 (m, 2H), 2.68 (t, J = 7.2 Hz, 2H), 2.41 (t, J = 7.2 Hz, 2H ), 2.13 (s, 3H), 1.50–1.44 (m, 2H), 1.24–1.18 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H).

Example 5: 2-(5-(3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzyl)-2H-tetrazol-2-yl)acetic acid ( Connection 5)

Example 6: 2-(5-(3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzyl)-1H-tetrazol-1-yl)acetic acid ( Connection 6)

To the stirred solution 5–(5–((2H-tetrazol-5-yl)methyl)-2-methoxybenzyl)-N ^four-butyl-6-methylpyrimidine-2,4-diamine (1.0 eq., Example 3) in acetone (0.05 M) was added K₂CO₃(1.5 equiv.) at 0°C in N₂. The resulting mixture was stirred at 0°C for 30 minutes, and ethyl 2-bromoacetate was added dropwise (1.5 eq.). The mixture was slowly warmed to room temperature and stirred for 5 hours. The mixture quenched us. NH_fourCl. The mixture was separated in DCM/water. The organic phase was dried over Na₂SO_four, concentrated and purified by preparative HPLC to give the two regioisomers in a 3:2 ratio as white powders. To a stirred solution of each isomer (1.0 equiv.) in MeOH (0.02 M) was added 1N. NaOH (5.0 eq.). The resulting mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC and LC–MS. The mixture was neutralized with 1N. HCl and purified to give the title compounds.

Isomer 1: 2–(5–(3–((2–amino–4–(butylamino)–6–methylpyrimidin–5–yl)methyl)–4–methoxybenzyl)–2 H –tetrazol–2–yl)acetic acid

LC-MS: [M+H] = 441.5

¹ H NMR (400 MHz, DMSO– d ₆ ) δ 12.62 (br s, 1H), 7.82 (br s, 1H), 7.50 (br s, 2H), 7.11 (d, J =7.6Hz, 1H), 6.95(d, J =8.8Hz, 1H), 6.79(s, 1H), 5.31(s, 2H), 4.16(s, 2H ), 3.82 (s, 3H), 3.66 (s, 2H), 3.39–3.30 (m, 2H), 2.10 (s, 3H), 1.45–1.38 ( m, 2H), 1.3–1.2 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H).

Isomer 2: 2–(5–(3–((2–amino–4–(butylamino)–6–methylpyrimidin–5–yl)methyl)–4–methoxybenzyl)–1 H –tetrazol–1–yl)acetic acid

LC-MS: [M+H] = 441.5

¹ H NMR (400 MHz, DMSO– d ₆ ) δ 12.69 (s, 1H), 7.85 (br s, 1H), 7.51 (br s, 2H), 7.10 (d, J = 8.0 Hz, 1H), 6.95 (d, J =8.4 Hz, 1H), 6.82 (s, 1H), 5.58 (s, 2H), 4.11 (s, 2H) , 3.81 (s, 3H), 3.67 (s, 2H), 3.38–3.35 (m, 2H), 2.11 (s, 3H), 1.49–1.42 (m , 2H), 1.24–1.18 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H).

Example 7: (3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzyl)phosphonic acid (Compound 7)

Stage 1: N4-butyl-5-(5-(chloromethyl)-2-methoxybenzyl)-6-methylpyrimidine-2,4-diamine

The title compound was prepared according to the procedures described in Example 2 - Step 1, but using (3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxyphenyl )methanol instead of (4-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-3-methoxyphenyl)methanol.

Stage 2: diethyl (3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzyl)phosphonate

N ⁴ -butyl-5-(5-(chloromethyl)-2-methoxybenzyl)-6-methylpyrimidine-2,4-diamine (1.0 eq.) in undiluted triethylphosphite (0.1 M) was stirred at 140°C in over 2 h. The mixture was concentrated to give the title compound.

Stage 3: (3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzyl)phosphonic acid

To a stirred solution of diethyl (3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzyl)phosphonate (1.0 eq.) in DCM (0.04 M) bromotrimethylsilane (4.0 eq.) was added. The resulting mixture was stirred for 2 hours at room temperature and then partitioned between DCM/water. The organic layer was dried over Na ₂ SO ₄ , concentrated. The crude product was purified by preparative HPLC (mobile phase CH ₃ CN/H ₂ O/NH ₃ ) and lyophilized to give a white powder which was redissolved in MeCN/H ₂ O/1N. HCl (4:2:1) and lyophilized to give the title compound as a white solid (HCl salt).

LC-MS: [M+H] = 395.1

¹ H NMR (400 MHz, DMSO– d ₆ ) δ 12.64 (br s, 2H), 7.82 (t, J = 5.6 Hz, 1H), 7.48 (br s, 2H), 7 .08 (d, J =8.0 Hz, 1H), 6.91 (d, J =8.4 Hz, 1H), 6.74 (s, 1H), 3.81 (s, 3H), 3 .66 (s, 2H), 3.37–3.34 (m, 2H), 2.80 (d, J = 20.9 Hz, 2H), 2.12 (s, 3H), 1.50– 1.45 (m, 2H), 1.27–1.22 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H).

Example 8: (S)-2-((5-(5-((2H-tetrazol-5-yl)methyl)-2-methoxybenzyl)-2-amino-6-methylpyrimidin-4-yl)amino)pentan- 1-ol (Compound 8)

Step A: (S)-1-((tert-butyldiphenylsilyl)oxy)pentan-2-amine

To a mixture of ( S )-2-aminopentan-1-ol (1.0 eq.) in DCM (0.2 M), TEA (5.0 eq.) and DMAP (0.3 eq.) at 0°C TBDPSCl (1.5 eq) was added. The resulting mixture was stirred at room temperature for 3 hours. The mixture was diluted with water and DCM, separated and the aqueous layer was extracted twice with DCM. The combined organic layers were dried over Na ₂ SO ₄ , concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: DCM/MeOH=200:1 to 80:1) to give the title compound as a brown oil.

Preparation of methyl (S)–3–((2–amino–4–((1–((tert–butyldiphenylsilyl)oxy)pentan–2–yl)amino)–6–methylpyrimidin–5–yl)methyl)–4 – methoxybenzoate

Preparation of methyl (S)–3–((2–amino–4–((1–((tert–butyldiphenylsilyl)oxy)pentan–2–yl)amino)–6–methylpyrimidin–5–yl)methyl)–4– methoxybenzoate following Example 1 - Step 4 but using methyl 3-((2-amino-4-chloro-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzoate instead of methyl 4-((2-amino-4- chloro-6-methylpyrimidin-5-yl)methyl)-3-methoxybenzoate and (S)-1-((tert-butyldiphenylsilyl)oxy)pentan-2-amine instead of butane-1-amine.

Preparation of (S)–(3–((2–amino–4–((1–((tert–butyldiphenylsilyl)oxy)pentan–2–yl)amino)–6–methylpyrimidin–5–yl)methyl)–4 methoxyphenyl ) methanol

Preparation of (S)–(3–((2–amino–4–((1–((tert–butyldiphenylsilyl)oxy)pentan–2–yl)amino)–6–methylpyrimidin–5–yl)methyl)–4– methoxyphenyl)methanol following Example 1 - Step 5 but using methyl (S)-3-((2-amino-4-((1-((tert-butyldiphenylsilyl)oxy)pentan-2-yl)amino)-6 -methylpyrimidin-5-yl)methyl)-4-methoxybenzoate instead of methyl 4-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-3-methoxybenzoate.

Preparation of (S)–5–(5–((2H–tetrazol–5–yl)methyl)–2–methoxybenzyl)–N4–(1–((tert–butyldiphenylsilyl)oxy)pentan–2–yl)–6– methylpyrimidine-2,4-diamine

Preparation of (S)–5–(5–((2H–tetrazol–5–yl)methyl)–2–methoxybenzyl)–N ⁴ –(1–((tert–butyldiphenylsilyl)oxy)pentan–2–yl)–6 -methylpyrimidine-2,4-diamine according to Example 2 - Steps 1 to 3, but using (S)-(3-((2-amino-4-((1-((tert-butyldiphenylsilyl)oxy)pentane) -2-yl)amino)-6-methylpyrimidin-5-yl)methyl)-4-methoxyphenyl)methanol instead of (4-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl) -3-methoxyphenyl)methanol.

Preparation of (S)–2–((5–(5–((2H–tetrazol–5–yl)methyl)–2–methoxybenzyl)–2–amino–6–methylpyrimidin–4–yl)amino)pentan–1– ola

To the solution _ ^_ -6-methylpyrimidine-2,4-diamine (1.0 eq.) in anhydrous THF (0.05 M) at 0°C was added TBAF (10 eq.). The resulting mixture was stirred at room temperature for 16 hours. LCMS indicated completion of the reaction. The mixture was then concentrated under reduced pressure. The residue was purified by preparative HPLC (mobile phase CH ₃ CN/H ₂ O/HCOOH), lyophilized to give the title compound as a white solid (formic acid salt)

LC-MS: [M+H] = 413.2

¹ H NMR (400 MHz, DMSO) δ 8.19 (s, 1H), 7.05 (d, J =8.4 Hz, 1H), 6.91 (d, J =8.4 Hz, 1H) , 6.85 (s, 1H), 6.68–6.60 (m, 2H), 6.39–6.34 (m, 1H), 4.23–4.20 (m, 1H), 3 .99 (s, 2H), 3.81 (s, 3H), 3.69–3.60 (s, 2H), 3.41–3.33 (m, 2H), 2.11 (s, 3H ), 1.48–1.45 (m, 1H), 1.35–1.28 (m, 1H), 1.13–1.09 (m, 2H), 0.79 (t, J = 7 .2 Hz, 3H).

Example 9: 2-(3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxyphenyl)-2-methylpropanoic acid (Compound 9)

Stage 1: (4-methoxy-3-methylphenyl)methanol

To a solution of methyl 4-methoxy-3-methylbenzoate (1.0 eq.) in anhydrous THF (0.3 M) at 0°C was added dropwise LiAlH ₄ (2.5 M, 2.5 eq.) N2 _. The resulting mixture was stirred at room temperature for 2 hours, then the mixture was quenched with 1.25 M NaOH solution at 0°C and extracted three times with EtOAc. The organic layer was dried over Na ₂ SO ₄ , concentrated under reduced pressure to give the title compound, which was used directly in the next step without further purification.

Step 2: 4-(chloromethyl)-1-methoxy-2-methylbenzene

To a solution of (4-methoxy-3-methylphenyl)methanol (1.0 eq.) in DCM (0.3 M) at 0°C was added SOCl ₂ (2.0 eq.). The resulting mixture was stirred at room temperature for 2 hours. The mixture was then quenched with NaHCO ₃ solution and extracted with DCM. The organic layer was dried over Na ₂ SO ₄ , concentrated under reduced pressure to give the title compound as a yellow oil.

Stage 3: 2-(4-methoxy-3-methylphenyl)acetonitrile

To a solution of 4–(chloromethyl)–1–methoxy–2–methylbenzene (1.0 eq.) in 1:1 DMSO/DMF (0.5 M) was added NaCN (3.0 eq.). The resulting mixture was stirred at room temperature for 16 hours, then water was added and the mixture was extracted with EtOAc. The organic layer was washed with brine twice, dried over Na₂SO_four, concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: PE/EA=100:1 to 30:1) to give the title compound as a yellowish oil.

Step 4: 2-(4-methoxy-3-methylphenyl)-2-methylpropanenitrile

To a mixture of 2-(4-methoxy-3-methylphenyl)acetonitrile (1.0 eq.) in DMSO (0.4 M) at 0°C was added iodomethane (10 eq.) and a solution of 50% NaOH (6.0 eq.). The resulting mixture was stirred at room temperature for 3 hours. Then the mixture was diluted with water and EtOAc, the aqueous layer was again extracted twice with EtOAc. The organic layer was combined, dried over Na₂SO_four, concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: PE/EA=100:1 to 30:1) to give the title compound as a slightly yellowish oil.

Step 5: 2-(3-(bromomethyl)-4-methoxyphenyl)-2-methylpropanenitrile

To a solution of 2-(4-methoxy-3-methylphenyl)-2-methylpropanenitrile (1.0 eq.) in CCl_four (0.2 M) was added NBS (1.1 eq.) and AIBN (0.2 eq.). The resulting mixture was stirred at 95° C. for 16 hours. The mixture was then filtered, and the filtrate was concentrated under reduced pressure to give a crude crude product, which was purified by silica column chromatography (eluent: PE/EA=100:1 to 30 :1) to give the title compound as a yellow oil.

Stage 6: ethyl 2–(5–(2–cyanopropan–2–yl)–2–methoxybenzyl)–3–oxobutanoate

To a solution of ethyl 3-oxobutanoate (1.2 equiv.) in anhydrous THF (0.17 M) at 0°C was added portionwise NaH (60% in mineral oil, 1.3 equiv.). After stirring for 10 minutes, a solution of 2-(3-(bromomethyl)-4-methoxyphenyl)-2-methylpropanenitrile (1.0 eq.) in THF (0.3 M) was added dropwise to the above mixture over 10 minutes. The resulting mixture was stirred at 70° C. for 16 h, quenched with water and the mixture was extracted with EtOAc, dried over Na ₂ SO ₄ , concentrated under reduced pressure. The residue was purified by silica column chromatography (eluent: PE/EA=50:1 to 10:1) to give the title compound as a yellow oil.

Stage 7: 2-(3-((2-amino-4-hydroxy-6-methylpyrimidin-5-yl)methyl)-4-methoxyphenyl)-2-methylpropanenitrile

A mixture of ethyl 2–(5–(2–cyanopropan–2–yl)–2–methoxybenzyl)–3–oxobutanoate (1.0 eq.) and guanidine carbonate (1.0 eq.) in MeOH (0.3 M) were stirred at 65° C. for 16 hours. The precipitated solid was collected by filtration. The solid was washed with water and dried in vacuo to give the title compound as a white solid.

Stage 8: 2-(3-((2-amino-4-chloro-6-methylpyrimidin-5-yl)methyl)-4-methoxyphenyl)-2-methylpropanenitrile

A solution of 2-(3-((2-amino-4-hydroxy-6-methylpyrimidin-5-yl)methyl)-4-methoxyphenyl)-2-methylpropanenitrile (1.0 eq.) in POCl₃ (0.3 M) was stirred at 100°C for 2 h. The reaction mixture was allowed to cool to room temperature and POCl₃ evaporated to dryness under reduced pressure. The residue was diluted with water and the pH was adjusted to 8 with solid NaHCO₃. The mixture was then stirred at 50° C. for 1 hour, cooled to room temperature, and the precipitated solid was collected by filtration. The filter residue was washed with water, dried in vacuo to give the title compound as a white solid.

Step 9: 2-(3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxyphenyl)-2-methylpropanenitrile

To a mixture of 2-(3-((2-amino-4-chloro-6-methylpyrimidin-5-yl)methyl)-4-methoxyphenyl)-2-methylpropanenitrile (1.0 eq.) in NMP (0.2 M ) added butane-1-amine (4.5 eq.) and stirred at 110°C for 16 h. Then water and EtOAc were added to the above mixture, the organic layer was dried over Na₂SO_four, concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: DCM/MeOH=100:1 to 10:1) to give the title compound as a white solid.

Stage 10: 2-(3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxyphenyl)-2-methylpropanoic acid

To a mixture of 2–(3–((2–amino–4–(butylamino)–6–methylpyrimidin–5–yl)methyl)–4–methoxyphenyl)–2–methylpropanenitrile (1.0 eq.) in 1:1 ethane-1,2-diol/H₂O (0.075 M) KOH (10 eq.) was added and stirred at 150° C. for 2 h. The mixture was then allowed to cool to room temperature and the pH was adjusted to 8 with 1 M HCl solution. The precipitated solid was filtered and washed three times with water. The filter residue was dissolved in MeCN, H₂O and 4M HCl in dioxane, then the solution was lyophilized to give the title compound as a white solid (HCl salt).

LC-MS: [M+H] = 387.2

¹ H NMR (400 MHz, DMSO) δ 12.34 (s, 1H), 7.92 (s, 1H), 7.45 (br s, 2H), 7.20 (d, J =8.4 Hz , 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.85 (s, 1H), 3.82 (s, 3H), 3.70 (s, 2H), 3.5 –3.4 (m, 2H), 2.13 (s, 3H), 1.51–1.45 (m, 2H), 1.36 (s, 6H), 1.27–1.18 (m , 2H), 0.86 (t, J = 7.2 Hz, 3H).

Example 10: 5-(5-(2-(2H-tetrazol-5-yl)propan-2-yl)-2-methoxybenzyl)-N4-butyl-6-methylpyrimidine-2,4-diamine (Compound 10)

A mixture of 2-(3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxyphenyl)-2-methylpropanenitrile (1.0 eq., Example 9 - Step 9) in dioxane (0.06 M), TMSN₃ (10 equiv.) and Bu₂SnO (2.0 equiv.) was sealed in a tubular reactor. The mixture was stirred at 125° C. for 16 hours. LCMS indicated completion of the reaction. The mixture was then concentrated under reduced pressure. The residue was purified by preparative HPLC (mobile phase CH₃CN/H₂O/HCOOH), lyophilized to give the title compound as a white solid (formic acid salt)

LC-MS: [M+H] ⁺ = 411.2

¹ H NMR (400 MHz, DMSO) δ 6.97 (d, J =6.4 Hz, 1H), 6.88 (d, J =8.4 Hz, 1H), 6.72 (s, 1H) , 6.44 (br s, 1H), 6.16 (br s, 2H), 3.79 (s, 3H), 3.58 (s, 2H), 3.27–3.25 (m, 2H ), 1.98 (s, 3H), 1.61 (s, 6H), 1.44–1.40 (m, 2H), 1.24–1.18 (m, 2H), 0.85 ( t, J = 7.2 Hz, 3H).

Example 11: N4-butyl-5-(2-methoxy-5-(2H-tetrazol-5-yl)benzyl)-6-methylpyrimidine-2,4-diamine (Compound 11)

Step 1: 4-bromo-2-(bromomethyl)-1-methoxybenzene

A mixture of 4-bromo-1-methoxy-2-methylbenzene (1.0 eq.) in CCl_four (0.3 M), NBS (1.1 eq.), and AIBN (0.2 eq.) were stirred at 95° C. for 3 h. The mixture was then filtered and the filtrate concentrated under reduced pressure to give a crude product which purified by silica gel column chromatography (eluent: PE) to give the title compound as a white solid.

Stage 2: ethyl 2-(5-bromo-2-methoxybenzyl)-3-oxobutanoate

To a stirred solution of ethyl 3-oxobutanoate (1.2 eq.) in anhydrous THF (0.5 M) at 0°C was added in portions of 60% NaH (1.3 eq.). After stirring for 10 minutes, a solution of 4-bromo-2-(bromomethyl)-1-methoxybenzene (1.0 eq.) in THF (0.8 M) was added dropwise to the above mixture over 10 minutes. The resulting mixture was then stirred at 70° C. for 16 h, water was added and extracted with EtOAc. The combined organic phase was dried over Na₂SO_four, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE/EA=100:1 to 10:1) to give the title compound as a yellow oil.

Stage 3: 2-amino-5-(5-bromo-2-methoxybenzyl)-6-methylpyrimidin-4-ol

A mixture of ethyl 2–(5–bromo–2–methoxybenzyl)–3–oxobutanoate (1.0 equiv.) and guanidine carbonate (1.0 equiv.) in MeOH (0.3 M) were stirred at 65°C for 16 h. After completion of the reaction, the mixture was cooled to room temperature. The precipitated solid was collected by filtration and the filtration residue was washed with water, dried in vacuo to give the title compound as a white solid.

Step 4: 5-(5-bromo-2-methoxybenzyl)-4-chloro-6-methylpyrimidine-2-amine

A solution of 2-amino-5-(5-bromo-2-methoxybenzyl)-6-methylpyrimidin-4-ol (1.0 eq.) in POCl₃ (0.5 M) was stirred at 100°C for 16 h. The reaction mixture was allowed to cool to room temperature and POCl₃ evaporated to dryness under reduced pressure. The residue was diluted with water and the pH was adjusted to 8 with solid NaHCO₃, and then the mixture was stirred at 50°C for 1 h, cooled to room temperature. The precipitated solid was collected by filtration. The filter residue was washed with water and MeOH, dried in vacuo to give the title compound as a white solid.

Stage 5: 5-(5-bromo-2-methoxybenzyl)-N4-butyl-6-methylpyrimidine-2,4-diamine

A mixture of 5-(5-bromo-2-methoxybenzyl)-4-chloro-6-methylpyrimidine-2-amine (1.0 eq.) in NMP (0.4 M) and butane-1-amine (4.5 eq.) was stirred at 130°C for 16 h. The mixture was diluted with water and EtOAc, the organic ball was washed with brine and dried over Na₂SO_four, concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: DCM/MeOH=500:1 to 50:1) to give the title compound as a white solid.

