Bicyclic compound

Abstract

Provided herein are compounds of formula (I) or pharma- ceutical acceptable salts thereof, pharmaceutical compositions comprising the compounds described herein (including pharma- ceutical acceptable salts of the compounds described herein), and methods of synthesizing the same.Also provided herein are methods of treating diseases and / or conditions, including hepatitis B virus (HBV) and hepatitis D virus (HDV) infections, with compounds of formula (I) or pharma- ceutical acceptable salts thereof.

Description

[Technical field]

[0001] (Incorporation by reference of any priority application) For example, any and all applications that identify a claim of foreign or domestic priority in an Application Data Sheet or claim submitted with this application, including U.S. Provisional Patent Application No. 63 / 363,296, filed April 20, 2022, and U.S. Provisional Patent Application No. 63 / 484,135, filed February 9, 2023, are incorporated by reference herein under 37 CFR 1.57 and Rules 4.18 and 20.6.

[0002] (Description of the sequence) This application contains a Sequence Listing that has been submitted electronically and is incorporated herein by reference in its entirety. The Sequence Listing was created on April 18, 2023, is named ALIG_084.xml, and is 12kb in size.

[0003] FIELD OF THEINVENTION This application relates to the fields of chemistry, biochemistry, and medicine. Disclosed herein are compounds of formula (I) or pharma- ceutically acceptable salts thereof, pharmaceutical compositions comprising the compounds described herein (including pharma- ceutically acceptable salts of the compounds described herein), and methods of synthesizing them. Also disclosed herein are methods of treating diseases and / or conditions with compounds of formula (I) or pharma- ceutically acceptable salts thereof. [Background technology]

[0004] Hepatitis B virus (HBV) is a DNA virus and a member of the family Hepadnaviridae. HBV infects over 300 million people worldwide and is the causative agent of chronic hepatitis, cirrhosis, and liver cancer and liver diseases, such as hepatocellular carcinoma. Although approved drugs exist to treat HBV by either boosting the immune system or slowing HBV viral replication, HBV remains problematic due to drawbacks associated with each of the approved drugs. Summary of the Invention [Means for solving the problem]

[0005] Some embodiments disclosed herein relate to a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0006] Some embodiments disclosed herein relate to pharmaceutical compositions that can contain an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0007] Some embodiments described herein relate to methods of treating HBV and / or HDV infection, which may include administering to a subject identified as suffering from HBV and / or HDV infection an effective amount of a compound described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharma- ceutically acceptable salt thereof. Other embodiments described herein relate to a compound described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharma- ceutically acceptable salt thereof, for use in treating HBV and / or HDV infection.

[0008] Some embodiments disclosed herein relate to methods of inhibiting HBV and / or HDV replication, which may include contacting a cell infected with HBV and / or HDV with an effective amount of a compound described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharma- ceutically acceptable salt thereof. Other embodiments described herein relate to a compound described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharma- ceutically acceptable salt thereof, for use in inhibiting HBV and / or HDV replication.

[0009] These and other embodiments are described in more detail below. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] HBV is a partially double-stranded circular DNA of approximately 3.2 kilobases (kb) pairs and is classified into eight genotypes, A-H. The HBV replication pathway has been studied in great detail. TJ Liang, Hepatology (2009) 49 (5 Suppl): S13-S21. Part of the replication involves the formation of a covalently closed circular (cccDNA) form. The presence of cccDNA creates a risk of re-emergence of the virus over the lifespan of the host organism. HBV carriers can transmit the disease for many years. An estimated 300 million people live with hepatitis B virus infection, and it is estimated that more than 750,000 people die from hepatitis B annually worldwide. In addition, immunosuppressed individuals or those undergoing chemotherapy are particularly at risk for reactivation of HBV infection. HBV can be acute and / or chronic. Acute HBV infection can be either asymptomatic or present with symptomatic acute hepatitis.

[0011] HBV can be transmitted by blood, semen, and / or other bodily fluids. This can occur through direct blood-to-blood contact, unprotected sex, sharing of needles, and from an infected mother to her newborn during the birth process. HBV surface antigen (HBsAg) is most frequently used to screen for the presence of this infection. Currently available drugs do not cure HBV and / or HDV infections. Rather, these drugs suppress the replication of the virus.