Stage 6: 3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzonitrile

A mixture of 5-(5-bromo-2-methoxybenzyl) -N ⁴ -butyl-6-methylpyrimidine-2,4-diamine (1.0 eq.) in DMF (0.1 M), Zn(CN) ₂ (1 .5 equiv.), Pd ₂ (dba) ₃ (0.08 equiv.), and X-Phos (0.2 equiv.) were stirred at 110°C for 1 h in an argon atmosphere. The resulting mixture was cooled to room temperature and diluted with water and EtOAc. The organic layer was separated, dried over Na ₂ SO ₄ , concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: DCM/MeOH=100:1 to 10:1) to give the title compound as a white solid.

Stage 7: N4-butyl-5-(2-methoxy-5-(2H-tetrazol-5-yl)benzyl)-6-methylpyrimidine-2,4-diamine

A mixture of 3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzonitrile (1.0 eq.) in dioxane (0.07 M), TMSN₃ (10 equiv.) and Bu₂SnO (2.0 equiv.) was stirred at 120°C for 4 hours LCMS showed the completion of the reaction. The mixture was then concentrated under reduced pressure. The residue was purified by preparative HPLC (mobile phase CH₃CN/H₂O/HCOOH), lyophilized to give the title compound as a white solid (formic acid salt).

LC-MS: [M+H] = 369.1

¹ H NMR (400 MHz, DMSO) δ 7.84 (d, J =8.4 Hz, 1H), 7.56 (br s, 1H), 7.44 (s, 1H), 7.09 (d , J = 8.4 Hz, 1H), 7.05 (w s, 2H), 3.90 (s, 3H), 3.73 (s, 2H), 3.4–3.3 (m, 2H ), 2.13 (s, 3H), 1.49–1.41 (m, 2H), 1.19–1.12 (m, 2H), 0.76 (t, J = 7.6 Hz, 3H).

Example 12: (3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxyphenyl)phosphonic acid (Compound 12)

Obtaining N4-butyl-5-(5-iodine-2-methoxybenzyl)-6-methylpyrimidine-2,4-diamine

In obtaining N ⁴ -butyl-5-(5-iodine-2-methoxybenzyl)-6-methylpyrimidine-2,4-diamine followed the methods described in Example 11, Steps 1-5, but using 4-iodine-1-methoxy -2-methylbenzene instead of 4-bromo-1-methoxy-2-methylbenzene in Stage 1.

Stage 1: diethyl (3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxyphenyl)phosphonate

To a solution of N ⁴ -butyl-5-(5-iodine-2-methoxybenzyl)-6-methylpyrimidine-2,4-diamine (1.0 eq.) in toluene (0.06 M), diethyl phosphite (3.5 eq. .) and triethylamine (6.0 eq.) were added Pd(dppf)Cl ₂ (0.05 eq.). The mixture was stirred at 110°C for 16 h. The reaction mixture was allowed to cool to room temperature and evaporated to dryness under reduced pressure to give the crude product, which was purified by flash column chromatography (eluent: DCM/MeOH=50:1 to 10:1 ) to get the connection specified in the header.

Stage 2: (3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxyphenyl)phosphonic acid

To a solution of diethyl (3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxyphenyl)phosphonate (1.0 eq.) in DCM (0.08 M) was added dropwise TMSBr (20 eq.). The mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and DCM, the organic ball was washed with brine and dried over Na₂SO_four, concentrated under reduced pressure. The residue was purified by preparative HPLC (mobile phase CH₃CN/H₂O/HCOOH), lyophilized to give the title compound as a white solid (formic acid salt).

LC-MS: [M+H] = 381.3

¹ H NMR (400 MHz, DMSO– d ₆ ) δ 12.00 (s, 1H), 7.99 (t, J =4.8 Hz, 1H), 7.59–7.53 (m, 1H) , 7.47 (br s, 2H), 7.10–7.06 (m, 2H), 3.89 (s, 3H), 3.72 (s, 2H), 3.40–3.35 ( m, 2H), 2.10 (s, 3H), 1.53–1.45 (m, 2H), 1.25–1.19 (m, 2H), 0.87 (t, J = 7, 2 Hz, 3H).

Example 13: 5-(5-(1-(2H-tetrazol-5-yl)cyclopropyl)-2-methoxybenzyl)-N4-butyl-6-methylpyrimidine-2,4-diamine (Compound 13)

Stage 1: 1-(4-methoxy-3-methylphenyl)cyclopropane-1-carbonitrile:

To a flask containing 2-(4-methoxy-3-methylphenyl)acetonitrile (1.0 eq., Example 9 - Step 3), 1-bromo-2-chloroethane (1.5 equiv.), Et₃NBnCl (0.02 eq.) was added 0.77 g/ml NaOH solution (6.0 eq.). The resulting mixture was stirred overnight at 50^oC. The mixture was partitioned between EA/water. The organic layer was dried over Na₂SO_four, concentrated and purified by flash chromatography on silica (eluent PE/EA=100:1~20:1) to give the title compound.

Preparation of 1–(3–((2–amino–4– (butylamino)–6–methylpyrimidin–5–yl)methyl)–4–methoxyphenyl)cyclopropane–1–carbonitrile

In the preparation of 1-(3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxyphenyl)cyclopropane-1-carbonitrile, the procedures described in Example 9 - Step 5- 9, but using 1-(4-methoxy-3-methylphenyl)cyclopropane-1-carbonitrile instead of 2-(4-methoxy-3-methylphenyl)-2-methylpropanenitrile in Step 5.

Getting 5-(5-(1-(2H-tetrazol-5-yl)cyclopropyl)-2-methoxybenzyl)-N4-butyl-6-methylpyrimidin-2,4-diamine:

A mixture of 1–(3–((2–amino–4–(butylamino)–6–methylpyrimidin–5–yl)methyl)–4–methoxyphenyl)cyclopropane–1–carbonitrile (1.0 eq.) in dioxane (0.1 M), TMSN₃(10.0 equiv.), Bu₂SnO (2.0 equiv.) was stirred overnight at 120^oC. The reaction was monitored by LC–MS. The mixture was concentrated and purified by preparative HPLC (mobile phase CH₃CN/H₂O/HCOOH), lyophilized to give the title compound as a white powder (formic acid salt).

LC-MS: [M+H]=409.2

¹ H NMR (400 MHz, DMSO– d ₆ ) δ 8.19 (s, 1H), 7.16 (d, J =8.8 Hz, 1H), 6.92 (d, J =8.4 Hz , 1H), 6.77 (s, 1H), 6.69 (br s, 1H), 6.42 (br s, 2H), 3.82 (s, 3H), 3.61 (s, 2H) , 3.30–3.25 (m, 2H), 2.03 (s, 3H), 1.43–1.35 (m, 4H), 1.21–1.11 (m, 4H), 0 .83 (t, J = 7.2 Hz, 3H).

Example 14: 1-(3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxyphenyl)cyclopropane-1-carboxylic acid (Compound 14)

A mixture of 1–(3–((2–amino–4–(butylamino)–6–methylpyrimidin–5–yl)methyl)–4–methoxyphenyl)cyclopropane–1–carbonitrile (1.0 eq.) in 1:1 ethylene glycol/H₂O (0.1 M) and KOH (10 equiv.) were stirred for 3 hours at 150^oC. The reaction was monitored by LC-MS until completion. The mixture was neutralized with 1N. HCl to pH=7. The resulting suspension was filtered. The filtered residue was washed with water. MeCN, H₂O and 4N HCl/dioxane. The solution was lyophilized to give the title compound as a white solid (HCl salt).

LC-MS: [M+H]=385.2

¹ H NMR (400 MHz, DMSO– d ₆ ) δ 12.21 (s, 1H), 12.16 (s, 1H), 7.90 (t, J=5.2 Hz, 1H), 7.41 (w s, 2H), 7.16 (d, J =6.0 Hz, 1H), 6.92 (d, J =8.4 Hz, 1H), 6.81 (s, 1H), 3, 81 (s, 3H), 3.68 (s, 2H), 3.4–3.3 (m, 2H), 2.12 (s, 3H), 1.51–1.43 (m, 2H) , 1.38 (s, 2H), 1.26–1.17 (m, 2H), 0.99 (s, 2H), 0.86 (t, J = 7.2 Hz, 3H).

Example 15 3-(2-amino-6-(butylamino)-5-(2-methoxybenzyl)pyrimidin-4-yl)propanoic acid (Compound 15)

Step 1: 1-(bromomethyl)-2-methoxybenzene

To a solution of 1-methoxy-2-methylbenzene (1 equiv.) in CCl_four (0.9 M) added AIBN (0.2 eq.) and NBS (1.1 eq.). The reaction mixture was heated under reflux for 2 hours. After completion of the reaction, the reaction mixture was concentrated and diluted with water. The aqueous phase was extracted with DCM. The combined organic layers were washed with water then brine, dried over Na₂SO_four and concentrated to give the title compound as a light yellow oil.

Stage 2: dimethyl 2-(2-methoxybenzyl)malonate

NaH was added to a solution of dimethylmalonate (1.2 eq.) in THF (0.4 M). (1.25 equiv.) at 0 °C portions in nitrogen. The solution was stirred at 0°C for 15 min., and 1-(bromomethyl)-2-methoxybenzene (1.0 eq) was added. The reaction mixture was stirred for 2 hours at room temperature. After completion of the reaction, the reaction mixture was quenched by adding water. The aqueous phase was extracted with EA. The combined organic layers were washed with water then brine, dried over Na₂SO_four and concentrated. The crude product was purified by column chromatography (PE/EA=40:1) to give the title compound as a light yellow oil.

Step 3: 2-amino-5-(2-methoxybenzyl)pyrimidine-4,6-diol

To a solution of dimethyl 2–(2–methoxybenzyl)malonate (1.0 eq.) in MeOH (0.4 M) was added guanidine carbonate (1.0 eq.). The reaction was heated at 75°C for 16 hours under nitrogen. After cooling, the solids were filtered off and collected from solution to give the title compound as a white solid.

Step 4: 4,6-dichloro-5-(2-methoxybenzyl)pyrimidine-2-amine

To a suspension of 2-amino-5-(2-methoxybenzyl)pyrimidine-4,6-diol (1.0 eq.) in POCl₃ (0.4 M) 2 drops of DMF were added. The reaction was heated at 100°C for 15 hours under nitrogen. After cooling, the solution was poured into ice water. Solids were filtered off and collected from solution to give the title compound as a white solid.

Stage 5: ethyl (E)-3-(2-amino-6-chloro-5-(2-methoxybenzyl)pyrimidin-4-yl)acrylate

To a solution of 4,6-dichloro-5-(2-methoxybenzyl)pyrimidine-2-amine (1.0 eq.) in 3:1 dioxane/H₂O (0.14 M) was added ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (1.2 equiv.), K₂CO₃(2.0 equiv.) and Pd(dppf)Cl₂ (0.1 eq.). The mixture was stirred at 100° C. for 3 hours under nitrogen. The reaction mixture was diluted with water and the aqueous phase was extracted with EA. The combined organic layers were washed with water then brine, dried over Na₂SO_four and concentrated. The crude product was purified by column chromatography (PE/EA=40:3) to give the title compound as a light yellow solid.

Stage 6: ethyl (E)-3-(2-amino-6-(butylamino)-5-(2-methoxybenzyl)pyrimidin-4-yl)acrylate

To a solution of ethyl (E)–3–(2–amino–6–chloro–5–(2–methoxybenzyl)pyrimidin–4–yl)acrylate (1.0 equiv.) in NMP (0.2 M) was added butan-1-amine (3.0 equiv.) and DIEA (3.0 equiv.) and the mixture was stirred at 150°C for 2 h. After completion of the reaction, the reaction mixture was diluted with water. The aqueous phase was extracted with EA. The combined organic layers were washed with water then brine, dried over Na₂SO_four and concentrated. The crude product was purified by column chromatography (DCM/MeOH=10:1) to give the title compound as a yellow oil.

Stage 7: ethyl 3-(2-amino-6-(butylamino)-5-(2-methoxybenzyl)pyrimidin-4-yl)propanoate

To a solution of ethyl (E)–3–(2–amino–6–(butylamino)–5–(2–methoxybenzyl)pyrimidin–4–yl)acrylate (1.0 equiv.) in MeOH (0.04 M) was added Pd/C (1/3 wt. equiv.). The mixture was stirred at room temperature for 1 hour in hydrogen. After completion of the reaction, the solids were filtered off and the filtrate was concentrated to give the title compound as a yellow oil.

Step 8: 3-(2-amino-6-(butylamino)-5-(2-methoxybenzyl)pyrimidin-4-yl)propanoic acid

To a solution of ethyl 3-(2-amino-6-(butylamino)-5-(2-methoxybenzyl)pyrimidin-4-yl)propanoate (1 eq.) in 1:1 MeOH/H ₂ O (0.04 M) NaOH (5.0 eq.) was added. The solution was stirred at room temperature for 1 hour. After completion of the reaction, the pH was adjusted to 7 using acetic acid and the solution was concentrated and purified by preparative HPLC (mobile phase: NH ₃ .H ₂ O/MeCN/H ₂ O) to give the title compound as a white solid (ammonium salt).

LC-MS: [M+H]=359.4

¹ H NMR (400 MHz, MeOD) δ 7.23 (t, J = 6.8 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 6.91–6.88 ( m, 2H), 3.90 (s, 3H), 3.80 (s, 2H), 3.44 (t, J =6.8 Hz, 2H), 2.85 (t, J =6.0 Hz, 2H), 2.42 (t, J = 6.0 Hz 2H), 1.51–1.46 (m, 2H), 1.25–1.19 (m, 2H), 0.88 ( t, J =6.8 Hz, 3H).

Example 16: 2-(3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzamido)ethane-1-sulfonic acid (Compound 16)

In preparing methyl 3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzoate Example 1 - Steps 1-4 was followed but using methyl 3-(bromomethyl)-4 -methoxybenzoate as starting material in Stage 1.

Stage 1: 3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzoic acid

To a suspension of methyl 3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzoate (1.0 eq.) in MeOH (0.3 M) was added 1 n. NaOH (5.0 eq.). The resulting mixture was stirred at 60°C for 2 hours. The progress of the reaction was monitored by TLC. The mixture was cooled to room temperature. The mixture was neutralized with 2N. HCl and purified to give the title compound.

Stage 2: 2–(3–((2–amino–4–(butylamino)–6–methylpyrimidin–5–yl)methyl)–4–methoxybenzamido)ethane–1–sulfonic acid

To a solution of 3–((2–amino–4–(butylamino)–6–methylpyrimidin–5–yl)methyl)–4–methoxybenzoic acid (1.0 eq.) in DMF (0.6 M) were added HATU (1.0 eq.), 2-aminoethane-1-sulfonic acid (1.1 eq.) and DIEA (3.0 eq.). The resulting mixture was stirred at room temperature for 3 hours. The mixture was filtered and the filtrate was purified by preparative HPLC (mobile phase CH₃CN/H₂O/HCOOH), then lyophilized to give the title compound as a white solid.

LC-MS: [M+H] ⁺ = 452.2

^oneH NMR (400 MHz, DMSO)δ 11.89 (s, 1H), 8.35 (t,J=3.2 Hz, 1H), 7.90 (s, 1H), 7.68 (d,J= 8.4 Hz, 1H), 7.40 (w s, 2H), 7.26 (s, 1H), 7.09 (d,J= 8.4 Hz, 1H), 3.90 (s, 3H), 3.71 (s, 2H), 3.48-3.42 (m, 2H), 3.39-3.33 (m, 2H), 2.62 (t,J=6.8 Hz, 2H), 2.12 (s, 3H), 1.49–1.41 (m, 2H), 1.23–1.15 (m, 2H), 0.82 (t,J=7.2 Hz, 3H).

Example 17: 3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzenesulfonic acid (Compound 17)

In the preparation of 5-(5-bromo-2-methoxybenzyl) -N ⁴ -butyl-6-methylpyrimidine-2,4-diamine, Example 1 - Steps 1-4 was followed, but with 4-bromo-2-(bromomethyl)-1 –methoxybenzene as starting material in Step 1.

Stage 1: N4-butyl-5-(2-methoxybenzyl)-6-methylpyrimidine-2,4-diamine

Pd ^/ C (10 % wt. equiv.). The resulting mixture was stirred at room temperature for 1 hour under H ₂ and then filtered. The filtrate was concentrated to give the title compound.

Step 2: 3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzene-sulfonyl chloride

N ^four-butyl-5-(2-methoxybenzyl)-6-methylpyrimidine-2,4-diamine (1.0 equiv.) in ClSO₃H (0.7 M) was stirred at room temperature for 2 hours, and then poured into ice water. The mixture was separated in DCM/water. The organic layer was dried over Na₂SO_four, filtered, concentrated to give the title compound.

Stage 3: 3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzenesulfonic acid

To a stirred solution of 3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzenesulfonyl chloride (1.0 eq.) in 1:1 MeCN/H ₂ O ( 0.025 M) was added K ₂ CO ₃ (2.0 eq.). The resulting mixture was stirred overnight at room temperature and then concentrated. The residue was purified by preparative HPLC (mobile phase CH ₃ CN/H ₂ O/HCOOH), lyophilized to give the title compound.

LC-MS: [M-H] ^- = 379.2

¹ H NMR (400 MHz, DMSO– d ₆ ) δ 11.92 (br s, 1H), 7.79 (br s, 1H), 7.46 (d, J =6.8 Hz, 1H), 7 .22 (br s, 2H), 7.04 (s, 1H), 6.95 (d, J = 8.4 Hz, 1H), 3.85 (s, 3H), 3.68 (s, 2H ), 3.37–3.34 (m, 2H), 2.08 (s, 3H), 1.54–1.44 (m, 2H), 1.26–1.23 (m, 2H), 0.86 (t, J =7.2 Hz, 3H).

Example 18: (S)-3-((5-(5-((2H-tetrazol-5-yl)methyl)-2-methoxybenzyl)-2-amino-6-methylpyrimidin-4-yl)amino)heptan- 1-ol (Compound 18)

The title compound was prepared according to the procedures described in Example 8, but using ( S )-3-aminoheptan-1-ol (from J. Med. Chem, 2016, 59, 7936-7949) instead of ( S )- 2-aminopentan-1-ol in Step A. In the last step, the crude product was purified by preparative HPLC (mobile phase CH ₃ CN/H ₂ O/HCOOH), then lyophilized to give the title compound as a white solid (salt formic acid).

LC-MS: [M+H] ⁺ = 441.3

¹ H NMR (400 MHz, DMSO) δ 8.22 (s, 1H), 7.03 (d, J =8.8 Hz, 1 H), 6.90 (d, J =8.4 Hz, 1 H), 6.78 (s, 1H), 6.52 (s, 2H), 6.35 (d, J = 8.0 Hz, 1 H), 4.27–4.21 (m, 1H) , 3.99–3.91 (m, 2H), 3.80 (s, 3H), 3.62 (s, 2H), 3.39–3.26 (m, 3H), 2.07 (s , 3H), 1.64–1.50 (m, 2H), 1.48–1.37 (m, 2H), 1.24–1.14 (m, 2H), 1.12–1.04 (m, 2H), 0.76 (t, J = 7.2 Hz, 3 H).

Example 19 3-(2-amino-6-(butylamino)-5-(4-methoxyphenethyl)pyrimidin-4-yl)propanoic acid (Compound 19)

Stage 1: 4,6-dichloropyrimidine-2-amine

A solution of 2-aminopyrimidine-4,6-diol (1.0 equiv.) in POCl ₃ (1 M) was stirred at 100°C for 4 h. The reaction mixture was allowed to cool to room temperature and the mixture was poured into ice water. The precipitated solid was collected by filtration. The solid was washed with water and dried in vacuo to give the title compound as a yellow solid.

Stage 2: ethyl (E)-3-(2-amino-6-chloropyrimidin-4-yl)acrylate

To a solution of 4,6-dichloropyrimidine-2-amine (1.0 eq.) in 3:1 dioxane/H₂O (0.3 M) was added ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (1.1 eq.), K₂CO₃(2.0 equiv.) and Pd(dppf)Cl₂ (0.1 eq.). The mixture was stirred at 100° C. for 2 hours under nitrogen. The reaction mixture was diluted with water and the aqueous layer was extracted with EA. The combined organic layers were washed with water, brine, dried over Na₂SO_four and concentrated. The crude product was purified by column chromatography (PE/EA=10:1) to give the title compound as a yellow solid.

Stage 3: ethyl (E)-3-(2-amino-6-(butylamino)pyrimidin-4-yl)acrylate

To a solution of ethyl (E)–3–(2–amino–6–chloropyrimidin–4–yl)acrylate (1.0 equiv.) butane-1-amine (3.0 equiv.) and DIEA (3.0 equiv.) were added to NMP (0.4 M). The mixture was stirred at 150° C. for 3 hours. The reaction mixture was diluted with water and the aqueous phase was extracted with EA. The combined organic layers were washed with water, brine, dried over Na₂SO_four and concentrated. The crude product was purified by column chromatography (PE/EA=1:1) to give the title compound as a yellow solid.

Stage 4: ethyl 3–(2–amino–6–(butylamino)pyrimidin–4–yl)propanoate

To a solution of ethyl (E)–3–(2–amino–6–(butylamino)pyrimidin–4–yl)acrylate (1.0 equiv.) in MeOH (0.2 M) was added Pd/C (20% wt. equiv.). The mixture was stirred at 25°C for 2 h in H₂ and then filtered. The filtrate was concentrated to give the title compound as a colored solid.

Stage 5: ethyl 3-(2-amino-6-(butylamino)-5-iodopyrimidin-4-yl)propanoate

To a solution of ethyl 3–(2–amino–6–(butylamino)pyrimidin–4–yl)propanoate (1.0 eq.) in 2:1 DCM/H₂O (0.05 M) NaOH was added (2.0 eq.), followed by the addition of I₂(1.0 equiv.). The mixture was stirred at 25° C. for 16 hours. The reaction mixture was diluted with water and the aqueous phase was extracted with EA. The combined organic layers were washed with water, brine, dried over Na₂SO_four, and concentrated. The crude product was purified by column chromatography (PE/EA=4:3) to give the title compound as a yellow solid.

Stage 6: ethyl 3-(2-amino-6-(butylamino)-5-((4-methoxyphenyl)ethynyl)pyrimidin-4-yl)propanoate

To a solution of ethyl 3–(2–amino–6–(butylamino)–5–iodopyrimidin–4–yl) propanoate (1.0 equiv.) in DMF (0.1 M) was added 1-ethynyl-4-methoxybenzene (1.2 equiv.), TEA (1/5^th reaction volume), CuI (0.2 equiv.) and Pd(PPh₃)₂Cl₂ (0.1 eq.). The mixture was stirred at 50° C. for 16 hours under nitrogen. The reaction mixture was diluted with water and the aqueous phase was extracted with EA. The combined organic layers were washed with water, brine, dried over Na₂SO_four and concentrated. The crude product was purified by column chromatography (PE/EA=1:1) to give the title compound as a brown oil.

Stage 7: ethyl 3-(2-amino-6-(butylamino)-5-(4-methoxyphenethyl)pyrimidin-4-yl)propanoate

To a solution of ethyl 3-(2-amino-6-(butylamino)-5-((4-methoxyphenyl)ethynyl)pyrimidin-4-yl)propanoate (1.0 equiv.) in MeOH (0.08 M) was added Pd/C (30% wt. equiv.). The mixture was stirred at 50°C for 2 h in H₂ and then filtered. The filtrate was concentrated to give the title compound as a yellow oil.

Step 8: 3-(2-amino-6-(butylamino)-5-(4-methoxyphenethyl)pyrimidin-4-yl)propanoic acid

To a solution of ethyl 3–(2–amino–6–(butylamino)–5–(4–methoxyphenethyl)pyrimidin–4–yl)propanoate (1.0 eq.) in 1:1 MeOH/H₂O (0.2 M) NaOH (5.0 eq.) was added. The resulting mixture was stirred at 25° C. for 1 h. The pH was adjusted to 7 using acetic acid and the solution was concentrated and purified by preparative HPLC (mobile phase: NH_fourOH/MeCN/H₂O) to give the title compound as a white solid (ammonium salt).

LC-MS: [M+H] ⁺ = 373.4

¹ H NMR (400 MHz, CD ₃ OD) δ 7.00 (d, J =8.4 Hz, 2H), 6.81 (d, J =8.8 Hz, 2H), 3.75 (s, 3H), 3.48 (t, J = 7.6 Hz, 2H), 2.75–2.71 (m, 4H), 2.43 (t, J = 6.0 Hz, 2H), 2, 18 (t, J = 6.4 Hz, 2H), 1.60–1.54 (m, 2H), 1.40–1.35 (m, 2H), 0.97 (t, J = 6, 8Hz, 3H)

Example 20A: (S)-3-((5-(5-((2H-tetrazol-5-yl)methyl)-2-methoxybenzyl)-2-amino-6-methylpyrimidin-4-yl)amino)heptanoic acid (Compound 20)

Methyl 3-((2-amino-4-chloro-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzoate was prepared according to Example 1 - Steps 1-3, but using methyl 3-(bromomethyl)-4- methoxybenzoate as starting material instead of methyl 4-(bromomethyl)-3-methoxybenzoate.

Stage 1: (3-((2-amino-4-chloro-6-methylpyrimidin-5-yl)methyl)-4-methoxyphenyl)methanol

To a stirred solution of methyl 3–((2–amino–4–chloro–6–methylpyrimidin–5–yl)methyl)–4–methoxybenzoate (1.0 equiv.) in THF (0.2 M) at 0°C was added dropwise 2.5M LiAlH_four (2.5 eq.). The resulting mixture was stirred at room temperature for 1 hour. The mixture was then quenched with 1 M NaOH and filtered. The filtrate was extracted with EtOAc. The organic layer was dried over Na₂SO_four, filtered, concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent DCM/MeOH=100:1 to 10:1) to give the title compound as a yellow solid.

Stage 2: tert-butyl (S)-3-((2-amino-5-(5-(hydroxymethyl)-2-methoxybenzyl)-6-methylpyrimidin-4-yl)amino)heptanoate

Mixturetert-butyl(S)-3-aminoheptanoate (4.0 eq.; prepared according to the procedure presented in J. Med. Chem, 2016, 59, 7936-7949) and (3-((2-amino-4-chloro-6-methylpyrimidine -5-yl)methyl)-4-methoxyphenyl)methanol (1.0 eq.) in NMP (0.8 M) was stirred at 120°C for 16 hours Then water and EtOAc were added to the reaction mixture. The organic layer was separated, dried over Na₂SO_four, concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: DCM/MeOH=100:1 to 20:1) to give the title compound as a yellow oil.

Steps 3-5: tert-butyl (S)-3-((5-(5-((2H-tetrazol-5-yl)methyl)-2-methoxybenzyl)-2-amino-6-methylpyrimidin-4-yl )amino)heptanoate

The title compound was prepared according to Example 2 - Steps 1-3 but using tert -butyl ( S )-3-((2-amino-5-(5-(hydroxymethyl)-2-methoxybenzyl)-6- methylpyrimidin-4-yl)amino)heptanoate as starting material. The crude product was purified by preparative HPLC (CH ₃ CN/H ₂ O/HCOOH mobile phase) and lyophilized to give the title compound as a white solid (formic acid salt).

LC-MS: [M+H] ⁺ = 511.4

¹ H NMR (400 MHz, DMSO) δ 8.20 (s, 1 H), 7.04 (dd, J =8.4, 2.0 Hz, 1H), 6.93 (d, J =8, 0 Hz, 1H), 6.77 (s, 1H), 6.60 (br s, 2H), 6.39 (br s, 1H), 4.55–4.52 (m, 1H), 4, 02 (s, 2H), 3.83 (s, 3H), 3.67–3.57 (m, 2H), 2.37 (d, J = 6.8 Hz, 2H), 2.07 (s , 3H), 1.46–1.38 (m, 2H), 1.32 (s, 9H), 1.26–1.13 (m, 2H), 1.09–1.01 (m, 2H ), 0.77 (t, J =7.2 Hz, 3H).

Step 6: (S)-3-((5-(5-((2H-tetrazol-5-yl)methyl)-2-methoxybenzyl)-2-amino-6-methylpyrimidin-4-yl)amino)heptanoic acid

Totert–butyl (S)–3–((5–(5–((2H-tetrazol-5-yl)methyl)-2-methoxybenzyl)-2-amino-6-methylpyrimidin-4-yl)amino)heptanoate (1 equiv.) was added 3.0 M HCl/dioxane (20 equiv.) at 0°C and warmed to room temperature. After stirring for 1 hour, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (mobile phase CH₃CN/H₂O/HCOOH), lyophilized to give the title compound as a white solid.

LC-MS: [M+H] ⁺ = 455.2

^oneH NMR (400 MHz, DMSO)δ 7.35 (br s, 1H), 7.07 (br s, 2H), 6.96 (d,J= 7.6 Hz, 1H), 6.88 (d,J= 8.4 Hz, 1H), 6.76 (s, 1H), 4.56-4.54 (m, 1H), 4.07-3.97 (m, 2H), 3.79 (s, 3H), 3.68–3.66 (m, 2H), 2.46–2.38 (m, 2H), 2.05 (s, 3H), 1.53–1.50 (m, 2H) , 1.27–1.16 (m, 4H), 0.82 (t,J=6.8 Hz, 3H).

Example 20B: (S)-3-((5-(5-((2H-tetrazol-5-yl)methyl)-2-methoxybenzyl)-2-amino-6-methylpyrimidin-4-yl)amino)heptanoic acid (Compound 20)

Stage 1: tert –butyl ( E )-hept-2-enoate

Pentanal mixture (1.0 eq.) andtert–butyl 2–(triphenyl–λ⁵-phosphanilidine)acetate (1.05 eq.) was stirred at 50°C for 16 h. The mixture was then concentrated under reduced pressure and petroleum ether (PE) was added. The solids were filtered off and the filtrate was evaporated to dryness, which was purified by flash column chromatography (eluent: 0-1% EA in PE) to give the title compound as a yellow oil.

Stage 2: tert –butyl ( S )–3–(benzyl(( S )-1-phenylethyl)amino)heptanoate

to solution (S)–N-benzyl-1-phenylethane-1-amine (1.3 eq.) in THF (0.9 M) at -78°C was added dropwise 2.5 M n-BuLi (1.2 eq.) over 20 minutes. The mixture was stirred at –78°C for 10 minutes, then added dropwise to the above mixturetert–butyl (E)-hept-2-enoate (1.0 equiv.) in THF (0.7 M). The resulting mixture was stirred at –78°C for 30 minutes. The mixture was then quenched with aq. NH_fourCl and extracted with EtOAc. The organic layer was dried over Na₂SO_four, filtered, concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-1% EA in PE) to give the title compound as a yellow oil.

Stage 3: tert –butyl ( S )-3-aminoheptanoate

10% wt. Pd/C (1/10 weight equivalent). The resulting mixture was stirred at 50°C for 16 hours at H ₂ . The solid was filtered off and the filtrate was concentrated under reduced pressure to give the title compound as a brown oil which was used directly in the next step without further purification.

Stage 4: (3-((2-amino-4-chloro-6-methylpyrimidin-5-yl)methyl)-4-methoxyphenyl)methanol

To a stirred solution of methyl 3-((2-amino-4-chloro-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzoate (1.0 eq.; from Example 3B - Step 4) in THF (0.2 M) at 0°C was added dropwise 2.5M LiAlH ₄ (2.5 eq.). The resulting mixture was stirred at room temperature for 1 hour. The mixture was then quenched with 1 M NaOH and filtered. The filtrate was extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent DCM/MeOH=100:1 to 10:1) to give the title compound as a yellow solid.

Stage 5: tert -butyl (S)-3-((2-amino-5-(5-(hydroxymethyl)-2-methoxybenzyl)-6-methylpyrimidin-4-yl)amino)heptanoate

A mixture of tert -butyl ( S )-3-aminoheptanoate (4.0 eq.) and (3-((2-amino-4-chloro-6-methylpyrimidin-5-yl)methyl)-4-methoxyphenyl)methanol (1 0 eq.) in NMP (0.8 M) was stirred at 120° C. for 16 h. Water and EtOAc were then added to the reaction mixture. The organic layer was separated, dried over Na ₂ SO ₄ , concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: DCM/MeOH=100:1 to 20:1) to give the title compound as a yellow oil.

Stage 6: tert –butyl ( S )–3–((2–amino–5–(5–(chloromethyl)–2–methoxybenzyl)–6–methylpyrimidin–4–yl)amino)heptanoate

To the stirred solutiontert-butyl (S)-3-((2-amino-5-(5-(hydroxymethyl)-2-methoxybenzyl)-6-methyl-pyrimidin-4-yl)amino)heptanoate (1.0 equiv.) in DCM (0.05 M) at 0°C was added SOCl₂(2.0 eq.). The resulting mixture was stirred at 0°C for 1 h. Then the mixture was quenched with a solution of NaHCO₃ and extracted with DCM. The organic layer was dried over Na₂SO_four, concentrated under reduced pressure to give the title compound as a yellow oil.

Stage 7: tert –butyl ( S )–3–((2–amino–5–(5–(cyanomethyl)–2–methoxybenzyl)–6–methylpyrimidin–4–yl)amino)heptanoate

Mixturetert–butyl (S)–3–((2–amino–5–(5–(chloromethyl)–2–methoxybenzyl)–6–methylpyrimidin–4–yl)amino)heptanoate (1.0 eq.) in 1:1 DMSO/DMF (0.12 M) and NaCN (3.0 eq.) was stirred at room temperature for 16 h. The resulting mixture was partitioned into EtOAc and water. The organic layer was washed with brine, dried over Na₂SO_four, concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: DCM/MeOH=100:1 to 20:1) to give the title compound as a yellow oil.

Stage 8: tert –butyl ( S )–3–((5–(5–((2 H -tetrazol-5-yl)methyl)-2-methoxybenzyl)-2-amino-6-methylpyrimidin-4-yl)amino)heptanoate

Mixturetert–butyl (S)–3–((2–amino–5–(5–(cyanomethyl)–2–methoxybenzyl)–6–methyl–pyrimidin–4–yl)amino)heptanoate (1.0 eq.) in dioxane (1.2 M), TMSN₃ (10 equiv.) and Bu₂SnO (2.0 eq) was stirred at 120° C. for 2 hours. The mixture was then concentrated under reduced pressure to give the crude product as a brown oil which was used directly to the next step without further purification.

Step 9: (S)-3-((5-(5-((2H-tetrazol-5-yl)methyl)-2-methoxybenzyl)-2-amino-6-methylpyrimidin-4-yl)amino)heptanoic acid

K tert -butyl ( S )-3-((5-(5-((2 H -tetrazol-5-yl)methyl)-2-methoxybenzyl)-2-amino-6-methylpyrimidin-4-yl)amino) heptanoate (1 eq.) was added 3.0 M HCl/dioxane (20 eq.) at 0°C and warmed to room temperature. After stirring for 1 hour, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (mobile phase CH ₃ CN/H ₂ O/HCOOH), lyophilized to give the title compound as a white solid (formic acid salt).

LC-MS: [M+H] ⁺ = 455.2

¹ H NMR (400 MHz, DMSO) δ 7.35 (br s, 1H), 7.07 (br s, 2H), 6.96 (d, J =7.6 Hz, 1H), 6.88 ( e, J = 8.4 Hz, 1H), 6.76 (s, 1H), 4.56–4.54 (m, 1H), 4.07–3.97 (m, 2H), 3.79 (s, 3H), 3.68–3.66 (m, 2H), 2.46–2.38 (m, 2H), 2.05 (s, 3H), 1.53–1.50 (m , 2H), 1.27–1.16 (m, 4H), 0.82 (t, J = 6.8 Hz, 3H).

Example 20C: (R)-3-((5-(5-((2H-tetrazol-5-yl)methyl)-2-methoxybenzyl)-2-amino-6-methylpyrimidin-4-yl)amino)heptanoic acid (Compound 20C)

The title compound was prepared following the procedure described in Example 20B, but using ( R ) -N -benzyl-1-phenylethane-1-amine instead of ( S ) -N -benzyl-1-phenylethane-1-amine in Step 2. The title compound showed identical H NMR and LCMS data as in Example 20A/20B.

To demonstrate chirality, samples of Example 20A/20B (e.g. (S)-enantiomer) and Example 20C (e.g. (R)-enantiomer) were loaded onto a Superchiral S-OZ column (0.46 cm I.D. x 25 cm D) and eluted with hexane/EtOH/MeOH/diethylamine (v/v/v/v = 80/6.6/13.4/0.05) at 0.8 ml/min. The (R)-enantiomer showed a retention time of 12.2 minutes, while Example 20A/20B (eg, the (S)-enantiomer) showed a retention time of 13.2 minutes.

Example 21: (S)-3-(2-amino-6-((1-hydroxyheptan-3-yl)amino)-5-methoxypyrimidin-4-yl)propanoic acid (Compound 21)

The title compound can be prepared according to the steps of Example 15.

Example 22: ( S )–5–(5–((2 H -tetrazol-5-yl)methyl)-2-methoxybenzyl)-6-methyl- N ^four –(1–(methylthio)heptan–3–yl)pyrimidin–2,4–diamine (Compound 22)

Stage 1: methyl ( S )–3–((2–amino–4–methyl–6–((1–(methylthio)heptan–3–yl)amino)pyrimidin–5–yl)methyl)–4–methoxybenzoate

A mixture of methyl 3-((2-amino-4-chloro-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzoate (1.0 eq., from Example 3B - Step 4) in NMP (0.8 M) , ( S )-1-(methylthio)heptan-3-amine (1.0 eq.; prepared according to the procedures described in WO2014/128189, page 8, compound D) and DIEA (3.0 eq.) was stirred for 48 hours at 120°C in an atmosphere of N ₂ . The reaction mixture was allowed to cool, diluted with EtOAc, washed with water and brine. The organic layer was dried over Na ₂ SO ₄ , concentrated and purified by silica gel column chromatography (eluent 0-5% MeOH in DCM) to give the title compound.

Stage 2: ( S )–(3–((2–amino–4–methyl–6–((1–(methylthio)heptan–3–yl)amino)pyrimidin–5–yl)methyl)–4–methoxyphenyl)methanol

To a stirred solution of methyl (S)–3–((2–amino–4–methyl–6–((1–(methylthio)heptan–3–yl)amino)–pyrimidin–5–yl)methyl)–4–methoxybenzoate (1.0 equiv.) in THF (0.18 M) was added dropwise 2.5M LiAlH_four(2.0 equiv.) at 0^oC. The reaction mixture was stirred at room temperature for 1 hour and then quenched with EA and 1N hydrochloric acid. NaOH. The mixture was filtered and the filtrate was partitioned between EA/water. The organic layer was dried over Na₂SO_four, concentrated and purified by silica gel column chromatography (eluent 0-5% MeOH in DCM) to give the title compound.

Stage 3: ( S )–5–(5–(chloromethyl)–2–methoxybenzyl)–6–methyl– N ^four –(1–(methylthio)heptan–3–yl)pyrimidin–2,4–diamine

To the stirred solution (S)–(3–((2–amino–4–methyl–6–((1–(methylthio)heptan–3–yl)amino)–pyrimidin–5–yl)methyl)–4–methoxyphenyl)methanol (1.0 equiv.) in DCM (0.1 M) was added SOCl₂ (5.0 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 2 hours and then quenched with sat. NaHCO₃. The mixture was partitioned between DCM/water. The organic layer was dried over Na₂SO_four and concentrated to give the title compound.

Stage 4: ( S )–2–(3–((2–amino–4–methyl–6–((1–(methylthio)heptan–3–yl)amino)pyrimidin–5–yl)methyl)–4–methoxyphenyl)acetonitrile

To the stirred solution (S)–5–(5–(chloromethyl)–2–methoxybenzyl)–6–methyl–N ^four–(1–(methylthio)–heptan–3–yl)pyrimidin–2,4–diamine (1.0 eq.) in 1:1 DMSO/DMF (0.1 M) was added NaCN (3.0 eq.). The mixture was stirred at room temperature for 16 hours and then quenched with sat. NaHCO₃. The mixture was partitioned between EA/water. The organic layer was dried over Na₂SO_four, concentrated and purified to give the title compound.

Stage 5: ( S )–5–(5–((2 H -tetrazol-5-yl)methyl)-2-methoxybenzyl)-6-methyl- N ^four –(1–(methylthio)–heptan–3–yl)pyrimidin–2,4–diamine

To the mixture (S)–2–(3–((2–amino–4–methyl–6–((1–(methylthio)heptan–3–yl)amino)pyrimidin–5–yl)methyl)–4–methoxyphenyl)acetonitrile (1.0 eq.) in dioxane (0.15 M) was added TMSN₃ (10.0 equiv.), Bu₂SnO (2.0 equiv.) and stirred overnight at 120^oC. The mixture was concentrated and purified by preparative HPLC (mobile phase CH₃CN/H₂O/HCOOH), lyophilized to give the title compound in the form of a white powder (salt of formic acid).

LCMS: [M+H] ⁺ =471.3

¹ H NMR (400 MHz, DMSO) δ 7.03 (d, J =8.4 Hz, 1H), 6.92 (d, J =8.4 Hz, 1H), 6.79 (s, 1H) , 6.44 (s, 2H), 6.24 (d, J = 8.8 Hz, 1H), 4.25–4.22 (m, 1H), 4.00 (s, 2H), 3, 82 (s, 3H), 3.64 (s, 2H), 2.29–2.27 (m, 2H), 2.08 (s, 3H), 1.95 (s, 3H), 1.68 –1.64 (m, 2H), 1.44–1.34 (m, 2H), 1.19–1.16 (m, 2H), 1.12–1.02 (m, 2H), 0 .78 (t, J = 7.2 Hz, 3H).

Example 23: ( S )–5–(5–((2 H -tetrazol-5-yl)methyl)-2-methoxybenzyl)-6-methyl- N ^four –(1–(methylsulfonyl)heptan–3–yl)pyrimidin–2,4–diamine (Compound 23)

To a stirred solution of ( S )–5–(5–((2 H –tetrazol–5–yl)methyl)–2–methoxybenzyl)–6–methyl– N ⁴ –(1–(methylthio)heptan–3–yl) pyrimidine-2,4-diamine (1.0 eq., Example 22) in acetone (0.02 M) was added oxone (2.0 eq.) at room temperature. The resulting mixture was stirred at room temperature for 3 hours before being filtered and purified by preparative HPLC (mobile phase CH ₃ CN/H ₂ O/HCOOH), lyophilized to give the title compound as a white powder (formic acid salt) .