[0012] Hepatitis D virus (HDV) is a DNA virus and also a member of the Hepadnaviridae family. HDV can only be transmitted in the presence of HBV. The route of transmission of HDV is similar to that of HBV. Transmission of HDV can occur either through coinfection with HBV (co-infection) or in addition to chronic hepatitis B or hepatitis B carriage (superinfection). Both superinfection and coinfection with HDV result in more serious complications compared to infection with HBV alone. These complications include a higher likelihood of undergoing liver failure, rapid progression to cirrhosis in acute infections, and an increased risk of developing liver cancer in chronic infections. When combined with hepatitis B, hepatitis D has the highest case fatality rate of 20% of all hepatitis infections. Currently, there is no cure or vaccine for hepatitis D.

[0013] definition Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. All patents, applications, published applications, and other publications referenced herein are incorporated by reference in their entirety unless otherwise specified. In the event that there are a plurality of definitions for a term herein, the definition in this section prevails unless otherwise specified.

[0014] Whenever a group is described as being "optionally substituted," the group can be unsubstituted or substituted with one or more of the indicated substituents. Similarly, when a group is described as being "unsubstituted or substituted," if substituted, the substituents may be selected from one or more of the indicated substituents. If no substituents are indicated, the indicated "optionally substituted" or "substituted" group can be any of the following: deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl, hydroalkyl, hydroxy, alkoxyalkyl, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, C-amido(alkyl), isocyanato, thiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, monosubstituted amine group, disubstituted amine group, unsubstituted C-amido (C 1~3 alkyl), -O-(unsubstituted C 1~4 Alkyl)-OH, -O-(unsubstituted C 1~4 Alkyl)-(unsubstituted alkoxy), -O-(unsubstituted C 1~4 alkyl)-(unsubstituted C-carboxy), -O-(C 1~3 Alkyl)-O-(unsubstituted C-amide), -O-(unsubstituted C 1~4 Alkyl)-NH2, -O-(unsubstituted C 1~4 Alkyl)-NH(unsubstituted C 1~4 alkyl), -O-(unsubstituted C 1~4 Alkyl)-N(unsubstituted C 1~4 alkyl)2, and unsubstituted -O-(unsubstituted C 1~4 The alkyl group may be substituted with one or more (such as 1, 2, or 3) groups individually and independently selected from the group consisting of -CN, -C, -C-C-C-N ...C-N-N-C-N-C-N-C-N-C-N-C-N-C-N

[0015] As used herein, "C" refers to a set of integers where "a" and "b" are integers.a ~C b " refers to the number of carbon atoms in an alkyl, alkenyl, or alkynyl group, or the number of carbon atoms in a cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl group ring. That is, an alkyl, alkenyl, alkynyl, cycloalkyl ring, cycloalkenyl ring, aryl ring, heteroaryl ring, or heterocyclyl ring can contain from "a" to "b" (inclusive) carbon atoms. Thus, for example, a "C1-C4 alkyl" group refers to all alkyl groups having one to four carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-. When "a" and "b" are not specified for an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl group, the broadest range described in these definitions is assumed.

[0016] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain that includes a fully saturated (no double or triple bonds) hydrocarbon group. The alkyl group may have 1-20 carbon atoms (whenever it appears herein, a numerical range such as "1-20" refers to each integer within the given range, e.g., "1-20 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 20 carbon atoms, but this definition also extends to the appearance of the term "alkyl" where no numerical range is specified). The alkyl group may also be a medium-sized alkyl having 1-10 carbon atoms. The alkyl group may also be a lower alkyl having 1-6 carbon atoms. The alkyl group of the compound may be designated as "C1-C4 alkyl" or similar designation. By way of example only, "C1-C4 alkyl" indicates that there are 1-4 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl. Alkyl groups can be substituted or unsubstituted.