LCMS: [M+H] ⁺ =503.3

¹ H NMR (400 MHz, DMSO) δ 7.05 (d, J =8.4 Hz, 1H), 6.93 (d, J =8.4 Hz, 1H), 6.76 (s, 1H) , 6.47 (s, 2H), 6.38 (d, J = 6.4 Hz, 1H), 4.25–4.23 (m, 1H), 4.04 (s, 2H), 3, 82 (s, 3H), 3.66 (s, 2H), 3.01–2.85 (m, 5H), 2.05 (s, 3H), 1.92–1.90 (m, 1H) , 1.81–1.80 (m, 1H), 1.49–1.34 (m, 2H), 1.18–1.15 (m, 2H), 1.11–0.99 (m, 2H), 0.77 (t, J =7.2 Hz, 3H).

Example 24: (3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxyphenyl)boric acid (Compound 24)

Stage 1: N ^four -butyl-5-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-6-methylpyrimidine-2,4-diamine

A mixture of 5-(5-bromo-2-methoxybenzyl) -N ⁴ -butyl-6-methylpyrimidine-2,4-diamine (1.0 eq., Example 11 - Step 5) in dioxane (0.03 M), 4 ,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.2 eq.), KOAc (3.0 eq. .) and Pd(dppf)Cl ₂ (0.1 eq.) was stirred at 90° C. for 4 h. The mixture was then filtered and the filtrate was concentrated under reduced pressure to give a crude product which was purified by silica gel column chromatography (eluent : 0-5% MeOH in DCM) to give the title compound as a white solid.

Stage 2: (3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxyphenyl)-boric acid

To the mixtureN ^four-butyl-5-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-6-methylpyrimidine-2,4-diamine (1.0 eq.) in MeOH (0.05 M) was addedⁱBuB(OH)₂(2.0 eq.) and 6 n. HCl (1/10 of the total reaction volume). The mixture was stirred at room temperature for 16 hours under nitrogen. The mixture was concentrated under reduced pressure and purified by preparative HPLC (mobile phase: FA/H₂O/CH₃CN) to give the title compound as a solid (formic acid salt).

LCMS: [M+H] ⁺ =345.3

¹ H NMR (400 MHz, DMSO– d ₆ ) δ 7.76 (s, 2H), 7.66 (d, J =7.6 Hz, 1H), 7.25 (s, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.76 (br s, 1H), 6.56 (br s, 2H), 3.86 (s, 3H), 3.63 (s, 2H) , 3.30–3.28 (m, 2H), 2.06 (s, 3H), 1.44–1.41 (m, 2H), 1.18–1.15 (m, 2H), 0 .82 (t, J = 7.2 Hz, 3H).

Example 25 4-(3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzamido)butanoic acid (Compound 25)

Stage 1: methyl 4-(3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxy-benzamido)butanoate

A mixture of 3–((2–amino–4–(butylamino)–6–methylpyrimidin–5–yl)methyl)–4–methoxybenzoic acid (1.0 eq, Example 16 - Step 1) in DMF (0.06 M), methyl 4-aminobutanoate (1.0 eq), HATU (1.5 eq.) and DIEA (4.0 eq.) were stirred at 50°C for 5 h. The mixture was cooled to room temperature and water was added. The aqueous layer was extracted with DCM. The combined organic layers were dried over Na₂SO_four and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM/MeOH=100:1 to 10:1) to give the title compound as a brown solid.

Stage 2: 4-(3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxy-benzamido)butanoic acid

To a stirred solution of methyl 4–(3–((2–amino–4–(butylamino)–6–methylpyrimidin–5–yl)methyl)–4–methoxybenzamido)butanoate (1.0 eq.) in MeOH (0.025 M) was added 1 N. NaOH (6 equiv.). The resulting mixture was stirred at 50° C. for 2 hours. The mixture was cooled to room temperature and adjusted to pH 7 using 1N HCl. HCl. The precipitated solids were collected by filtration and triturated with water, dried in vacuo to give the title compound as a white solid.

LCMS: [M+H] ⁺ = 430.3

¹ H NMR (400 MHz, DMSO) δ 8.28 (br s, 1H), 7.70 (d, J =9.2 Hz, 1H), 7.29 (s, 1H), 7.02 (d , J = 8.8 Hz, 1H), 5.99 (w s, 1H), 5.81–5.79 (m, 2H), 3.89 (s, 3H), 3.62 (s, 2H ), 2.36–3.16 (m, 4H), 2.21 (t, J = 7.2 Hz, 2H), 1.98 (s, 3H), 1.72–1.67 (m, 2H), 1.42–1.38 (m, 2H), 1.20–1.14 (m, 2H), 0.81 (t, J = 7.6 Hz, 3H).

Example 26: 5–(5–((2 H -tetrazol-5-yl)methyl)-2-methoxybenzyl)-6-methyl- N ^four -pentylpyrimidine-2,4-diamine (Compound 26)

The title compound was prepared according to the procedure described in Example 3, but using pentane-1-amine instead of butane-1-amine in Step 5. The resulting product was purified by preparative HPLC (mobile phase CH ₃ CN/H ₂ O /HCOOH), lyophilized to give the title compound as a white solid (formic acid salt).

LC-MS: [M+H] ⁺ = 397.2

¹ H NMR (400 MHz, DMSO) δ 7.03 (d, J =8.8 Hz, 1H), 6.91 (d, J =8.0 Hz, 1H), 6.74 (s, 1H) , 6.64 (br s, 1H), 6.48 (br s, 2H), 3.97 (s, 2H), 3.81 (s, 3H), 3.61 (s, 2H), 3. 30–3.24 (m, 2H), 2.04 (s, 3H), 1.46–1.40 (m, 2H), 1.29–1.21 (m, 2H), 1.20– 1.39 (m, 2H), 0.83 (t, J =6.8 Hz, 3H).

Example 27: ( S )-3-(2-amino-6-((1-hydroxyheptan-3-yl)amino)-5-(2-methoxybenzyl)-pyrimidin-4-yl)propanoic acid (Compound 27)

Stage 1: diethyl 3-oxohexanedioate

To a solution of 4-ethoxy-4-oxobutanoic acid (1.0 eq.) in anhydrous THF (0.5 M) at room temperature was added carbonyldiimidazole (1.2 eq.) in N ₂ . The resulting mixture was stirred at room temperature for 1 hour, then MgCl ₂ (1.0 eq.) and potassium 3-ethoxy-3-oxopropanoate (1.0 eq.) was added to the above solution at room temperature and heated at 60 ^o C within 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica column chromatography (eluent: PE/EA=100:1 to 3:1) to give the title compound as a yellow oil.

Stage 2: diethyl 2-(2-methoxybenzyl)-3-oxohexanedioate

To a solution of diethyl 3-oxohexanedioate (1.2 eq.) in anhydrous THF (1.2 M) was added 60% NaH (1.3 eq.) in portions at 0^oC. After stirring for 10 minutes, a solution of 1-(bromomethyl)-2-methoxybenzene (1.0 eq; Example 15 - Step 1) in THF (1 M) was added dropwise to the above mixture. The resulting mixture was stirred at 60° C. for 16 hours and quenched with water. The mixture was extracted with EA and the combined organic layers were dried over Na₂SO_four, concentrated under reduced pressure. The residue was purified by flash chromatography on silica (eluent: PE/EA=50:1 to 10:1) to give the title compound as a yellow oil.

Step 3: 3-(2-amino-6-hydroxy-5-(2-methoxybenzyl)pyrimidin-4-yl)propanoic acid

A mixture of diethyl 2–(2–methoxybenzyl)–3–oxohexanedioate (1.0 eq.) and guanidine carbonate (1.0 eq.) in MeOH (0.3 M) were stirred at 90° C. for 16 h. The precipitate was collected by filtration, washed with water and dried in vacuo to give the title compound as a white solid.

Step 4: 3-(2-amino-6-chloro-5-(2-methoxybenzyl)pyrimidin-4-yl)propanoic acid

Solution of 3-(2-amino-6-hydroxy-5-(2-methoxybenzyl)pyrimidin-4-yl)propanoic acid (1.0 eq.) in POCl₃ (0.26 M) was stirred at 100°C for 2 hours in nitrogen. The reaction mixture was cooled to room temperature and POCl₃ evaporated under reduced pressure. The residue was diluted with water and the pH was adjusted to 7 with solid NaHCO₃. The mixture was stirred at 50°C for 1 hour, then cooled to room temperature and the precipitate was collected by filtration. The filter cake was washed with water, dried in vacuo to give the title compound as a white solid.

Stage 5: ( S )-3-(2-amino-6-((1-hydroxyheptan-3-yl)amino)-5-(2-methoxybenzyl)pyrimidin-4-yl)propanoic acid

Solution of 3-(2-amino-6-chloro-5-(2-methoxybenzyl)pyrimidin-4-yl)propanoic acid (1.0 equiv.) in undiluted (S)-3-aminoheptan-1-ole (1.6M; obtained according toJ. Med. Chem,2016,59, 7936-7949) was stirred at 120°C for 2 hours. The mixture was diluted with water and the aqueous phase was extracted with EA. The combined organic layers were washed with 1 N. HCl, brine, dried over Na₂SO_four, and concentrated. The crude product was purified by preparative HPLC (mobile phase: NH_fourOH/MeCN/H₂O) to give the title compound as a white solid.

LCMS: [M+H] ⁺ = 417.3

¹ H NMR (400 MHz, CD ₃ OD) δ 7.24 (t, J =8.0 Hz, 1H), 7.02-6.96 (m, 2H), 6.89 (t, J =7 .2 Hz, 1H), 4.42–4.40 (m, 1H), 3.92 (s, 3H), 3.82 (s, 2H), 3.46–3.38 (m, 2H) , 2.95–2.90 (m, 2H), 2.48 (t, J =7.2 Hz, 2H), 1.8–1.0 (m, 8H), 0.80 (t, J =7.2 Hz, 3H).

Example 28: N –(3–(2 H -tetrazol-5-yl)propyl)-3-((2-amino-4-(butylamino)-6-methyl-pyrimidin-5-yl)methyl)-4-methoxybenzamide (Compound 28)

Step 1: 4-(1,3-dioxoisoindolin-2-yl)butanenitrile

A mixture of 4-bromobutanenitrile (1.5 eq.) and 1,3-dioxoisoindoline-2-ide (1.0 eq.) in DMF (0.3 M) was stirred at 100°C for 8 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica (eluent: PE/EA=100:1 to 1:1) to give the title compound as a white solid.

Stage 2: 4-aminobutanenitrile

To a solution of 4-(1,3-dioxoisoindolin-2-yl)butanenitrile (1.0 eq.) in EtOH (0.26 M) was added NH₂NH₂–H₂O (2.0 eq.) and stirred at room temperature for 16 h. The mixture was concentrated, then diluted with water. The aqueous phase was extracted with DCM. The combined organic phase was dried over Na₂SO_four, concentrated under reduced pressure to give the title compound as a brown oil.

Stage 3: 3–((2–amino–4–(butylamino)–6–methylpyrimidin–5–yl)methyl)– N –(3-cyanopropyl)-4-methoxybenzamide

A mixture of 3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzoic acid (1.0 eq.; Example 16 - Step 1) in DMF (0.09 M ), 4-aminobutanitrile (2.0 equiv.), HATU (2.0 eq.) DIEA (3.0 eq.) was stirred at 50°C for 5 h. The mixture was cooled to room temperature, then water was added and the aqueous phase was extracted with DCM. The combined organic phase was dried over Na₂SO_four, concentrated under reduced pressure. The residue was purified by flash chromatography on silica (PE/EA=50:1 to 1:2) to give the title compound as a brown solid.

Stage 4: N –(3–(2 H -tetrazol-5-yl)propyl)-3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzamide

To a stirred solution of 3–((2–amino–4–(butylamino)–6–methylpyrimidin–5–yl)methyl)–N–(3-cyanopropyl)-4-methoxybenzamide (1.0 equiv.) in NMP (0.08 M) was added Bu₂SnO (2.0 eq.) and TMSN₃(10.0 eq.). The resulting mixture was stirred overnight at 125°C under N₂. The mixture was cooled to room temperature, concentrated and purified by preparative HPLC (mobile phase: CH₃CN/H₂O/ 0.1%NH_fourOH) to give the title compound as a solid.

LC-MS: [M+H] ⁺ = 454.5

^oneH NMR (400 MHz, DMSO)δ 8.45 (s, 1H), 7.74 (d,J= 8.0 Hz, 1H), 7.32 (s, 1H), 7.04 (d,J=8.8 Hz, 1H), 6.57 (w s, 1H), 6.30-6.20 (m, 2H), 3.90 (s, 3H), 3.65 (s, 2H), 3.30–3.26 (m, 4H), 2.82 (t,J= 7.2 Hz, 2H), 2.03 (s, 3H), 1.90 (t,J=6.8 Hz, 2H), 1.46–1.38 (m, 2H), 1.23–1.12 (m, 2H), 0.80 (t,J=7.2 Hz, 3H).

Example 29: ( S )–3–((2–amino–6–(2–carboxyethyl)–5–(2–methoxybenzyl)pyrimidin–4–yl)amino)heptanoic acid (Compound 29)

Stage 1: tert -butyl (S, E )–3–((2–amino–6–(3–ethoxy–3–oxoprop–1–en–1–yl)–5–(2–methoxybenzyl)–pyrimidin–4–yl)amino)heptanoate

Ethyl solution (E)-3-(2-amino-6-chloro-5-(2-methoxybenzyl)pyrimidin-4-yl)acrylate (1.0 eq., Example 15 - Step 5) in neattert–butyl (S)-3-aminoheptanoate (0.6M, Example 20B - Step 3) was stirred at 120°C for 2 hours. The reaction solution was diluted with water, and the aqueous layer was extracted with EA. The combined organic layers were washed with water, brine, dried over Na₂SO_four and concentrated. The crude product was purified by column chromatography (DCM/MeOH=10:1) to give the title compound as a yellow solid.

Stage 2: tert –butyl ( S )–3–((2–amino–6–(3–ethoxy–3–oxopropyl)–5–(2–methoxybenzyl)pyrimidin–4–yl)amino)heptanoate

To solutiontert-butyl (S,E)–3–((2–amino–6–(3–ethoxy–3–oxoprop–1–en–1–yl)–5–(2–methoxy–benzyl)–pyrimidin–4–yl)amino)heptanoate (1.0 equiv.) in MeOH (0.04 M) was added Pd/C (1/3 wt. equiv.). The mixture was stirred under H₂ at room temperature for 2 hours. The Pd/C was filtered off and the filtrate was concentrated to give the title compound as a yellow solid.

Stage 3: ( S )–3–((2–amino–6–(2–carboxyethyl)–5–(2–methoxybenzyl)pyrimidin–4–yl)amino)–heptanoic acid

To solutiontert–butyl (S)–3–((2–amino–6–(3–ethoxy–3–oxopropyl)–5–(2–methoxybenzyl)–pyrimidin–4–yl)amino)heptanoate (1.0 eq.) in 4:1 EtOH/H₂O (0.06 M) KOH (5.0 eq.) was added. The solution was stirred at 100° C. for 3 hours. The pH was adjusted to 7 using acetic acid and the solution was concentrated and then purified by preparative HPLC (mobile phase: NH_fourOH/MeCN/H₂O) to give the title compound as a white solid.

LC-MS: [M+H] ⁺ =431.4

¹ H NMR (400 MHz, CD ₃ OD) δ 7.23 (t, J =7.2 Hz, 1H), 7.01-6.97 (m, 2H), 6.89 (t, J =7 .2 Hz, 1H), 4.61 (m, 1H), 3.91 (s, 3H), 3.82 (s, 2H), 2.94–2.92 (m, 2H), 2.47 –2.41 (m, 2H), 1.6–0.9 (m, 8H), 0.80 (t, J = 7.2 Hz, 3H).

Example 30: (3-(3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzamido)propyl)phosphonic acid (Compound 30)

Stage 1: diethyl (3-(1,3-dioxoisoindolin-2-yl)propyl)phosphonate

A mixture of diethyl (3-bromopropyl)phosphonate (1.2 eq.) and 1,3-dioxoisoindoline-2-ide (1.0 eq.) in DMF (0.2 M) was stirred at 100°C for 8 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a white solid.

Stage 2: diethyl (3-aminopropyl)phosphonate

A mixture of diethyl (3-(1,3-dioxoisoindolin-2-yl)propyl)phosphonate (1.0 eq.) in EtOH (0.25 M) and NH₂NH₂ H₂O (2.0 eq.) was stirred at room temperature for 16 hours. The reaction mixture was filtered, the filtrate was poured into water, and the aqueous phase was extracted with DCM. The organic phase was dried over Na₂SO_four, concentrated under reduced pressure to give the title compound as a brown oil.

Stage 3: diethyl (3-(3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxy-benzamido)propyl)phosphonate

A mixture of 3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzoic acid (1.0 eq.; Example 16 - Step 1) in DMF (0.1 M ), diethyl (3-aminopropyl)phosphonate (2.0 equiv.),HATU (2.0 equiv.) and DIEA (3.0 equiv.) were stirred at 50°C for 5 hours in nitrogen. The mixture was cooled to room temperature, diluted with water and the aqueous phase was extracted with DCM. The organic phase was dried over Na₂SO_four, concentrated under reduced pressure to give the title compound as a brown solid.

Stage 4: (3-(3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxy-benzamido)propyl)phosphonic acid

A solution of diethyl (3–(3–((2–amino–4–(butylamino)–6–methylpyrimidin–5–yl)methyl)–4–methoxybenzamide)propyl)phosphonate (1.0 eq.) in DCM (0.08 M) and TMSBr (10.0 eq.) was stirred overnight at room temperature under nitrogen. The mixture was concentrated, purified by preparative HPLC (mobile phase CH₃CN/H₂O/0.1%NH_fourOH) to give the title compound as a solid.

LC-MS: [M+H] ⁺ = 466.4

¹ H NMR (400 MHz, DMSO) δ 8.59 (s, 1H), 7.76 (d, J =8.0 Hz, 1H), 7.27 (s, 1H), 7.20 (br s , 1H), 7.03 (d, J = 8.4 Hz, 1H), 3.88 (s, 3H), 3.64 (s, 2H), 3.35–3.28 (m, 2H) , 3.25–3.16 (m, 2H), 2.07 (s, 3H), 1.74–1.62 (m, 2H), 1.48–1.33 (m, 4H), 1 .22–1.11 (m, 2H), 0.81 (t, J = 7.2 Hz, 3H).

Example 31: 5–((5–((2 H -tetrazol-5-yl)methyl)-2-methoxyphenyl)thio)- N ^four -butyl-6-methylpyrimidine-2,4-diamine (Compound 31)

Stage 1: methyl 3-((dimethylcarbamothioyl)oxy)-4-methoxybenzoate

To a stirred solution of methyl 3-hydroxy-4-methoxybenzoate (1.0 eq.) in DMF (0.55 M) was added NaH (1.1 eq.) at 0 ^° C. The mixture was warmed to room temperature and stirred for 30 minutes and then treated with dimethylcarbamothioid chloride (1.1 eq.). The mixture was stirred overnight and partitioned into ether/water. The resulting suspension was filtered. The solid was collected and dried in vacuo to give the title compound as a white solid.

Stage 2: methyl 3-((dimethylcarbamoyl)thio)-4-methoxybenzoate

Methyl 3–((dimethylcarbamoyl)oxy)–4–methoxybenzoate (1.0 equiv.) in PhOPh (1 M) was stirred for 16 hours at 260^oC. The mixture was cooled to room temperature and the mixture was purified by flash chromatography on silica (eluent PE/EA=100:1-2:1) to give the title compound.

Stage 3: methyl 3-mercapto-4-methoxybenzoate

To a stirred solution of methyl 3–((dimethylcarbamoyl)thio)–4–methoxybenzoate (1.0 eq.) in THF (0.3 M) was added MeONa (2.0 eq.) at room temperature. The resulting mixture was stirred at 60° C. for 2 hours. The mixture was cooled to room temperature and quenched with 1N HCl. HCl. The mixture was partitioned between EA/water. The organic phase was dried over Na₂SO_four and concentrated and purified by flash chromatography on silica (eluent PE/EA=100:1~5:1) to give the title compound.

Stage 4: methyl 3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)thio)-4-methoxy-benzoate

A mixture of methyl 3-mercapto-4-methoxybenzoate (1.0 equiv.) in dioxane (0.3 M),N ^four-butyl-5-iodo-6-methylpyrimidine-2,4-diamine (1.5 eq.), Cs₂CO₃ (2.0 equiv.), CuI (2.0 equiv.) was stirred overnight at 100^oC. The mixture was separated in EA/NH_fourOh. The organic layer was washed with brine, dried over Na₂SO_four, concentrated and purified by flash chromatography on silica (eluent PE/EA=100:1~1:1) to give the title compound.