[0017] As used herein, "alkenyl" refers to an alkyl group that contains one or more double bonds in the straight or branched hydrocarbon chain. The length of the alkenyl can vary. For example, an alkenyl can be any of the C 2~4 Alkenyl, C 2~6 Alkenyl, or C 2~8 It may be alkenyl. Examples of alkenyl groups include arenyl, vinylmethyl, and ethenyl. The alkenyl group may be unsubstituted or substituted.

[0018] As used herein, "alkynyl" refers to an alkyl group that contains one or more triple bonds in the straight or branched hydrocarbon chain. The length of an alkynyl can vary. For example, an alkynyl can be any of the C2~4 Alkynyl, C 2~6 Alkynyl, or C 2~8 It may be alkynyl. Examples of alkynyl include ethynyl and propynyl. Alkynyl groups may be unsubstituted or substituted.

[0019] As used herein, "cycloalkyl" refers to a monocyclic or polycyclic hydrocarbon ring system that is fully saturated (no double or triple bonds). When composed of two or more rings, the rings may be joined by fusion. Cycloalkyl groups can contain 3 to 10 atoms in the ring; 3 to 8 atoms in the ring or 3 to 6 atoms in the ring. Cycloalkyl groups may be unsubstituted or substituted. Exemplary cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0020] As used herein, "cycloalkenyl" refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring, but if more than one is present, the double bonds cannot form a completely delocalized pi-electron system throughout all rings (otherwise the group is an "aryl" as defined herein). When composed of more than one ring, the rings may be joined by fusion. Cycloalkenyl groups can contain 3 to 10 atoms in the ring or 3 to 8 atoms in the ring. Cycloalkenyl groups may be unsubstituted or substituted.

[0021] As used herein, "aryl" refers to a carbocyclic (all carbon) monocyclic or polycyclic aromatic ring system (including fused ring systems in which two carbon rings share a chemical bond) having a completely delocalized pi-electron system throughout all rings. The number of carbon atoms in an aryl group can vary. For example, aryl groups include C6 to C7 14 Aryl groups, C6-C 10The aryl group may be an aryl group or a C6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. The aryl group may be substituted or unsubstituted.

[0022] As used herein, "heteroaryl" refers to monocyclic, bicyclic, and tricyclic aromatic ring systems (ring systems having a fully delocalized π-electron system) containing one or more heteroatoms (e.g., 1-5 heteroatoms), i.e., elements other than carbon, including, but not limited to, nitrogen, oxygen, and sulfur. The number of atoms in the rings of a heteroaryl group can vary. For example, a heteroaryl group can contain 4-14 atoms in the ring, 5-10 atoms in the ring, or 5-6 atoms in the ring. Furthermore, the term "heteroaryl" includes fused ring systems in which two rings share at least one chemical bond, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine. Heteroaryl groups can be substituted or unsubstituted.

[0023] As used herein, "heterocyclyl" refers to monocyclic, bicyclic, and tricyclic ring systems in which carbon atoms together with one to five heteroatoms constitute the ring system. Heterocycles may optionally contain one or more unsaturated bonds positioned as such, but a completely delocalized pi-electron system does not occur throughout all rings. The number of atoms in the rings of a heterocyclyl group may vary. For example, a heterocyclyl group may contain 4 to 14 atoms in a ring, 5 to 10 atoms in a ring, or 5 to 6 atoms in a ring. Heteroatoms are elements other than carbon, including, but not limited to, oxygen, sulfur, and nitrogen. Heterocycles may further contain one or more carbonyl or thiocarbonyl functionalities, to define them as including oxo and thio systems, such as lactams, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. When composed of two or more rings, the rings may be joined by fusion. In addition, any nitrogen in a heterocyclyl may be quaternized. A heterocyclyl group can be substituted or unsubstituted.Examples of such "heterocyclyl" groups include 1,3-dioxine, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiine, 1,3-oxathiolane, 1,3-dithiole, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, imidazolidine, isoxyl aryl, aryl ... These include, but are not limited to, thiazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrroldione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline, and 3,4-methylenedioxyphenyl).

[0024] As used herein, "aryl(alkyl)" refers to an aryl group bonded as a substituent through a lower alkylene group. The lower alkylene and aryl groups of the aryl(alkyl) may be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenyl(alkyl), 3-phenyl(alkyl), and naphthyl(alkyl).