Stage 5: (3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)thio)-4-methoxyphenyl)-methanol

To a stirred solution of methyl 3–((2–amino–4–(butylamino)–6–methylpyrimidin–5–yl)thio)–4–methoxybenzoate (1.0 equiv.) in THF (0.2 M) was added 1M LiAlH_four(2.0 equiv.) dropwise at 0^oC. The resulting mixture was stirred at 0°C for 10 minutes and at room temperature for 1 hour. The mixture was diluted with EA and quenched with 2N. NaOH. The mixture was partitioned between EA/water. The organic layer was dried over Na₂SO_four, filtered and concentrated to give the title compound.

Stage 6: N ^four -butyl-5-((5-(chloromethyl)-2-methoxyphenyl)thio)-6-methylpyrimidine-2,4-diamine

To a stirred solution of (3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)thio)-4-methoxyphenyl)methanol (1.0 equiv.) in DCM (0.2 M) was added SOCl₂ (2.0 equiv.) at room temperature in N₂. The mixture was stirred at room temperature for 1 h. The mixture was partitioned between DCM and saturated aqueous NaHCO₃. The organic layer was dried over Na₂SO_four, filtered and concentrated to give the title compound.

Step 7: 2-(3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)thio)-4-methoxyphenyl)acetonitrile

MixtureN ^four-butyl-5-((5-(chloromethyl)-2-methoxyphenyl)thio)-6-methylpyrimidine-2,4-diamine (1.0 eq.) in 1:1 DMSO/DMF (0.1 M) and NaCN (3.0 eq.) was stirred overnight at room temperature. The mixture was partitioned between EA/water. The organic layer was dried over Na₂SO_four, filtered, concentrated and purified by flash chromatography on silica (eluent 0-5% MeOH in DCM) to give the title compound.

Stage 8: 5–((5–((2 H -tetrazol-5-yl)methyl)-2-methoxyphenyl)thio)- N ^four -butyl-6-methylpyrimidine-2,4-diamine

A mixture of 2-(3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)thio)-4-methoxyphenyl)acetonitrile (1.0 equiv.) in NMP (0.1 M), Bu₂SnO (2.0 eq.), and TMSN₃(10.0 equiv.) was stirred for 3 hours at 120°C in N₂. The mixture was cooled to room temperature and the mixture was concentrated and purified by preparative HPLC (mobile phase CH₃CN/H₂O/NH_fourOH), lyophilized to give the title compound as a white powder.

LCMS: [M+H] ⁺ = 401.4

¹ H NMR (400 MHz, DMSO) δ 7.03-6.92 (m, 2H), 6.46-6.42 (m, 2H), 6.39 (s, 2H), 4.06 (s , 2H), 3.83 (s, 3H), 3.26–3.21 (m, 2H), 2.14 (s, 3H), 1.39–1.32 (m, 2H), 1, 17–1.1.10 (m, 2H), 0.81 (t, J = 7.2 Hz, 3H).

Example 32: ( S )–5–(5–((2 H -tetrazol-5-yl)methyl)-2-methoxybenzyl)- N ^four –(1-methoxyheptan-3-yl)-6-methylpyrimidin-2,4-diamine (Compound 32)

Stage 1: (3-((2-amino-4-chloro-6-methylpyrimidin-5-yl)methyl)-4-methoxyphenyl)methanol

To a solution of methyl 3–((2–amino–4–chloro–6–methylpyrimidin–5–yl)methyl)–4–methoxybenzoate (1.0 eq., Example 3B - Step 4) in THF (1.6 M) was added LiAlH_four (3.0 eq.) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water. The aqueous layer was extracted with DCM. The organic layer was washed with water, brine, separated, dried over Na₂SO_four and concentrated to give the title compound as a pale solid.

Stage 2: ( S )–(3–((2–amino–4–((1–methoxyheptan–3–yl)amino)–6–methylpyrimidin–5–yl)methyl)–4–methoxyphenyl)methanol

A mixture of (3-((2-amino-4-chloro-6-methylpyrimidin-5-yl)methyl)-4-methoxyphenyl)methanol (1.0 equiv.) in NMP (0.4 M) and (S)-1-methoxyheptane-3-amine (2.0 equiv.) was stirred at 120°C for 16 hours in nitrogen. The reaction solution was diluted with water. The aqueous phase was extracted with EA. The organic layer was washed with water, brine, dried over Na₂SO_four and concentrated. The crude product was purified by column chromatography (DCM/MeOH=50:1) to give the title compound as a yellow solid.

Stage 3: ( S )–5–(5–(chloromethyl)–2–methoxybenzyl)– N ^four -(1-methoxyheptan-3-yl)-6-methylpyrimidin-2,4-diamine

To the stirred solution (S)–(3–((2–amino–4–((1–methoxyheptan–3–yl)amino)–6–methylpyrimidin–5–yl)methyl)–4–methoxyphenyl)methanol (1.0 equiv.) in DCM (0.3 M) was added SOCl₂ (2.0 eq.) drop by drop. The resulting mixture was stirred at 20°C for 1 h, then quenched with H₂O. The mixture was separated in DCM/water. The organic layer was separated, dried over Na₂SO_four, filtered and concentrated to give the title compound as a brown oil.

Stage 4: ( S )–2–(3–((2–amino–4–((1–methoxyheptan–3–yl)amino)–6–methylpyrimidin–5–yl)methyl)–4–methoxyphenyl)acetonitrile

Blend (S)–5–(5–(chloromethyl)–2–methoxybenzyl)–N ^four-(1-methoxyheptan-3-yl)-6-methylpyrimidin-2,4-diamine (1.0 eq.) in DMSO (0.4 M) and KCN (3.0 eq.) was stirred at 80°C for 4 hours, then cooled to room temperature. Water was added and the solution was extracted with DCM. The organic phase was dried over Na₂SO_four, concentrated, and purified by column chromatography (DCM/MeOH=40:1) to give the title compound as a white solid.

Stage 5: ( S )–5–(5–((2 H -tetrazol-5-yl)methyl)-2-methoxybenzyl)- N ^four -(1-methoxyheptan-3-yl)-6-methylpyrimidin-2,4-diamine

To the stirred mixture (S)–2–(3–((2–amino–4–((1–methoxyheptan–3–yl)amino)–6–methylpyrimidin–5–yl)methyl)–4–methoxyphenyl)acetonitrile (1.0 equiv.) in dioxane (0.2 M) and Bu₂SnO (2.0 equiv.) was added TMSN₃(10.0 eq.). The resulting mixture was stirred at 110°C for 4 h in N₂, then cooled to room temperature. The mixture was concentrated and purified by preparative HPLC (mobile phase 0.1% NH₃ ^. H₂O/CH₃CN) to give the title compound as a solid.

LC-MS: [M+H] ⁺ = 455.4

^oneH NMR (400 MHz, CDCl₃) δ 6.86 (s, 1H), 6.84 (d,J= 8.4 Hz, 1H), 6.50 (d,J = 8.4 Hz, 1H), 4.28-4.23 (m, 3H), 3.90 (s, 3H), 3.58 (s, 2H), 3.19-3.16 (m, 2H), 3.14 (s, 3H), 2.50 (s, 3H), 1.83–1.81 (m, 1H), 1.59–1.06 (m, 7H), 0.83 (t,J=7.2 Hz, 3H).

Example 33: ( S )–2–(3–((2–amino–4–methyl–6–((1–(methylthio)heptan–3–yl)amino)pyrimidin–5–yl)methyl)–4–methoxyphenyl)–2– methylpropanoic acid (Compound 33)

Stage 1: ( S )–2–(3–((2–amino–4–methyl–6–((1–(methylthio)heptan–3–yl)amino)pyrimidin–5–yl)methyl)–4–methoxyphenyl)–2– methylpropanenitrile

A mixture of 2-(3-((2-amino-4-chloro-6-methylpyrimidin-5-yl)methyl)-4-methoxyphenyl)-2-methylpropanenitrile (1.0 eq., Example 9 - Step 8) in NMP (0.6 M), (S)-1-(methylthio)heptan-3-amine (1.5 eq.; prepared according to the methods of WO2014/128189, page 8, compound D) and DIEA (3.0 eq.) was stirred at 120°C for 48 hours. Water was added to the mixture and extracted with EtOAc. The organic layer was dried over Na₂SO_four and concentrated under reduced pressure. The residue was purified by flash chromatography on silica (eluent: DCM/MeOH=100:1~20:1) to give the title compound as a brown oil.

Stage 2: ( S )–2–(3–((2–amino–4–methyl–6–((1–(methylthio)heptan–3–yl)amino)pyrimidin–5–yl)methyl)–4–methoxyphenyl)–2– methylpropanoic acid

To the stirred solution (S)–2–(3–((2–amino–4–methyl–6–((1–(methylthio)heptan–3–yl)amino)pyrimidin–5–yl)methyl)–4–methoxyphenyl)–2– methylpropanenitrile (1.0 eq.) in 1:1 ethane-1,2-diol/H₂O (0.1 M) was added KOH (10 equiv.) and heated in a sealed tube at 150°C for 16 hours. The mixture was acidified with 1N. HCl solution to pH=2–3 and filtered. The filtrate was purified by preparative HPLC (mobile phase CH₃CN/H₂O/NH₃ ^. H₂O), then lyophilized to give the title compound as a white solid.

LC-MS: [M+H] ⁺ = 475.3

¹ H NMR (400 MHz, DMSO– d ₆ ) δ 7.14 (dd, J =8.4, 2.0 Hz, 1H), 6.91 (d, J =8.8 Hz, 1H), 6 .86 (s, 1H), 5.91 (br s, 2H), 5.72 (d, J = 9.2 Hz, 1H), 4.25–4.15 (m, 1H), 3.82 (s, 3H), 3.62 (s, 2H), 2.31–2.25 (m, 2H), 2.02 (s, 3H), 1.95 (s, 3H), 1.70– 1.52 (m, 2H), 1.44–1.34 (m, 2H), 1.31 (s, 6H), 1.25–1.05 (m, 4H), 0.78 (t, J = 6.8 Hz, 3H).

Example 34: ( S )–5–(2–methoxy–5–(2 H –tetrazol–5–yl)benzyl)–6–methyl– N ^four –(1–(methylthio)heptan–3–yl)pyrimidin–2,4–diamine (Compound 34)

Stage 1: 4-methoxy-3-methylbenzonitrile

A mixture of 4-bromo-1-methoxy-2-methylbenzene (1.0 equiv.) in DMF (1 M), Zn(CN)₂ (1.5 equiv.), Pd₂(dba)₃ (0.02 equiv.) and S-phos (0.05 equiv.) were stirred at 80°C for 16 h. The resulting mixture was concentrated and purified by silica gel column chromatography (eluent PE/EA=100:1~20 :1) to give the header compound.

Step 2: 3-(bromomethyl)-4-methoxybenzonitrile

A mixture of 4-methoxy-3-methylbenzenitrile (1.0 eq) in CCl ₄ (0.7 M), NBS (1.1 eq) and AIBN (0.1 eq) was stirred at 95°C for 16 h in nitrogen. The resulting mixture was concentrated and partitioned into DCM and water. The organic layer was dried over Na ₂ SO ₄ , concentrated and purified by silica gel column chromatography (eluent PE/EA=100:1~20:1) to give the title compound as a white solid.

Stage 3: ethyl 2–(5–cyano–2–methoxybenzyl)–3–oxobutanoate

To a solution of 3-(bromomethyl)-4-methoxybenzonitrile (1.5 equiv.) in THF (0.6 M) at 0°C was added portionwise 60% NaH (1.5 equiv.) in N ₂ . The resulting suspension was stirred at 0°C for 10 minutes, then a solution of ethyl 3-oxobutanoate (1.0 equiv.) in THF (1 M) was added dropwise over 10 minutes at 0 ^o C. The resulting mixture was stirred at 70°C over 15 hours. The reaction mixture was cooled to room temperature and ice water was added. The mixture was extracted with ethyl acetate. The organic layer was dried over Na ₂ SO ₄ , concentrated and purified by silica gel column chromatography (eluent PE/EA=50:1~5:1) to give the title compound as a yellow oil.

Step 4: 3-((2-amino-4-hydroxy-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzonitrile

To a solution of ethyl 2-(5-cyano-2-methoxybenzyl)-3-oxobutanoate (1.0 equiv.) in MeOH (0.7 M) was added guanidine carbonate (1.0 equiv.). The resulting mixture was stirred at 70° C. for 16 hours. The mixture was concentrated and the residue was suspended in EtOAc and then filtered. The filtration residue was washed with water and EtOAc. The resulting solid was collected and dried in vacuo to give the title compound as a white solid.

Stage 5: 3-((2-amino-4-chloro-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzonitrile

Suspension of 3-((2-amino-4-hydroxy-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzonitrile (1.0 eq.) in POCl₃ (0.3 M) was stirred at 100°C for 16 hours the Reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was diluted with water and the pH was adjusted to 7 using solid NaHCO₃. The precipitate was collected by filtration and the filtration residue was washed with water and EtOAc, dried in vacuo to give the title compound.

Stage 6: ( S )–3–((2–amino–4–methyl–6–((1–(methylthio)heptan–3–yl)amino)pyrimidin–5–yl)methyl)–4–methoxybenzonitrile

A mixture of 3-((2-amino-4-chloro-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzonitrile (1.0 eq.) in NMP (0.3 M) and ( S )-1-( methylthio)heptan-3-amine (1.5 eq., prepared according to the methods of WO2014/128189, page 8, compound D) was stirred at 150°C for 4 h under nitrogen. The reaction solution was diluted with water and the aqueous phase was extracted with EA. The organic layer was washed with water, brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (DCM/MeOH=50:1) to give the title compound as a yellow solid.

Stage 7: ( S )–5–(2–methoxy–5–(2 H –tetrazol–5–yl)benzyl)–6–methyl– N ^four –(1–(methylthio)heptan–3–yl)pyrimidin–2,4–diamine

To the stirred mixture (S)–3–((2–amino–4–methyl–6–((1–(methylthio)heptan–3–yl)amino)pyrimidin–5–yl)methyl)–4–methoxybenzonitrile (1.0 equiv.) in dioxane (0.4 M), Bu₂SnO (2.0 equiv.) was added TMSN₃(10.0 eq.). The resulting mixture was stirred at 110°C for 4 h in N₂. The mixture was cooled to room temperature and the mixture was concentrated and purified by preparative HPLC (mobile phase 0.1% NH₃ ^. H₂O/CH₃CN) to give the title compound.

LC-MS: [M+H] ⁺ = 457.3

^oneH NMR (400 MHz, DMSO–d ₆) δ 7.82 (d,J= 8.8 Hz, 1H), 7.50 (s, 1H), 7.07 (d,J =8.4 Hz, 1H), 6.55 (br, 3H), 4.28-4.26 (m, 1H), 3.89 (s, 3H), 3.73 (s, 2H), 2 .27 (t,J=7.6 Hz, 2H), 2.14 (s, 3H), 1.88 (s, 3H), 1.67–1.65 (m, 2H), 1.41–1.39 (m, 2H), 1.12–1.04 (m, 4H), 0.69 (t,J=6.8 Hz, 3H).

Example 35: ( S )–(3–(3–((2–amino–4–methyl–6–((1–(methylthio)heptan–3–yl)amino)pyrimidin–5–yl)methyl)–4–methoxybenzamido)propyl) phosphonic acid (Compound 35)

Stage 1: methyl ( S )–3–((2–amino–4–methyl–6–((1–(methylthio)heptan–3–yl)amino)pyrimidin–5–yl)methyl)–4–methoxybenzoate

A mixture of methyl 3-((2-amino-4-chloro-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzoate (1.0 eq., Example 3B - Step 4) in NMP (0.16 M) and ( S )-1-(methylthio)heptan-3-amine (1.5 equiv., prepared according to methods WO2014/128189, page 8, compound D) was stirred at 150°C for 4 hours under nitrogen. The mixture was diluted with water. The aqueous phase was extracted with EA. The organic layer was washed with water, brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (DCM/MeOH=50:1) to give the title compound as a yellow solid.

Stage 2: ( S )–3–((2–amino–4–methyl–6–((1–(methylthio)heptan–3–yl)amino)pyrimidin–5–yl)methyl)–4–methoxybenzoic acid

Methyl mixture (S)–3–((2–amino–4–methyl–6–((1–(methylthio)heptan–3–yl)amino)pyrimidin–5–yl)methyl)–4–methoxybenzoate (1.0 eq.) in 1:1 EtOH/H₂O (0.02 M) and NaOH (10.0 equiv.) were stirred at 70^oC for 16 hours. The mixture was neutralized using 1N. HCl and the resulting suspension was filtered. The filter residue was washed with water to give a solid which was dissolved in MeCN/H₂O. Added 4 n. HCl/dioxane and the resulting solution was lyophilized to give the title compound as a white solid.

Stage 3: diethyl ( S )–(3–(3–((2–amino–4–methyl–6–((1–(methylthio)heptan–3–yl)amino)pyrimidin–5–yl)methyl)–4–methoxybenzamido)propyl) phosphonate

Blend (S)–3–((2–amino–4–methyl–6–((1–(methylthio)heptan–3–yl)amino)pyrimidin–5–yl)methyl)–4–methoxybenzoic acid (1.0 eq.) in DMF (0.1 M), diethyl (3-aminopropyl)phosphonate (1.1 equiv., Example 30 - Stage 2), HATU (1.5 eq.) and DIEA (2.0 eq.) were stirred at 30°C for 16 h. The mixture was cooled to room temperature and water was added. The mixture was extracted with DCM. The organic phase was dried over Na₂SO_four, concentrated under reduced pressure to give the title compound as a colorless oil.

Stage 4: ( S )–(3–(3–((2–amino–4–methyl–6–((1–(methylthio)heptan–3–yl)amino)pyrimidin–5–yl)methyl)–4–methoxybenzamido)propyl) phosphonic acid

diethyl mixture (S)–(3–(3–((2–amino–4–methyl–6–((1–(methylthio)heptan–3–yl)amino)pyrimidin–5–yl)methyl)–4–methoxybenzamido)propyl) phosphonate (1.0 eq.) in DCM (0.05 M) and TSMBr (10.0 eq.) were stirred at 35°C for 5 hours in N_2.The mixture was cooled and concentrated. The residue was purified by preparative HPLC (mobile phase CH₃CN/H₂O/NH_3.H₂O) to obtain the connection specified in the header.

LC-MS: [M+H] ⁺ = 554.3

^oneH NMR (400 MHz, CDCl₃)δ13.93 (s, 1H), 10.36 (s, 1H), 10.12 (s, 1H), 7.94 (d,J= 8.0 Hz, 1H), 7.80 (s, 1H), 6.96 (d,J= 8.8 Hz, 1H), 5.94 (d,J= 8.4 Hz, 1H), 4.23-4.21 (m, 1H), 3.98 (s, 3H), 3.73-3.30 (m, 4H), 2.76 (s, 3H), 2.43–2.41 (m, 1H), 2.05–1.80 (m, 7H), 1.70 (s, 3H), 1.55–1.20 (m, 6H) , 0.86 (t,J=4.0 Hz, 3H).

Example 36: ( S )– N ^four –(1–(2 H -tetrazol-5-yl)heptan-3-yl)-5-(2-methoxybenzyl)-6-methylpyrimidin-2,4-diamine (Compound 36)

Stage 1: ( S )–3–(benzyl(( S )-1-phenylethyl)amino)heptyl methanesulfonate

To the stirred solution (S)–3–(benzyl((S)-1-phenylethyl)amino)heptan-1-ol (1.0 equiv., obtained fromJ. Med. Chem.2016,59, 7936–7949) and DIEA (1.1 eq.) in DCM (0.5 M) MsCl (1.1 eq.) was added at 0^oC. The resulting mixture was warmed to room temperature over 3 hours. The solvent was removed and the residue was diluted with EA. The organic layer was washed with 1N. HCl, 1 N NaOH, brine, dried and concentrated to give the title compound.

Stage 2: ( S )–4–(benzyl(( S )-1-phenylethyl)amino)octannitrile

Blend (S)–3–(benzyl((S)-1-phenylethyl)amino)heptyl methanesulfonate (1.0 eq.) in DMSO (0.3 M) and KCN (7.5 eq.) was stirred at 30°C for 16 h. The reaction mixture was diluted with water. The aqueous layer was extracted with EA. The organic layer was separated, dried and concentrated to give the title compound as a light yellow oil.

Stage 3: ( S )– N -benzyl- N –(( S )–1–phenylethyl)–1–(2 H -tetrazol-5-yl)heptan-3-amine

Mixture of ( S )-4-(benzyl(( S )-1-phenylethyl)amine)octannitrile (1.0 eq.) in dioxane (0.2 M), TMSN ₃ (2.5 eq.) and Bu ₂ SnO (2.0 eq.) was stirred at 120° C. in a sealed tube for 18 hours. The mixture was diluted with EA and then washed with water. The organic layer was dried and concentrated. The crude product was purified by column chromatography (eluent PE:EA=10:1) to give the title compound as a light brown oil.

Stage 4: ( S )–1–(2 H -tetrazol-5-yl)heptan-3-amine

to solution (S)–N-benzyl-N–((S)–1–phenylethyl)–1–(2H-tetrazol-5-yl)heptan-3-amine (1.0 eq.) in MeOH (0.2 M) was added 50% Pd/C (0.3 wt. eq.) in nitrogen. The reaction mixture was stirred at 40°C under H₂ over 16 h. Pd/C was filtered off and the filtrate was concentrated to give the title compound as a light yellow solid.