[0025] As used herein, "heteroaryl(alkyl)" refers to a heteroaryl group bonded as a substituent via a lower alkylene group. The lower alkylene and heteroaryl groups of heteroaryl(alkyl) may be substituted or unsubstituted. Examples include, but are not limited to, 2-thienyl(alkyl), 3-thienyl(alkyl), furyl(alkyl), thienyl(alkyl), pyrrolyl(alkyl), pyridyl(alkyl), isoxazolyl(alkyl), imidazolyl(alkyl), and their benzo-fused analogs.

[0026] "(Heterocyclyl)alkyl" refers to a heterocyclic group bonded as a substituent via a lower alkylene group. The lower alkylene and heterocyclyl of the heterocyclyl(alkyl) may be substituted or unsubstituted. Examples include, but are not limited to, tetrahydro-2H-pyran-4-yl(methyl), piperidin-4-yl(ethyl), piperidin-4-yl(propyl), tetrahydro-2H-thiopyran-4-yl(methyl), and 1,3-thiazinane-4-yl(methyl).

[0027] A "lower alkylene group" is a linear -CH2- linking group that forms bonds to connect molecular fragments through their terminal carbon atoms. Examples include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), and butylene (-CH2CH2CH2CH2-). A lower alkylene group may be substituted by replacing one or more hydrogens of the lower alkylene group with a substituent group listed in the definition of "substituted." Additionally, when a lower alkylene group is substituted, the lower alkylene may be substituted by replacing both hydrogens on the same carbon with a cycloalkyl group (e.g.,

[0028] [ka] ).

[0029] As used herein, "alkoxy" refers to the formula -OR, where R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. A non-limiting list of alkoxy is methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy, and benzoxy. In some cases, alkoxy may be -OR, where R is an unsubstituted C 1~4 Alkyl. Alkoxy can be substituted or unsubstituted.

[0030] As used herein, "acyl" refers to hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl) bonded as a substituent through a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. Acyl may be substituted or unsubstituted.

[0031] As used herein, "hydroxyalkyl" refers to an alkyl group in which one or more of the hydrogen atoms have been replaced by a hydroxy group. Exemplary hydroxyalkyl groups include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, and 2,2-dihydroxyethyl. Hydroxyalkyl can be substituted or unsubstituted.

[0032] As used herein, "alkoxyalkyl" refers to an alkyl group in which one or more of the hydrogen atoms are replaced by an alkoxy group. Exemplary alkoxyalkyl groups include, but are not limited to, methoxymethyl, ethoxymethyl, methoxyethyl, and ethoxyethyl. An alkoxyalkyl may be substituted or unsubstituted.

[0033] As used herein, "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms are replaced by halogen (e.g., mono-haloalkyl, di-haloalkyl, and tri-haloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl, and 2-fluoroisobutyl. Haloalkyl can be substituted or unsubstituted.

[0034] As used herein, "haloalkoxy" refers to O-alkyl and O-monocyclic cycloalkyl groups in which one or more of the hydrogen atoms are replaced by halogen (e.g., mono-haloalkoxy, di-haloalkoxy, and tri-haloalkoxy). In some cases, the haloalkoxy can be -OR, where R is a C substituted with 1, 2, or 3 halogens. 1~4 Alkyl. Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoro-2-ethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, 2-fluoroisobutoxy, chloro-substituted cyclopropyl, fluoro-substituted cyclopropyl, chloro-substituted cyclobutyl, and fluoro-substituted cyclobutyl. Haloalkoxy can be substituted or unsubstituted.

[0035] A "sulfenyl" group refers to a "-SR" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). Sulfenyl can be substituted or unsubstituted.

[0036] A "sulfinyl" group refers to a "-S(=O)-R" group, where R can be the same as defined for sulfenyl. Sulfinyl can be substituted or unsubstituted.

[0037] A "sulfonyl" group refers to a "SO2R" group, where R may be the same as defined for sulfenyl. The sulfonyl may be substituted or unsubstituted.

[0038] An "O-carboxy" group refers to an "RC(=O)O-" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. O-carboxy can be substituted or unsubstituted.

[0039] The terms "ester" and "C-carboxy" refer to the group "-C(=O)OR", where R can be the same as defined for O-carboxy. Ester and C-carboxy can be substituted or unsubstituted.

[0040] A "thiocarbonyl" group refers to a "-C(=S)R" group, where R can be the same as defined for O-carboxy. Thiocarbonyl can be substituted or unsubstituted.

[0041] A "trihalomethanesulfonyl" group refers to an "X3CSO2-" group where each X is a halogen.

[0042] The "trihalomethanesulfonamide" group is "X3CS(O)2N(R A )-" group, where each X is a halogen and R A is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl).

[0043] As used herein, the term "amino" refers to the group --NH.

[0044] As used herein, the term "hydroxy" refers to an --OH group.

[0045] A "cyano" group refers to a "-CN" group.

[0046] As used herein, the term "azido" refers to the group --N3.

[0047] An "isocyanato" group refers to a "-NCO" group.

[0048] A "thiocyanato" group refers to a "-SCN" group.

[0049] An "isothiocyanato" group refers to a "-NCS" group.

[0050] A "mercapto" group refers to a "-SH" group.

[0051] A "carbonyl" group refers to a -C(=O)- group.

[0052] The "S-sulfonamide" group is "-SO2N(R A R B )" group, where R A and R Bmay be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). S-sulfonamides may be substituted or unsubstituted.

[0053] The "N-sulfonamide" group is A )-" group, where R and R A may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). N-sulfonamides may be substituted or unsubstituted.

[0054] The "O-carbamyl" group is defined as "-OC(=O)N(R A R B )" group, where R A and R B may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). O-carbamyl may be substituted or unsubstituted.

[0055] The "N-carbamyl" group is ROC(=O)N(R A )-" group, where R and R A may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). N-carbamyl may be substituted or unsubstituted.

[0056] The "O-thiocarbamyl" group is defined as "-OC(=S)-N(R A R B)" group, where R A and R B may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). O-thiocarbamyl may be substituted or unsubstituted.

[0057] The "N-thiocarbamyl" group is ROC(=S)N(R A )-" group, where R and R A may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). N-thiocarbamyl may be substituted or unsubstituted.

[0058] A "C-amide" group is defined as -C(=O)N(R A R B )" group, where R A and R B may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). C-amides may be substituted or unsubstituted.

[0059] The "N-amide" group is defined as "RC(=O)N(R A )-" group, where R and R A may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). N-amides may be substituted or unsubstituted.

[0060] The "monosubstituted amine" group is defined as "-NHR A" group, where R A may be independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). Monosubstituted amines may be substituted or unsubstituted. In some cases, monosubstituted amines may be represented by -NHR A wherein R A is unsubstituted C 1~6 It can be alkyl or unsubstituted or substituted benzyl.

[0061] The "disubstituted amine" group is defined as "-NR A R B " group, where R A and R B may be independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). Monosubstituted amines may be substituted or unsubstituted. In some cases, a monosubstituted amine may be -NR A R B wherein R A and R B are independently unsubstituted C 1~6 It can be alkyl or unsubstituted or substituted benzyl.

[0062] As used herein, the term "halogen atom" or "halogen" means any one of the radiostable atoms in column 7 of the Periodic Table of the Elements, such as fluorine, chlorine, bromine, and iodine.

[0063] When the number of substituents is not specified (e.g., haloalkyl), one or more substituents may be present. For example, "haloalkyl" may include one or more of the same or different halogens. As another example, "C1-C3 alkoxyphenyl" may include one or more of the same or different alkoxy groups containing 1, 2, or 3 atoms.

[0064] As used herein, the abbreviations of any protecting groups, amino acids, and other compounds are in accordance with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (see Biochem. 11:942-944 (1972)), unless otherwise indicated.

[0065] The term "pharmaceutical acceptable salt" refers to a salt of a compound that does not cause significant irritation to the organism to which it is administered and does not abolish the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting the compound with inorganic acids such as hydrohalic acids (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid. Pharmaceutical salts can also be obtained by reacting the compound with organic acids such as aliphatic or aromatic carboxylic or sulfonic acids, for example, formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting the compounds with bases to form salts, such as ammonium salts, alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, salts of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamines, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine.