Stage 5: ( S )– N ^four –(1–(2 H -tetrazol-5-yl)heptan-3-yl)-5-(2-methoxybenzyl)-6-methylpyrimidin-2,4-diamine

A solution of 4-chloro-5-(2-methoxybenzyl)-6-methylpyrimidine-2-amine (1.0 eq., Example 41 - Step 3) in NMP (0.4 M) and ( S )-1-(2 H -tetrazol-5-yl)heptan-3-amine (2.0 equiv.) was stirred at 150°C for 3 h under nitrogen. The reaction mixture was diluted with water and the water was extracted with EA. The organic layers were combined and washed with water, brine, dried and concentrated. The crude product was purified by preparative HPLC (0.1% NH ₃ H ₂ O/CH ₃ CN mobile phase) to give the title compound.

LC-MS: [M+H] ⁺ = 411.4

¹ H NMR (400 MHz, MeOD) δ 7.17 (t, J =7.2 Hz, 1H), 6.96 (d, J =8.8 Hz, 2H), 6.85 (t, J = 7.2 Hz, 1H), 4.24–4.20 (m, 1H), 3.91 (s, 3H), 3.78–3.63 (m, 2H), 3.19–3.16 (m, 1H), 2.72 (t, J = 8.0 Hz, 2H), 2.28 (s, 3H), 2.28–0.80 (m, 8H), 0.77 (t, J = 7.2 Hz, 3H).

Example 37: 6–(2–(2 H –tetrazol–5–yl)ethyl)– N ^four -butyl-5-(2-methoxybenzyl)pyrimidine-2,4-diamine (Compound 37)

Stage 1: ethyl 5-cyano-3-oxopentanoate

CDI was added to a solution of 3-cyanopropanoic acid (1.0 equiv.) in THF (0.5 M). (1.2 eq.). The reaction solution was stirred at 25°C for 1 h. MgCl₂ (1.0 eq.) and potassium 3-ethoxy-3-oxopropanoate (1.0 eq.) were added to the above solution and stirred at 60°C for 2 h. The solution was cooled to room temperature and quenched with H₂O. The aqueous phase was extracted with EA. The combined organic layer was washed with water and then with brine. The organic layer was separated and dried over Na₂SO_four, concentrated and purified by column chromatography (PE/EA=3:1) to give the title compound as a yellow oil.

Stage 2: diethyl 2-(2-methoxybenzyl)-3-oxohexanedioate

To a solution of ethyl 5-cyano-3-oxopentanoate (1.2 equiv.) in THF (0.3 M) was added in portions of NaH (1.3 equiv.) at 0°C in nitrogen. The solution was stirred at 0°C for 15 minutes, then 1-(bromomethyl)-2-methoxybenzene was added (1.0 equiv.). The reaction mixture was stirred at 40° C. for 16 hours. The reaction mixture was quenched with water. The aqueous layer was extracted with EA. The combined organic layer was washed with water, brine, dried over Na₂SO_four and concentrated. The crude product was purified by column chromatography (PE/EA=5:1) to give the title compound as a light yellow oil.

Step 3: 3-(2-amino-6-hydroxy-5-(2-methoxybenzyl)pyrimidin-4-yl)propanenitrile

To a solution of diethyl 2-(2-methoxybenzyl)-3-oxohexanedioate (1.0 equiv.) in MeOH (0.6 M) was added guanidine carbonate (1.0 equiv.). The reaction was heated at 70° C. for 16 hours under nitrogen. After cooling, the reaction solution was concentrated under reduced pressure, and 1:1 H ₂ O/EA was added. The precipitates were filtered and collected to give the title compound as an off-white solid.

Step 4: 3-(2-amino-6-chloro-5-(2-methoxybenzyl)pyrimidin-4-yl)propanenitrile

A mixture of 3-(2-amino-6-hydroxy-5-(2-methoxybenzyl)pyrimidin-4-yl)propanenitrile (1.0 eq.) and POCl₃ (0.3 M) was stirred at 100°C for 2 hours in nitrogen. The reaction mixture was cooled to room temperature and poured into ice water. pH was adjusted to 7 using NaHCO solution₃. The aqueous solution was extracted with EA. The organic layer was washed with water, brine, dried over Na₂SO_four and concentrated to give the title compound as a gray solid.

Stage 5: 3-(2-amino-6-(butylamino)-5-(2-methoxybenzyl)pyrimidin-4-yl)propanenitrile

To a solution of 3-(2-amino-6-chloro-5-(2-methoxybenzyl)pyrimidin-4-yl)propanenitrile (1.0 equiv.) in NMP (0.16 M) was added butan-1-amine (3.0 eq.) and DIEA (3.0 eq.). The mixture was stirred at 100° C. for 16 hours under nitrogen. The reaction solution was diluted with water and extracted with EA. The organic layer was washed with water, brine, dried over Na₂SO_four and concentrated. The crude product was purified by column chromatography (DCM/MeOH=50:1) to give the title compound as a yellow solid.

Stage 6: 6–(2–(2 H –tetrazol–5–yl)ethyl)– N ^four -butyl-5-(2-methoxybenzyl)pyrimidine-2,4-diamine

TMSN ₃ (2, 0 eq.) and Bu ₂ SnO (2.0 eq.). The mixture was stirred at 120° C. for 3 hours. The solution was concentrated and purified by preparative HPLC (mobile phase: NH ₄ HCO ₃ /MeCN/H ₂ O) to give the title compound as a white solid.

LC-MS: [M+H] ⁺ =383.4

¹ H NMR (400 MHz, DMSO– d ₆ ) δ 7.18 (t, J = 8.4 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 6.81 (t , J = 7.2 Hz, 1H), 6.73 (d, J = 7.6 Hz, 1H), 6.59 (t, J = 5.6 Hz, 1H), 6.27 (w s, 2H), 3.84 (s, 3H), 3.65 (s, 2H), 3.30–3.25 (m, 2H), 3.02 (t, J = 7.6 Hz, 2H), 2.76 (t, J = 7.6 Hz, 2H), 1.49–1.37 (m, 2H), 1.23–1.16 (m, 2H), 0.83 (t, J = 7.6 Hz, 3H).

Example 38: ( S )–3–(2–amino–5–(2–methoxybenzyl)–6–((1–(methylthio)heptan–3–yl)amino)pyrimidin–4–yl)propanoic acid (Compound 38)

Stage 1: ( S )–3–(2–amino–5–(2–methoxybenzyl)–6–((1–(methylthio)heptan–3–yl)amino)pyrimidin–4–yl)propanoic acid

A mixture of 3-(2-amino-6-chloro-5-(2-methoxybenzyl)pyrimidin-4-yl)propanoic acid (1.0 eq., Example 27 - Step 4) and neat (S)–1–(methylthio)heptan–3–amine (4.0 eq., prepared according to the methods of WO2014/128189, page 8, compound D) was stirred at 120°C for 24 hours. The reaction mixture was diluted with water and the aqueous solution was extracted with EA. The organic layers were combined and washed with 1N. HCl, brine, dried over Na₂SO_four, concentrated and purified by preparative HPLC (mobile phase: 0.1% NH₃,H₂O/MeCN/H₂O) to give the title compound as a white solid.

LC-MS: [M+H] ⁺ = 447.3

¹ H NMR (400 MHz, MeOD) δ 7.23 (t, J =8.0 Hz, 1H), 7.02 (d, J =8.0 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.92 (t, J = 8.0 Hz, 1H), 4.41–4.34 (m, 1H), 3.92 (s, 3H), 3.83 ( s, 2H), 2.93 (t, J = 7.2 Hz, 2H), 2.49 (t, J = 6.8 Hz, 2H), 2.25 (t, J = 7.2 Hz, 2H), 1.96 (s, 3H), 1.76–0.90 (m, 8H), 0.81 (t, J = 7.6 Hz, 3H).

Example 39: 5–(5–((2 H -tetrazol-5-yl)methyl)-2-methoxybenzyl)-6-methyl- N ^four –(pentan–2–yl)pyrimidine–2,4–diamine (Compound 39)

The title compound was prepared according to the procedures described in Example 3, but using pentane-2-amine instead of butane-1-amine in Step 5.

LC-MS: [M+H] ⁺ = 397.4

^oneH NMR (400 MHz, CDCl₃)δ 7.26 (d,J= 8.4 Hz, 1H), 6.92 (s, 1H), 6.85 (d,J= 8.4 Hz, 1H), 6.49 (d,J =6.8 Hz, 1H), 4.26 (s, 2H), 4.20-4.18 (m, 1H), 3.92 (s, 3H), 3.58 (s, 2H), 2 .59 (s, 3H), 1.48–1.46 (m, 2H), 1.40–1.38 (m, 2H), 1.08 (d,J=6.4 Hz, 3H), 0.85 (t,J=7.2 Hz, 3H).

Example 40: 3–(5–(5–((2 H -tetrazol-5-yl)methyl)-2-methoxybenzyl)-2-amino-6-(butylamino)pyrimidin-4-yl)propanoic acid (Compound 40)

Stage 1: (4-methoxy-3-methylphenyl)methanol

To a stirred solution of methyl 4-methoxy-3-methylbenzoate (1.0 equiv.) in THF (0.6 M) was added LiAlH_four(1.2 equiv.) portions at 4°C in nitrogen. The resulting mixture was heated to room temperature for 2 hours. The mixture was quenched with an aqueous solution of Na₂SO_four. The solution was filtered and the filtrate was concentrated to give the title compound as a colorless oil.

Step 2: 4-(chloromethyl)-1-methoxy-2-methylbenzene

To a stirred solution of (4-methoxy-3-methylphenyl)methanol (1.0 eq.) in DCM (1.4 M) was added SOCl ₂ (1.5 eq.) at room temperature in N ₂ . The mixture was stirred at room temperature for 1 hour and then concentrated. The residue was separated in DCM and saturated aqueous NaHCO ₃ . The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound.

Stage 3: 2-(4-methoxy-3-methylphenyl)acetonitrile

A mixture of 4-(chloromethyl)-1-methoxy-2-methylbenzene (1.0 eq.) in 1:1 DMSO/DMF (0.9 M) and NaCN (2.0 eq.) was stirred for 16 hours at room temperature. The mixture was separated in EA and water. The organic layer was dried over Na ₂ SO ₄ , filtered, concentrated and purified by flash chromatography on silica (eluent PE/EA=100:1~20:1) to give the title compound.

Step 4: 2-(3-(bromomethyl)-4-methoxyphenyl)acetonitrile

To a solution of 2-(4-methoxy-3-methylphenyl)acetonitrile (1.0 eq.) in CCl ₄ (0.35 M) was added NBS (1.2 eq.) and AIBN (2.0 g, 13 mmol, 0.1 equiv.). The resulting mixture was refluxed for 1 h. The mixture was then filtered and the filtrate concentrated under reduced pressure to give a crude product which was purified by flash chromatography on silica (eluent: PE/EA=40:1 to 4:1) with yielding the title compound as a yellow solid.

Stage 5: diethyl 2-(5-(cyanomethyl)-2-methoxybenzyl)-3-oxohexanedioate

To a solution of 2-(3-(bromomethyl)-4-methoxyphenyl)acetonitrile (1.0 eq.) in anhydrous THF (0.73 M) at 0°C was added portionwise 60% NaH (1.2 eq.). After stirring for 10 min, a solution of diethyl 3-oxohexanedioate (1.1 eq., Example 27 - Step 1) in THF (2.4 M) was added dropwise to the above mixture over 10 min. The resulting mixture was warmed to room temperature and stirred for 20 hours. The reaction was quenched with water. The mixture was extracted with EtOAc, dried over Na ₂ SO ₄ , concentrated under reduced pressure. The residue was purified by flash chromatography on silica (eluent: PE/EA=50:1 to 10:1) to give the title compound as a yellow oil.

Stage 6: 3-(2-amino-5-(5-(cyanomethyl)-2-methoxybenzyl)-6-hydroxypyrimidin-4-yl)propanoic acid

A mixture of diethyl 2-(5-(cyanomethyl)-2-methoxybenzyl)-3-oxohexanedioate (1.0 eq.) in MeOH (0.3 M) and guanidine carbonate (1.5 eq.) was stirred at 70°C for 16 hours The solvent was removed and the residue was diluted with water and acidified by adding 1N. HCl to pH 5. The resulting precipitate was filtered and dried to give the title compound as a white solid.

Step 7: 3-(2-amino-6-chloro-5-(5-(cyanomethyl)-2-methoxybenzyl)pyrimidin-4-yl)propanoic acid

A mixture of 3-(2-amino-5-(5-(cyanomethyl)-2-methoxybenzyl)-6-hydroxypyrimidin-4-yl)propanoic acid (1.0 eq.) in POCl ₃ (1.9 M) was stirred at 100°C for 3 hours, the Reaction mixture was cooled to room temperature and POCl ₃ was evaporated under reduced pressure. The residue was diluted with water. The pH was adjusted to 7 with solid NaHCO ₃ . The precipitate was collected by filtration, washed with water, and dried in vacuo to give the title compound as a greenish solid.

Step 8: 3-(2-amino-6-(butylamino)-5-(5-(cyanomethyl)-2-methoxybenzyl)pyrimidin-4-yl)propanoic acid

A mixture of 3-(2-amino-6-chloro-5-(5-(cyanomethyl)-2-methoxybenzyl)pyrimidin-4-yl)propanoic acid (1.0 eq.) in EtOH (0.3 M), butane –1-amine (4 equiv.) and DIEA (5 equiv.) were stirred at 85°C for 48 h. The solvent was removed and the residue was purified by flash column chromatography (eluent: DCM/MeOH=40:1) to obtain the title compound as a pale solid.

Stage 9: 3–(5–(5–((2 H -tetrazol-5-yl)methyl)-2-methoxybenzyl)-2-amino-6-(butylamino)pyrimidin-4-yl)propanoic acid

A mixture of 3-(2-amino-6-(butylamino)-5-(5-(cyanomethyl)-2-methoxybenzyl)pyrimidin-4-yl)propanoic acid (1.0 eq.) in dioxane (0.1 M) , TMSN ₃ (5 eq) and Bu ₂ SnO (2.0 eq) were heated in a sealed tube at 70° C. for 3 h. The mixture was concentrated under reduced pressure and the crude product was purified by preparative HPLC (mobile phase: 0.1% NH _3, H ₂ O in CH ₃ CN) to give the title compound as a solid.

LC-MS: [M+H] ⁺ = 441.2

^oneH NMR (400 MHz, CDCl₃)δ 7.46 (s, 1H), 7.24 (d,J= 8.4 Hz, 1H), 6.84 (d,J=8.4 Hz, 1H), 5.78 (br s, 1H), 4.17 (s, 2H), 3.90 (s, 3H), 3.70 (s, 2H), 3.36– 3.31 (m, 2H), 3.17 (t,J=6.0 Hz, 2H), 2.77 (t,J=6.0 Hz, 2H), 1.41–1.38 (m, 2H), 1.18–1.13 (m, 2H), 0.84 (t,J=6.8 Hz, 3H).

Example 41: ( S )–3–((2–amino–5–(2–methoxybenzyl)–6–methylpyrimidin–4–yl)amino)heptanoic acid (Compound 41)

Stage 1: ethyl 2-(2-methoxybenzyl)-3-oxobutanoate

To a solution of 1-(bromomethyl)-2-methoxybenzene (1.2 equiv.) in THF (0.6 M) at 0°C was added portionwise 60% NaH (1.25 equiv.) in N ₂ . The resulting suspension was stirred at 0°C for 10 minutes, then a solution of ethyl 3-oxobutanoate (1.0 eq.) in THF (5 M) was added dropwise over 10 minutes. The resulting mixture was stirred for 15 hours at 70 ^° C. The mixture was cooled to room temperature and ice water was added. The mixture was extracted with ethyl acetate. The organic layer was dried over Na ₂ SO ₄ , concentrated and purified by silica gel column chromatography (eluent PE/EA=50:1~5:1) to give the title compound as a yellow oil.

Stage 2: 2-amino-5-(2-methoxybenzyl)-6-methylpyrimidin-4-ol

To a solution of ethyl 2–(2–methoxybenzyl)–3–oxobutanoate (1.0 eq.) in MeOH (0.9 M) was added guanidine carbonate (1.0 eq.). The resulting mixture was stirred overnight at 65^oC. The mixture was concentrated to dryness. The residue was suspended in EtOAc and then filtered. The filtration residue was washed with water and EtOAc and then dried in vacuo to give the title compound as a white solid.

Stage 3: 4-chloro-5-(2-methoxybenzyl)-6-methylpyrimidine-2-amine

A suspension of 2-amino-5-(2-methoxybenzyl)-6-methylpyrimidin-4-ol (1.0 eq.) in POCl ₃ (1 M) was stirred at 100°C for 24 h. The mixture was cooled to room temperature and POCl ₃ was evaporated to dryness under reduced pressure. The residue was diluted with water and the pH was adjusted to 7 using solid NaHCO ₃ . The precipitate was collected by filtration, washed with water and EtOAc and dried in vacuo to give the title compound.

Stage 4: tert –butyl ( S )–3–((2–amino–5–(2–methoxybenzyl)–6–methylpyrimidin–4–yl)amino)heptanoate

A mixture of 4-chloro-5-(2-methoxybenzyl)-6-methylpyrimidine-2-amine (1.0 eq.) in NMP (1.3 M) andtert–butyl (S)-3-aminoheptanoate (4.5 equiv., Example 20B - Stage 3) was stirred at 120°C for 3 h. The mixture was separated in water and EtOAc. The organic layer was washed with brine, dried over Na₂SO_four, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: DCM/MeOH=100:1 to 30:1) to give the title compound as a yellow solid.

Stage 5: ( S )–3–((2–amino–5–(2–methoxybenzyl)–6–methylpyrimidin–4–yl)amino)heptanoic acid

Mixturetert–butyl (S)–3–((2–amino–5–(2–methoxybenzyl)–6–methylpyrimidin–4–yl)amino)heptanoate (1.0 eq.) in 1:1 EtOH/H₂O (0.1 M) and NaOH (10.0 equiv.) were heated at 100°C for 2 hours, the Reaction mixture was cooled to room temperature, and the solvent was removed. The residue was diluted with H₂O and acidified using 1 N. HCl to pH 2. The resulting suspension was extracted with DCM. The combined organic layers were dried and concentrated. The crude product was purified by preparative TLC (CHCl₃:MeOH=10:1) to give an oil which was dissolved in 1:1 CH₃CN/H₂O and added 4 n. HCl/dioxane. The solution was lyophilized to give the title compound as a white solid.

LC-MS: [M+H] ⁺ = 373.2

^oneH NMR (400 MHz, DMSO–d ₆) δ 12.20 (w, 1H), 7.20–7.17 (m, 1H), 6.99 (d,J=8.4 Hz, 1H), 6.82-6.79(m, 2H), 6.68(br, 2H), 4.53-4.50(m, 1H), 3.85(s, 3H), 3.66 (s, 2H), 2.50–2.37 (m, 2H), 2.07 (s, 3H), 1.51–1.38 (m, 2H), 1.24 –0.98 (m, 4H), 0.77 (t,J=6.8 Hz, 3H).

Example 42: ( S )–3–((2–amino–5–(5–(2–carboxypropan–2–yl)–2–methoxybenzyl)–6–methylpyrimidin–4–yl)amino)heptanoic acid (Compound 42)

Stage 1: tert –butyl ( S )–3–((2–amino–5–(5–(2–cyanopropan–2–yl)–2–methoxybenzyl)–6–methylpyrimidin–4–yl)amino)heptanoate

2-(3-((2-amino-4-chloro-6-methylpyrimidin-5-yl)methyl)-4-methoxyphenyl)-2-methyl-propanenitrile mixture (1.0 eq., Example 9 - Step 8) in NMP (0.9 M) and tert -butyl ( S )-3-aminoheptanoate (1.3 eq., Example 20B - Stage 3) was stirred at 120°C for 16 hours in nitrogen. The reaction mixture was diluted with water. The aqueous phase was extracted with EA. The combined organic layer was washed with water then brine. The organic layer was separated and dried over Na ₂ SO ₄ , concentrated and purified by flash chromatography on silica (eluent DCM/MeOH=50:1) to give the title compound as a yellow solid.

Stage 2: ( S )–3–((2–amino–5–(5–(2–carboxypropan–2–yl)–2–methoxybenzyl)–6–methylpyrimidin–4–yl)amino)heptanoic acid

To the mixturetert–butyl (S)–3–((2–amino–5–(5–(2–cyanopropan–2–yl)–2–methoxybenzyl)–6–methyl–pyrimidin–4–yl)amino)heptanoate (1.0 eq.) in 1:1 ethylene glycol/H₂O (0.1 M) was added NaOH (10.0 equiv.) and stirred at 150°C for 16 h. The mixture was neutralized by adding 1N. HCl. The resulting suspension was filtered. The filter residue was washed with water and purified by preparative HPLC (mobile phase: 0.1% HCOOH/MeCN/H₂O) to give the title compound as a white solid.

LC-MS: [M+H] ⁺ = 459.3

¹ H NMR (400 MHz, DMSO– d ₆ ) δ 7.19 (br, 1H), 7.18 (dd, J = 8.4, 2.4 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 2.0 Hz, 1H), 4.58–4.56 (m, 1H), 3.83 (s, 3H), 3.79 ( s, 2H), 2.48–2.42 (m, 2H) 2.13 (s, 3H), 1.52–1.50 (m, 2H), 1.38 (s, 3H), 1, 35 (s, 3H), 1.25–1.18 (m, 2H), 1.24–1.07 (m, 2H), 0.91 (t, J =7.2 Hz, 3H).

Example 43: 2-(3-((2-amino-4-(butylamino)-6-(2-carboxyethyl)pyrimidin-5-yl)methyl)-4-methoxy-phenyl)-2-methylpropanoic acid (Compound 43 )

Stage 1: diethyl 2-(5-(2-cyanopropan-2-yl)-2-methoxybenzyl)-3-oxohexanedioate

To a solution of 2–(3–(bromomethyl)–4–methoxyphenyl)–2–methylpropanenitrile (1.1 equiv., Example 9 - Step 5) in THF (0.3 M) NaH was added in portions (1.2 equiv.) at 0°C in nitrogen. The mixture was stirred at 0°C for 10 minutes. Diethyl 3-oxohexanedioate solution (1.0 eq., Example 27 - Step 1) in THF (0.75 M) was added to the above solution and the reaction mixture was stirred at 60° C. for 16 hours. The reaction mixture was quenched with water. The aqueous solution was extracted with EA. The combined organic layers were washed with water, brine, dried over Na₂SO_four, and concentrated. The crude product was purified by column chromatography (PE/EA=10:1) to give the title compound as a yellow oil.

Step 2: 3-(2-amino-5-(5-(2-cyanopropan-2-yl)-2-methoxybenzyl)-6-hydroxypyrimidin-4-yl)propanoic acid

To a solution of diethyl 2–(5–(2–cyanopropan–2–yl)–2–methoxybenzyl)–3–oxohexanedioate (1.0 eq.) in MeOH (0.7 M) was added guanidine carbonate (1.0 eq.). The reaction was heated at 65°C for 16 hours under nitrogen. After cooling, the reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography (DCM/MeOH=5:1) to give the title compound as a white solid.

Step 3: 3-(2-amino-6-chloro-5-(5-(2-cyanopropan-2-yl)-2-methoxybenzyl)pyrimidin-4-yl)propanoic acid

Solution of 3-(2-amino-5-(5-(2-cyanopropan-2-yl)-2-methoxybenzyl)-6-hydroxypyrimidin-4-yl)propanoic acid (1.0 eq.) in POCl₃ (0.3 M) was stirred at 100°C for 16 hours in nitrogen. After cooling, the mixture was concentrated and poured into water. The pH value was adjusted to 8 by adding NaHCO₃. The aqueous phase was extracted with EA. The combined organic layers were dried over Na₂SO_four, concentrated and purified by column chromatography (DCM/MeOH=10:1) to give the title compound as a brown solid.

Stage 4: 3-(2-amino-6-(butylamino)-5-(5-(2-cyanopropan-2-yl)-2-methoxybenzyl)pyrimidin-4-yl)propanoic acid

A solution of 3-(2-amino-6-chloro-5-(5-(2-cyanopropan-2-yl)-2-methoxybenzyl)pyrimidin-4-yl)propanoic acid (1.0 eq.) in undiluted butane- 1-amine (0.15 M) was stirred at 120°C for 3 h under nitrogen. The reaction mixture was purified by column chromatography (DCM/MeOH=10:1) to give the title compound as a brown oil.

Stage 5: 2-(3-((2-amino-4-(butylamino)-6-(2-carboxyethyl)pyrimidin-5-yl)methyl)-4-methoxyphenyl)-2-methylpropanoic acid

To a solution of 3-(2-amino-6-(butylamino)-5-(5-(2-cyanopropan-2-yl)-2-methoxybenzyl)pyrimidin-4-yl)propanoic acid (1.0 eq.) in 1:1 ethylene glycol/H₂O (0.07 M) KOH (20 eq.) was added. The mixture was stirred at 150° C. for 16 hours. After cooling, the pH was adjusted to 6 by adding 4 N. HCl. The mixture was extracted with EA. The organic layer was washed with brine, dried over Na₂SO_four, concentrated. The crude product was purified by preparative HPLC (mobile phase: NH_fourHCO₃/MeCN/H₂O) to give the title compound as a white solid.

LC-MS: [M+H] ⁺ = 445.3

¹ H NMR (400 MHz, CD ₃ OD) δ 7.27 (dd, J =8.4, 2.4Hz, 1H), 6.95 (d, J =8.4Hz, 1H), 6.93 ( s, 1H), 3.89 (s, 3H), 3.78 (s, 2H), 3.45 (t, J= 7.0 Hz, 2H), 2.84 (t, J= 6.0 Hz, 2H), 2.42 (t, J =6.4 Hz, 2H), 1.54–1.47 (m, 2H), 1.45 (s, 6H), 1.26–1.21 (m, 2H), 0.88 (t, J =7.2 Hz, 3H).

Example 44: ( S )-3-((2-amino-5-(2-methoxy-5-((3-phosphonopropyl)carbamoyl)benzyl)-6-methyl-pyrimidin-4-yl)amino)heptanoic acid (Compound 44)

Stage 1: methyl ( S )–3–((2–amino–4–((1–( tert -butoxy)-1-oxoheptan-3-yl)amino)-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzoate

A mixture of methyl 3-((2-amino-4-chloro-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzoate (1.0 eq., Example 3B - Step 4) in NMP (2 M) and t- butyl ( S )-3-aminoheptanoate (2.0 eq., Example 20B - Step 3) was stirred at 120° C. for 16 hours under nitrogen. The reaction solution was diluted with water and extracted with EA. The organic layer was washed with water, brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (DCM/MeOH=50:1) to give the title compound as a yellow solid.

Stage 2: ( S )–3–((2–amino–4–((1–( tert -butoxy)-1-oxoheptan-3-yl)amino)-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzoic acid

Methyl mixture (S)–3–((2–amino–4–((1–(tert-butoxy)-1-oxoheptan-3-yl)amino)-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzoate (1.0 eq.) in 1:1 ethanol/H₂O (0.1 M) and NaOH (10.0 equiv.) were stirred at 30°C for 4 hours. The mixture was neutralized by adding 1N. HCl to pH 7. The resulting suspension was filtered. The filtration residue was washed with water to give the title compound.

Stage 3: tert –butyl ( S )–3–((2–amino–5–(5–((3–(diethoxyphosphoryl)propyl)carbamoyl)–2–methoxybenzyl)–6–methylpyrimidin–4–yl)amino)heptanoate

Blend (S)–3–((2–amino–4–((1–(tert-butoxy)-1-oxoheptan-3-yl)amino)-6-methylpyrimidin-5-yl)methyl)-4-methoxybenzoic acid (1.0 eq.) in DMF (0.1 M), diethyl (3-aminopropyl)phosphonate (2.0 eq., Example 30 - Stage 2), HATU (2.0 eq.) and DIEA (3.0 eq.) were stirred at 50°C for 16 h. The mixture was cooled to room temperature and water was added. The mixture was extracted with DCM. The combined organic phase was dried over Na₂SO_four, and concentrated under reduced pressure to give the title compound as a colorless oil.

Stage 4: ( S )–3–((2–amino–5–(2–methoxy–5–((3–phosphonopropyl)carbamoyl)benzyl)–6–methyl–pyrimidin–4–yl)amino)heptanoic acid

To solutiontert–butyl (S)-3-((2-amino-5-(5-((3-(diethoxyphosphoryl)propyl)carbamoyl)-2-methoxy-benzyl)-6-methylpyrimidin-4-yl)amino)heptanoate (1.0 equiv.) in DCM (0.08 M) was added TSMBr (10.0 equiv.) and stirred at 35°C for 16 hours in N_2.The mixture was concentrated and the residue was purified by trituration and preparative HPLC (mobile phase CH₃CN/H₂O/NH₃H₂O) to obtain the connection specified in the header.

LC-MS: [M+H] ⁺ = 538.3

^oneH NMR (400 MHz, DMSO)δ 8.69 (w, 1H), 7.72 (d,J= 8.8 Hz, 1H), 7.50 (s, 1H), 7.01 (d,J= 8.4 Hz, 1H), 6.63(br, 1H), 4.47–4.45 (m, 1H), 3.85 (s, 3H), 3.27–3.25 (m, 4H), 2.4 (d,J=6.0 Hz, 2H), 2.13 (s, 3H), 1.72-1.68 (m, 2H), 1.46-1.26 (m, 4H), 1.12-0, 96 (m, 2H), 0.96–0.94 (m, 2H), 0.70 (t,J=7.2 Hz, 3H).

Example 45: ( S )–3–((2–amino–6–(2–carboxyethyl)–5–(5–(2–carboxypropan–2–yl)–2–methoxy–benzyl)pyrimidin–4–yl)amino)heptanoic acid ( Compound 45)

Stage 1: ( S )–3–(2–amino–6–((1–( tert -butoxy)-1-oxoheptan-3-yl)amino)-5-(5-(2-cyanopropan-2-yl)-2-methoxybenzyl)pyrimidin-4-yl)propanoic acid

To a solution of 3-(2-amino-6-chloro-5-(5-(2-cyanopropan-2-yl)-2-methoxybenzyl)pyrimidin-4-yl)propanoic acid (1.0 eq., Example 43 - Stage 3) in NMP (0.15 M) was addedtert–butyl (S)-3-aminoheptanoate (5.0 eq., Example 20B - Step 3) and K₂CO₃ (3.0 equiv.). The mixture was stirred at 150° C. for 16 hours. The reaction solution was diluted with water/EA and concentrated to give the title compound as a crude oil.

Stage 2: ( S )–3–((2–amino–6–(2–carboxyethyl)–5–(5–(2–carboxypropan–2–yl)–2–methoxybenzyl)–pyrimidin–4–yl)amino)heptanoic acid

to solution (S)–3–(2–amino–6–((1–(tert-butoxy)-1-oxoheptan-3-yl)amino)-5-(5-(2-cyanopropan-2-yl)-2-methoxybenzyl)pyrimidin-4-yl)propanoic acid (crude) in 1:1 ethylene glycol/H₂O was added an excess of KOH and stirred at 150°C for 16 hours After cooling, the reaction mixture was diluted with water/EA. The pH was adjusted to 6 by adding 4N. HCl, then extracted with 3:1 CHCl₃/IPA. The combined organic layer was washed with brine, dried over Na₂SO_four, and concentrated. The crude product was purified by preparative HPLC (mobile phase: NH_fourOH/MeCN/H₂O) to give the title compound as a white solid.

LC-MS: [M+H] ⁺ = 517.3

¹ H NMR (400 MHz, CD ₃ OD) δ 7.27 (dd, J = 8.0, 2.4 Hz, 1H), 7.00–6.95 (m, 2H), 4.,61–4 .57 (m, 1H), 3.90 (s, 3H), 3.80 (s, 2H), 2.94–2.87 (m, 2H), 2.50–2.38 (m, 4H ), 1.56–1.53 (m, 1H), 1.48 (s, 3H), 1.45 (s, 3H), 1.46–1.44 (m, 1H), 1.27– 1.17 (m, 2H), 1.08–1.03 (m, 2H), 0.79 (t, J =7.4 Hz, 3H).

Example 46: ( S )–3–((5–(5–((2 H -tetrazol-5-yl)methyl)-2-methoxybenzyl)-2-amino-6-(2-carboxyethyl)-pyrimidin-4-yl)amino)heptanoic acid (Compound 46)

Stage 1: tert –butyl ( S )–3–(3–(2–amino–6–((( S )-one-( tert -butoxy)-1-oxoheptan-3-yl)amino)-5-(5-(cyanomethyl)-2-methoxybenzyl)pyrimidin-4-yl)propanamido)heptanoate

A mixture of 3-(2-amino-6-chloro-5-(5-(cyanomethyl)-2-methoxybenzyl)pyrimidin-4-yl)propanoic acid (1.0 eq., Example 40 - Step 7) andtert–butyl (S)-3-aminoheptanoate (3 eq., Example 20B - Step 3) was stirred at 140° C. for 3 hours. The crude product was used directly in the next step.

Stage 2: tert –butyl ( S )–3–(3–(5–(5–((2 H -tetrazol-5-yl)methyl)-2-methoxybenzyl)-2-amino-6-((( S )-one-( tert -butoxy)-1-oxoheptan-3-yl)amino)pyrimidin-4-yl)propanamido)heptanoate

A mixture of tert -butyl ( S )-3-(3-(2-amino-6-((( S )-1-( tert -butoxy)-1-oxoheptan-3-yl)amino)-5-(5- (cyanomethyl)-2-methoxybenzyl)pyrimidin-4-yl)propanamido)heptanoate (1.0 eq.) in dioxane (0.2 M), TMSN ₃ (3 eq.) and Bu ₂ SnO (2.0 eq. ) was heated at 110° C. in a sealed tube for 6 h. The mixture was diluted with EA and washed with water. The organic layer was dried, concentrated, and the residue was purified by column chromatography (DCM:MeOH=100:1~10:1) to give the title compound as a light brown solid.

Stage 3: ( S )–3–((5–(5–((2 H -tetrazol-5-yl)methyl)-2-methoxybenzyl)-2-amino-6-(2-carboxyethyl)-pyrimidin-4-yl)amino)heptanoic acid

To a solution of tert -butyl ( S )–3–(3–(5–(5–((2 H –tetrazol–5–yl)methyl)–2–methoxybenzyl)–2–amino–6–((( S ) -1-( tert -butoxy)-1-oxoheptan-3-yl)amino)pyrimidin-4-yl)propanamido)heptanoate (1.0 eq.) in ethane-1,2-diol (0.1 M) was added 10M aqueous KOH (44 eq.) and heated at 150°C for 5 days. The solid was filtered off and the filtrate was concentrated and purified by preparative HPLC (mobile phase: 0.1% NH ₃ ,H ₂ O, CH ₃ CN) to give the title compound as a white solid.

LC-MS: [M+H] ⁺ = 513.2

^oneH NMR (400 MHz, MeOD)δ 7.09 (dd,J=8.4, 2.0 Hz, 1H), 6.95 (s, 1H), 6.89 (d,J= 8.4 Hz, 1H), 4.51-4.49 (m, 1H), 4.04 (s, 2H), 3.87 (s, 3H), 3.77 (s, 2H), 2 .92–2.85 (m, 2H), 2.52–2.21 (m, 4H), 1.5–0.9 (m, 6H), 0.73 (t,J=7.6 Hz, 3H).

Example 47: 3-(2-amino-6-(butylamino)-5-(2-methoxybenzyl)pyrimidin-4-yl)propan-1-ol (Compound 47)

Step 1: 3-(2-amino-6-chloro-5-(2-methoxybenzyl)pyrimidin-4-yl)propan-1-ol

To a solution of 3-(2-amino-6-chloro-5-(2-methoxybenzyl)pyrimidin-4-yl)propanoic acid (1.0 eq., Example 27 - Step 4) in THF (0.16 M) was added LAH (3.0 equiv.). The reaction solution was stirred at room temperature for 2 hours and then quenched with water. The aqueous layer was extracted with DCM. The combined organic layers were washed with water, brine, dried over Na₂SO_four and concentrated to give the title compound as a pale solid.

Step 2: 3-(2-amino-6-(butylamino)-5-(2-methoxybenzyl)pyrimidin-4-yl)propan-1-ol

A solution of 3-(2-amino-6-chloro-5-(2-methoxybenzyl)pyrimidin-4-yl)propan-1-ol (1.0 eq.) in EtOH (0.2 M), butan-1- amine (4.0 eq.) and DIEA (5 eq.) were stirred at 85°C for 3 days. The reaction solution was concentrated, diluted with 1 N. HCl and extracted with DCM. The combined organic layers were washed with brine, dried over Na₂SO_four, concentrated, and purified by flash column chromatography (eluent: DCM/MeOH=100:1~20:1) to give the title compound as a pale solid.

LC-MS: [M+H] ⁺ = 345.4

^oneH NMR (400 MHz, DMSO)δ 7.80 (w, 1H), 7.40 (w, 2H), 7.22 (t,J= 8.0 Hz, 1H), 7.01 (d,J= 8.4 Hz, 1H), 6.84 (t,J= 7.6 Hz, 1H), 6.78 (d,J= 8.4 Hz, 1H), 3.85 (s, 3H), 3.72 (s, 2H), 3.38-3.34 (m, 2H), 2.50-2.44 (m, 2H), 1.61–1.54 (m, 2H), 1.50–1.42 (m, 2H), 1.34–1.15 (m, 4H), 0.84(t,J=7.6 Hz, 3H).

Example 48: ( S )–3–(5–(5–((2 H -tetrazol-5-yl)methyl)-2-methoxybenzyl)-2-amino-6-((1-(methylthio)-heptan-3-yl)amino)pyrimidin-4-yl)propanoic acid (Compound 48)

Stage 1: 3–(2–amino–5–(5–(cyanomethyl)–2–methoxybenzyl)–6–((( S )–1–(methylthio)heptan–3–yl)amino)–pyrimidin–4–yl)– N –(( S )–1–(methylthio)heptan–3–yl)propanamide

A solution of 3-(2-amino-6-chloro-5-(5-(cyanomethyl)-2-methoxybenzyl)pyrimidin-4-yl)propanoic acid (1.0 eq., Example 40 - Step 7) in EtOH (0 ,4 M) and (S)–1–(methylthio)heptane–3–amine (2.3 eq.) was stirred at 90°C for 3 days. The solvent was removed, the residue was purified by column chromatography (eluent DCM:MeOH=20:1) to give the title compound as a light brown oil.

Stage 2: 3–(5–(5–((2 H -tetrazol-5-yl)methyl)-2-methoxybenzyl)-2-amino-6-((( S )–1–(methylthio)heptan–3–yl)amino)pyrimidin–4–yl)– N –(( S )–1–(methylthio)heptan–3–yl)propanamide

A mixture of 3–(2–amino–5–(5–(cyanomethyl)–2–methoxybenzyl)–6–(((S)–1–(methylthio)heptan–3–yl)amino)–pyrimidin–4–yl)–N–((S)–1–(methylthio)heptan–3–yl)propanamide (1.0 eq.) in dioxane (0.04 M), TMSN₃ (3.8 equiv.) and Bu₂SnO (2.5 equiv.) was heated at 90°C for 6 hours in a sealed tube. The reaction solution was cooled and used directly in the next step without any purification.

Stage 3: ( S )–3–(5–(5–((2 H -tetrazol-5-yl)methyl)-2-methoxybenzyl)-2-amino-6-((1-(methylthio)heptan-3-yl)amino)pyrimidin-4-yl)propanoic acid

The crude product from the previous step was dissolved in ethane-1,2-diol and aqueous KOH (excess) was added. The reaction was heated at 150°C for 5 days. The solid was filtered and the filtrate was concentrated and purified by preparative HPLC (mobile phase: 0.1% TFA/CH ₃ CN/H ₂ O) to give the title compound as a white solid.

LC-MS: [M+H] ⁺ = 529.3

^oneH NMR (400 MHz, MeOD)δ 7.20 (d,J= 7.6 Hz, 1H), 7.01 (d,J=8.8 Hz, 1H), 6.93 (s, 1H), 4.43-4.40 (m, 1H), 4.19(s, 2H), 3.91 (s, 3H), 3 .83 (s, 2H), 2.92 (t,J= 6.8 Hz, 2H), 2.56 (t,J= 7.6 Hz, 2H), 2.24 (t,J=7.6 Hz, 2H), 1.93 (s, 3H), 1.78-1.75 (m, 1H), 1.67-1.63 (m, 1H), 1.51-1.49 (m, 1H), 1.41–1.39 (m, 1H), 1.26–1.19 (m, 2H), 1.10–1.04 (m, 2H), 0.80 (t ,J=7.6 Hz, 3H).

Example 49: ( S )–3–(5–(5–((2 H -tetrazol-5-yl)methyl)-2-methoxybenzyl)-2-amino-6-((1-methoxyheptan-3-yl)amino)pyrimidin-4-yl)propanoic acid (Compound 49)

The title compound was prepared according to the procedure described in Example 48, but using ( S )-1-methoxyheptan-3-amine instead of ( S )-1-(methylthio)heptan-3-amine in Step 1.

LC-MS: [M+H] ⁺ = 513.3

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.21 (d, J =8.4 Hz, 1H), 7.17 (s, 1H), 6.82 (d, J =8.4 Hz, 1H ), 6.14 (d, J = 8.0 Hz, 1H), 4.26–4.05 (m, 2H), 4.03 (d, J = 15.2 Hz, 1H), 3.88 (s, 3H), 3.74–3.61 (m, 2H), 3.33–3.25 (m, 2H), 3.17–3.05 (m, 2H), 3.04 (s , 3H), 2.72–2.68 (m, 1H), 2.53–2.48 (m, 1H), 1.81–1.76 (m, 1H), 1.55–1.50 (m, 1H), 1.41–1.15 (m, 4H), 1.03–0.95 (m, 2H), 0.78 (t, J =7.6 Hz, 3H).

Example 50: ( S )–3–(2–amino–5–(5–(carboxymethyl)–2–methoxybenzyl)–6–((1–(methylsulfonyl)heptan–3–yl)amino)pyrimidin–4–yl)propanoic acid (Compound fifty)

Stage 1: 3–(2–amino–5–(5–(cyanomethyl)–2–methoxybenzyl)–6–((( S )–1–(methylthio)heptan–3–yl)amino)–pyrimidin–4–yl)– N –(( S )–1–(methylthio)heptan–3–yl)propanamide

The title compound was prepared according to the procedure described in Example 48 - Step 1.

Stage 2: ( S )–3–(2–amino–5–(5–(carboxymethyl)–2–methoxybenzyl)–6–((1–(methylsulfonyl)heptan–3–yl)amino)pyrimidin–4–yl)propanoic acid

To a solution of KOH in 10% H2O in _nBuOH (10 M) was added 3–(2–amino–5–(5–(cyanomethyl)–2–methoxybenzyl)–6–((( S )–1–(methylthio)heptane -3-yl)amino)-pyrimidin-4-yl) -N -(( S )-1-(methylthio)heptan-3-yl)propanamide (1.0 eq.). The resulting mixture was heated in a sealed tube at 150° C. for 16 hours. The mixture was cooled to room temperature and filtered. Oxone (5.0 eq.) was added to the filtrate and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to 1/3 volume. The insoluble solid was filtered off and the filtrate was purified by preparative HPLC (mobile phase: 0.1% HCOOH/MeCN/H ₂ O) and lyophilized to give the title compound as a white solid.

LC-MS: [M+H] ⁺ = 537.4

Example 51: ( S )–2–(3–((2–amino–4–methyl–6–((1–(methylsulfonyl)heptan–3–yl)amino)pyrimidin–5–yl)methyl)–4–methoxyphenyl)acetic acid ( Compound 51)

Step 1: ( S )–2–(3–((2–amino–4–methyl–6–((1–(methylsulfonyl)heptan–3–yl)amino)pyrimidin–5–yl)methyl)–4– methoxyphenyl)acetonitrile

to solution (S)–2–(3–((2–amino–4–methyl–6–((1–(methylthio)heptan–3–yl)amino)pyrimidin–5–yl)methyl)–4–methoxyphenyl)acetonitrile (1 eq, Example 22 - Step 4) in 1:1:1 THF/MeOH/H₂O (0.2 M) was added oxone (1.2 eq.) in portions at room temperature. The reaction mixture was stirred at room temperature for 2 hours and then diluted with DCM. The organic layer was washed with water and brine, dried, and concentrated to give a light yellow solid which was used directly in the next step.

Step 2: ( S )–2–(3–((2–amino–4–methyl–6–((1–(methylsulfonyl)heptan–3–yl)amino)pyrimidin–5–yl)methyl)–4– methoxyphenyl)acetic acid

to solution (S)–2–(3–((2–amino–4–methyl–6–((1–(methylsulfonyl)heptan–3–yl)amino)pyrimidin–5–yl)methyl)–4–methoxyphenyl)acetonitrile (1.0 eq.) in 1:1 MeOH/H₂O (0.1 M) KOH (7.5 eq.) was added. The reaction mixture was stirred at 120° C. for 4 h. The solvent was removed and HCl was added to reach pH 9. The mixture was purified by preparative HPLC (0.1% NH₃.H₂O/CH₃CN) to give the title compound as a light yellow solid.

LCMS: [M+H] ⁺ = 479.3

¹ H NMR (400 MHz, CD ₃ OD) δ 7.16 (dd, J =8.4, 2.0 Hz, 1H), 6.98 (d, J =2.0 Hz, 1H), 6, 91 (d, J = 8.4 Hz, 1H), 4.30–4.22 (m, 1H), 3.89 (s, 3H), 3.77–3.68 (m, 2H), 3 .32 (s, 2H), 2.91–2.70 (m, 5H), 2.32 (s, 3H), 2.08–1.95 (m, 1H), 1.81–1.69 (m, 1H), 1.56–1.05 (m, 6H), 0.83 (t, J =7.2 Hz, 3H).

BIOLOGICAL EXAMPLES

Biological Example 1: HEK TLR7 Assay

HEK-Blue ^TM TLR7 cells were purchased from Invivogen (San Diego, CA). The following description has been taken from the product information sheet.

"HEK-Blue™ hTLR7 cells are designed to study human TLR7 (hTLR7) stimulation by monitoring NF-kB activation. HEK-Blue™ hTLR7 cells were generated by co-transfection of the hTLR7 gene and an optimized secreted embryonic alkaline phosphatase (SEAP) reporter gene into HEK293 cells. The SEAP reporter gene is under the control of a minimal IFN-b promoter fused to the five binding sites of NF-kB and AP-1 Stimulation with TLR7 ligand activates NF-kB and AP-1, which induce the production of SEAP, which is detected by the HEK- cell culture medium. Blue™ Detection".

A typical assay protocol included the following steps:

1. Cells were cultured according to the product information.

2. 10 mM parent compound in DMSO was first diluted to 3 mM and then serially diluted 3-fold using DMSO to give a 10-point dilution.

3. 3 µl of diluted DMSO was added to 57 µl of HEK-Blue™ detection medium for another 20-fold dilution.

4. 10 µl of diluted compound in assay medium was added to 40 µl of cell culture (in HEK-Blue™ detection medium) in a 384-well plate. Final cell concentration=8000 cells per well.

5. Plates were incubated at 37°C in 5% CO2 for 16 h. SEAP was determined using a spectrophotometer at 620–655 nm.

The HEK-TLR7 activity table below gives the results.

Example HEK–TLR7EC _fifty Example HEK–TLR7EC _fifty one C 31 C 2 C 32 A 3 B 33 A four C 34 A 5 C 35 A 6 C 36 B 7 C 37 B eight B 38 A 9 B 39 B ten B 40 B eleven B 41 B 12 B 42 B 13 B 43 C fourteen C 44 B fifteen B 45 C 16 B 46 B 17 A 47 B eighteen A 48 A 19 C 49 B twenty
(S-enantiomer) B fifty B 20C
(R-enantiomer) C 51 B 21 C 22 A 23 A 24 A 25 B 26 B 27 B 28 C 29 B thirty B

EC ₅₀ category:

A = ˂100 nM

B=100–1000 nM

C=1000–10000 nM

As discussed herein, R ^1A and R ^1B in formula (1) may form a chiral center. Compounds 20 and 20C differ in the carbon stereocenter bearing R ^1A and R ^1B .

twenty

20C

As shown above, the (S)-enantiomer (eg, Compound 20) is over 10 times more effective than the (R)-enantiomer (eg, Compound 20C) in the HEK-TLR7 assay. Other examples may follow the same trend.

Biological Example 2: Pharmacokinetic Experiments

BALB/c mice were orally dosed with 10 mg/kg of compound prepared in 0.5% carboxymethylcellulose + 0.5% Tween-80 suspension. Mice were bled retro-orbitally at various time points post-dose. Serum was obtained from blood by centrifugation followed by protein precipitation, reverse phase gradient elution, and detection of MRM by ESI+ mass spectrometry to determine compound concentration. Animals were sacrificed after the final blood sampling (5 hours), the liver was removed and quickly frozen in liquid nitrogen for tissue PK analysis. Liver:serum (L:S) concentration 5 hours post-dose is one parameter to identify compounds with potential hepatic accumulation.

The mouse liver:serum (P:S) concentration table below gives the results.

Example P:S at 5 o'clock 3 A 9 A ten B eleven A 12 B 13 B fifteen B 17 B eighteen A twenty A 22 A 23 A 24 B 29 A thirty A 32 A 33 A 34 A 40 A 41 B 42 A 43 A 44 B 45 A 46 B

P:S category:

A = >100 represents high liver enrichment

B=10–100 represents moderate liver enrichment

C=<10 represents low liver enrichment

EQUIVALENTS

While the present invention has been described in connection with the specific embodiments set forth above, many alternatives, modifications, and other variations thereof will be apparent to those skilled in the art. All such alternatives, modifications and variations are intended to be within the spirit and scope of the present invention.

Claims (120)

1. A compound having the structure of Formula (1), or a pharmaceutically acceptable salt thereof,

(one), where R ^1a is selected from the group consisting of H, C ₁ -C ₄ alkyl and A _, where alkyl is optionally substituted with –COOH, –SO ₂ CH ₃ , –SCH ₃ , –OCH ₃ ,

or A; R ^1b is C ₂ -C ₅ alkyl; X is C ₁ -C ₄ alkyl, where alkyl is optionally substituted with A or -OH; L ¹ is selected from the group consisting of bonds, -CH ₂ -, -O- and -CH ₂ CH ₂ -; Y is selected from the group consisting of C ₁ -C ₃ alkyl and C ₆ aryl, where C ₆ aryl is optionally substituted with 1-5 substituents independently selected from A, C ₁ -C ₃ alkyl and C ₁ -C ₃ alkoxy; A is selected from the group consisting of

,

,

,

,

and

; L ² is selected from the group consisting of a bond, –(CH ₂ ) _n –, –C(O)NH(CH ₂ ) _n –,

,

and

; m is an integer from zero to four; n is an integer from one to four; where the compound is substituted with at least one A; and, when X is -CH ₃ , L ¹ is -CH ₂ -, Y is C ₆ aryl substituted by A, and L ² is -CH ₂ - then A is not -L ² -COOH except when R ^1a contains -COOH or -SO ₂ CH ₃ ; and, when X is -CH ₃ , L ¹ is -CH ₂ -, Y is C ₆ aryl substituted with A, L ² is -CH ₂ - and A is

, then A and L ¹ are not in para-position with respect to each other. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that R ^1b is -(CH ₂ ) ₂ CH ₃ . 3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that R ^1b is -(CH ₂ ) ₃ CH ₃ . 4. The connection according to any one of paragraphs. 1-3, or a pharmaceutically acceptable salt thereof, characterized in that R ^1a is C ₁ -C ₄ alkyl optionally substituted with -OCH ₃ , -SCH ₃ or -SO ₂ CH ₃ . 5. Connection according to any one of paragraphs. 1-4, or a pharmaceutically acceptable salt thereof, characterized in that

represents

,

,

or

. 6. The connection according to any one of paragraphs. 1-4, or a pharmaceutically acceptable salt thereof, characterized in that R ^1a is C ₁ -C ₄ alkyl optionally substituted with -COOH. 7. Connection according to any one of paragraphs. 1-6, or a pharmaceutically acceptable salt thereof, characterized in that

represents

. 8. Connection according to any one of paragraphs. 1-3, or a pharmaceutically acceptable salt thereof, wherein R ^1a is H. 9. Connection according to any one of paragraphs. 1-8, or a pharmaceutically acceptable salt thereof, characterized in that X is C ₁ -C ₄ alkyl, where alkyl is substituted by A. 10. Connection according to any one of paragraphs. 1-9, or a pharmaceutically acceptable salt thereof, characterized in that X is C ₁ -C ₄ alkyl, where alkyl is substituted

, where L ² is a bond. 11. The connection according to any one of paragraphs. 1-8, or a pharmaceutically acceptable salt thereof, characterized in that X is CH ₃ . 12. Connection according to any one of paragraphs. 1-11, or a pharmaceutically acceptable salt thereof, characterized in that L ¹ is -CH ₂ -, -CH ₂ CH ₂ - or -O-. 13. Connection according to any one of paragraphs. 1-12, or a pharmaceutically acceptable salt thereof, characterized in that L ¹ is -CH ₂ -. 14. Connection according to any one of paragraphs. 1-13, or a pharmaceutically acceptable salt thereof, wherein Y is C ₁ -C ₃ alkyl or aryl. 15. Connection according to any one of paragraphs. 1-14, or a pharmaceutically acceptable salt thereof, characterized in that Y is aryl, where aryl is substituted with C ₁ -C ₃ alkoxy. 16. Connection according to any one of paragraphs. 1-14, or a pharmaceutically acceptable salt thereof, wherein Y is aryl, where aryl is substituted by A. 17. Connection according to any one of paragraphs. 1-16 or a pharmaceutically acceptable salt thereof, wherein A is

. 18. Connection according to any one of paragraphs. 1-16, or a pharmaceutically acceptable salt thereof, wherein A is

. 19. Connection according to any one of paragraphs. 1-16, or a pharmaceutically acceptable salt thereof, wherein A is

. 20. Connection according to any one of paragraphs. 1-16, or a pharmaceutically acceptable salt thereof, wherein A is

. 21. Connection according to any one of paragraphs. 1-16, or a pharmaceutically acceptable salt thereof, wherein A is

. 22. Connection according to any one of paragraphs. 1-16, or a pharmaceutically acceptable salt thereof, wherein A is

. 23. Connection according to any one of paragraphs. 1-22, or a pharmaceutically acceptable salt thereof, characterized in that L ² is –(CH ₂ ) _n –. 24. Connection according to any one of paragraphs. 1-23, or a pharmaceutically acceptable salt thereof, wherein n is one or two. 25. Connection according to any one of paragraphs. 1-22, or a pharmaceutically acceptable salt thereof, characterized in that L ² is

. 26. Connection according to any one of paragraphs. 1-22, or a pharmaceutically acceptable salt thereof, characterized in that L ² is

. 27. Connection according to any one of paragraphs. 1-22, or a pharmaceutically acceptable salt thereof, characterized in that L ² is -C(O)NH(CH ₂ ) _n -. 28. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that the compound of Formula (1) is a compound of Formula (1a)

, where X is CH ₃ ; L ¹ is selected from the group consisting of bond, -CH ₂ -, -O- and -CH ₂ CH ₂ -; A is selected from the group consisting of

,

,

,

,

and

; L ² is selected from the group consisting of a bond, -CH ₂ -, -CH ₂ CH ₂ -,

,

and –C(O)NH(CH ₂ ) _n –; and R ³ is H, C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy. 29. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that the compound of Formula (1) is a compound of Formula (1a)

, where X represents -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a or -CH ₂ C(CH ₃ ) ₂ -A ^1a ; A ^1a is selected from the group consisting of

,

,

,

,

or

; L ¹ is selected from the group consisting of bond, -CH ₂ -, -O- and -CH ₂ CH ₂ -; A is selected from the group consisting of

,

,

,

,

and

; L ² is selected from the group consisting of a bond, -CH ₂ -, -CH ₂ CH ₂ -,

,

and –C(O)NH(CH ₂ ) _n –; and R ³ is H, C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy. 30. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that the compound of Formula (1) is a compound of Formula (1b)

, where X is CH ₃ ; L ¹ is selected from the group consisting of bond, -CH ₂ -, -O- and -CH ₂ CH ₂ -; A is selected from the group consisting of

,

,

,

,

and

; L ² is selected from the group consisting of a bond, -CH ₂ -, -CH ₂ CH ₂ -,

,

and –C(O)NH(CH ₂ ) _n –; and R ³ is H, C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy. 31. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that the compound of Formula (1) is a compound of Formula (1b)

, where X represents -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a or -CH ₂ C(CH ₃ ) ₂ -A ^1a ; A ^1a is selected from the group consisting of

,

,

,

,

and

; L ¹ is selected from the group consisting of bond, -CH ₂ -, -O- and -CH ₂ CH ₂ -; A is selected from the group consisting of

,

,

,

,

and

; L ² is selected from the group consisting of a bond, -CH ₂ -, -CH ₂ CH ₂ -,

,

and –C(O)NH(CH ₂ ) _n –; and R ³ is H, C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy. 32. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that the compound of Formula (1) is a compound of Formula (1c)

, where X represents -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a or -CH ₂ C(CH ₃ ) ₂ -A ^1a ; A ^1a is selected from the group consisting of

,

,

,

,

and

; L ¹ is selected from the group consisting of bonds, -CH ₂ - and -CH ₂ CH ₂ -; R ³ is H, C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy; and R ⁴ is H or C ₁ -C ₃ alkoxy. 33. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that the compound of Formula (1) is a compound of Formula (1d)

, X is -CH ₂ -A ^1a , -CH ₂ CH ₂ -A ^1a , -CH ₂ CH ₂ CH ₂ -A ^1a or -CH ₂ C(CH ₃ ) ₂ -A ^1a ; A ^1a is selected from the group consisting of

,

,

,

,

and

; L ¹ is selected from the group consisting of bond, -CH ₂ -, -O- and -CH ₂ CH ₂ ; and Y is C ₁ -C ₃ alkyl. 34. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that the compound of Formula (1) is a compound of Formula (1e)

, where R ³ represents H, C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy. 35. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that the compound of Formula (1) is a compound of Formula (1f)

. 36. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that the compound of Formula (1) is a compound of Formula (1g)

, where R ³ represents H, C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy. 37. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that the compound of Formula (1) is a compound of Formula (1h)

, where R ⁴ represents H or C ₁ -C ₃ alkoxy. 38. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that the compound of Formula (1) is a compound of Formula (1i)

, where L ¹ is selected from the group consisting of communication, -CH ₂ -, -O- and -CH ₂ CH ₂ -; and Y is H or C ₁ -C ₃ alkyl. 39. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that the compound of Formula (1) is a compound of Formula (1j)

(1j). 40. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that the compound of Formula (1) is a compound of Formula (1k)

(1k). 41. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

Compound -X –L ¹ –Y

Compound one _–CH3

–(CH ₂ ) ₃ CH ₃

2 _–CH3

–(CH ₂ ) ₃ CH ₃

3 _–CH3

–(CH ₂ ) ₃ CH ₃

four _–CH3

–(CH ₂ ) ₃ CH ₃

5 _–CH3

–(CH ₂ ) ₃ CH ₃

6 _–CH3

–(CH ₂ ) ₃ CH ₃

7 _–CH3

–(CH ₂ ) ₃ CH ₃

9 _–CH3

–(CH ₂ ) ₃ CH ₃

ten _–CH3

–(CH ₂ ) ₃ CH ₃

eleven _–CH3

–(CH ₂ ) ₃ CH ₃

12 _–CH3

–(CH ₂ ) ₃ CH ₃

13 _–CH3

–(CH ₂ ) ₃ CH ₃

fourteen _–CH3

–(CH ₂ ) ₃ CH ₃

fifteen

–(CH ₂ ) ₃ CH ₃

16 _–CH3

–(CH ₂ ) ₃ CH ₃

17 _–CH3

–(CH ₂ ) ₃ CH ₃

19

–(CH ₂ ) ₃ CH ₃

twenty _–CH3

20C _–CH3

22 _–CH3

23 _–CH3

25 _–CH3

–(CH ₂ ) ₃ CH ₃

26 _–CH3

–(CH ₂ ) ₄ CH ₃

28 _–CH3

–(CH ₂ ) ₃ CH ₃

29

thirty _–CH3

–(CH ₂ ) ₃ CH ₃

31 _–CH3

–(CH ₂ ) ₃ CH ₃

32 _–CH3

33 _–CH3

34 _–CH3

35 _–CH3

36 _–CH3

37

–(CH ₂ ) ₃ CH ₃

38

39 _–CH3

40

–(CH ₂ ) ₃ CH ₃

41 _–CH3

42 _–CH3

43

–(CH ₂ ) ₃ CH ₃

44 _–CH3

45

46

47

–(CH ₂ ) ₃ CH ₃

48

49

fifty

51 _–CH3

42. Pharmaceutical composition for modulating the Toll-like TLR7 receptor, containing an effective amount of a compound according to any one of paragraphs. 1-41 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 43. A method of treating a condition associated with TLR7 modulation in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of paragraphs. 1-41 or a pharmaceutically acceptable salt thereof. 44. The method of claim 43, wherein the condition is a viral infection or cancer. 45. The method according to claim 43 or 44, characterized in that the administration is oral, intravenous, subcutaneous, intramuscular, intratumoral, intradermal, intranasal, inhalation, intravesical, local, sublingual, buccal, intrarectal, intrathecal, intracranial, or other forms of local delivery. 46. Connection according to any one of paragraphs. 1-41, or a pharmaceutically acceptable salt thereof, to modulate the Toll-like receptor TLR7. 47. Connection according to any one of paragraphs. 1-41, or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition associated with TLR7 modulation. 48. The compound according to claim 47, characterized in that the condition is a viral infection or cancer. 49. The use of a compound according to any one of paragraphs. 1-41 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a condition associated with TLR7 modulation. 50. Use according to claim 49, characterized in that the condition is a viral infection or cancer. 51. The pharmaceutical composition according to claim 42, additionally containing at least one or more additional therapeutic agents. 52. A pharmaceutical composition according to claim 51, characterized in that at least one or more additional therapeutic agents are an antiviral nucleoside. 53. A pharmaceutical composition according to claim 51, characterized in that at least one or more additional therapeutic agents are an anti-PD-1 antibody or an anti-PD-L1 antibody. 54. A method of treating HBV in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of paragraphs. 1-41 or a pharmaceutically acceptable salt thereof in combination with an antiviral nucleoside. 55. A method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of paragraphs. 1-41 or a pharmaceutically acceptable salt thereof in combination with an anti-PD-1 antibody or an anti-PD-L1 antibody.