[0066] Terms and phrases used in this application and variations thereof, particularly those in the appended claims, should be construed as open-ended rather than limiting, unless otherwise specified. As examples of the foregoing, the term "including" should be construed to mean "including without limitation," "including but not limited to," and the like; as used herein, the term "comprising" is synonymous with "including," "containing," or "featuring," is inclusive or open-ended, and does not exclude additional unrecited elements or method steps; the term "having" should be construed as "having at least," the term "including" should be construed as "including but not limited to," and the term "examples" is used to provide illustrative examples of the items under discussion, not an exhaustive or limiting list thereof. In addition, the term "comprising" should be construed as synonymous with the phrases "having at least" or "including at least." When used in the context of a compound or composition, the term "comprising" means that the compound or composition includes at least the recited features or components, but may also include additional features or components.

[0067] With respect to the use of substantially any plural and / or singular term herein, those skilled in the art can convert from plural to singular and / or from singular to plural as appropriate for the context and / or application. The various singular / plural permutations may be expressly set forth herein for clarity. The indefinite article "a" or "an" does not exclude a plurality.

[0068] In any compound described herein having one or more chiral centers, unless the absolute stereochemistry is explicitly indicated, it is understood that each center may be independently in the (R)-configuration or (S)-configuration, or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure compounds, enantiomerically enriched compounds, racemic mixtures, diastereomerically pure compounds, diastereomerically enriched compounds, or stereoisomeric mixtures. In addition, in any compound described herein having one or more double bonds that produce geometric isomers that can be defined as E or Z, it is understood that each double bond may be independently E or Z, or a mixture thereof. Similarly, it is understood that in any compound described, all tautomeric forms are also intended to be included.

[0069] It is understood that where the compounds disclosed herein have unfilled valences, the valences are filled with hydrogen or an isotope thereof, for example, hydrogen-1 (protium) and hydrogen-2 (deuterium).

[0070] It is understood that the compounds described herein may be isotopically labeled. Substitution with an isotope such as deuterium may result in certain therapeutic advantages due to greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. Each chemical element represented in a compound structure may include any isotope of that element. For example, in a compound structure, a hydrogen atom may be expressly disclosed or understood as being present in the compound. At any position of a compound where a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen, including, but not limited to, hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference to a compound herein encompasses all possible isotopic forms, unless the context clearly indicates otherwise.

[0071] When a range of values ​​is provided, it is understood that the upper and lower limits, as well as every intervening value between the upper and lower limits of that range, are included within an embodiment.

[0072] compound Some embodiments disclosed herein relate to a compound of formula (I) or a pharma- ceutically acceptable salt thereof:

[0073] [ka] In the formula, R 1 but,

[0074] [ka] R 2 but,

[0075] [ka] X may be selected from 1A , X 1B , and X 1C are independently hydrogen, halogen, or unsubstituted C 1~5 Alkyl and unsubstituted C 1~5 haloalkyl; Y 1A CH, C-CHF2, CF, C-Cl, C(NH2), C(NH(unsubstituted C 1~5 alkyl), C(N(unsubstituted C 1~5 alkyl)2) or N; Y 2A CH, C-halogen, C-OCH3, C(NH2), C(NH(unsubstituted C 1~5 alkyl), C(N(unsubstituted C 1~5 alkyl)2) or N; Y 3A can be CH or N, Y 4A can be CH or N, Y 1B CH, C-CHF2, CF, C-Cl, C(NH2), C(NH(unsubstituted C 1~5 alkyl), C(N(unsubstituted C 1~5 alkyl)2) or N (nitrogen), Y 2B CH, C-halogen, C-OCH3, C(NH2), C(NH(unsubstituted C 1~5 alkyl), C(N(unsubstituted C1~5 alkyl)2) or N (nitrogen), Y 3B can be CH or N (nitrogen), and Y 4B can be CH or N (nitrogen), and Y 1C , Y 2C , Y 3C , and Y 4C may each independently be CH, C- (halogen), or N (nitrogen); Y 1D can be CH, C-CH3, C-OCH3, C-(halogen), C-CHF2, C-CF3, or N (nitrogen); Y 2D can be CH, C-CH3, C-OCH3, C-(halogen), C-CHF2, C-CF3, or N (nitrogen); Y 3D can be CH, C- (halogen), or N (nitrogen); Y 1E , Y 1F , and Y 1G may each independently be CH, C- (halogen), or N (nitrogen); Y 1H , Y 2H , Y 3H , Y 4H , Y 5H , and Y 6H may each independently be CH, C- (halogen), or N (nitrogen); R A1 is hydrogen, unsubstituted or substituted C 1~5 Alkyl, or unsubstituted or substituted monocyclic C 3~6 may be cycloalkyl, C 1~5 Alkyl and monocyclic C 3~6 If cycloalkyl is substituted, C 1~5 Alkyl and C 3~6 Cycloalkyl is hydroxy, -NH2, unsubstituted C 1~5 Alkoxy, unsubstituted -NH(unsubstituted C 1~5 Alkyl), -N(unsubstituted C 1~5 alkyl), -C(=O)NH, -OP(=O)(OH), unsubstituted 5- or 6-membered monocyclic heterocyclyl, and one or more unsubstituted C 1~4 R may be substituted with one or more groups selected from 5- or 6-membered monocyclic heterocyclyl substituted with an alkyl group; A2 can be -CH3 or -CD3, R A3is -NH2, -NH(unsubstituted or substituted C 1~5 alkyl), -N(unsubstituted or substituted C 1~5 alkyl)2, -NH(unsubstituted or substituted C 3~6 monocyclic cycloalkyl), unsubstituted or substituted 5-membered monocyclic heteroaryl, unsubstituted or substituted 6-membered monocyclic heteroaryl, or unsubstituted or substituted 4-6-membered monocyclic heterocyclyl; R A4 is unsubstituted or substituted C 1~5 Alkyl, unsubstituted C 1~5 Haloalkyl, or unsubstituted or substituted monocyclic C 3~6 may be cycloalkyl, C 1~5 Alkyl and monocyclic C 3~6 If cycloalkyl is substituted, C 1~5 Alkyl and C 3~6 Cycloalkyl may be substituted with one or more groups selected from hydroxy, -C(=O)OH, and -C(=O)NH2; R A5 are hydrogen, halogens, -CN, -OH, -NH2, -C(=O)OH, -CH=CH2, unsubstituted C 1~5 Alkyl, and unsubstituted or substituted monocyclic C 3~6 cycloalkyl, monocyclic C 3~6 When cycloalkyl is substituted, C 3~6 The cycloalkyl may be substituted with one or more hydroxy groups.

[0076] In various embodiments, R of formula (I) 1 teeth,

[0077] [ka] In embodiments, R 1 teeth,

[0078] [ka] In another embodiment, R 1 teeth,

[0079] [ka] In another embodiment, R 1 teeth,

[0080] [ka] In another embodiment, R 1 teeth,

[0081] [ka] In another embodiment, R 1 teeth,

[0082] [ka] In another embodiment, R 1 teeth,

[0083] [ka] In another embodiment, R 1 teeth,

[0084] [ka] It could be.

[0085] In various embodiments, R of formula (I) 2 teeth,

[0086] [ka] wherein the variable X 1A , X 1B , X 1C , Y 1A , Y 2A , Y 3A , Y 4A , Y 1B , Y 2B , Y 3B , Y4B , Y 1C , Y 2C , Y 3C , Y 4C , Y 1D , Y 2D , Y 3D , Y 1E , Y 1F , Y 1G , Y 1H , Y 2H , Y 3H , Y 4H , Y 5H , Y 6H , R A1 , R A2 , R A3 , R A4 , and R A5 may be as defined elsewhere herein.

[0087] In some embodiments, R of formula (I) 2 teeth,

[0088] [ka] where R A1 But non-substituted C 1~5 For example, R A1 can be methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, or branched pentyl. 2 teeth,

[0089] [ka] where R A1 But substitution C 1~5 As provided herein, R A1 C 1~5 Alkyl can have one or more hydroxy groups (such as 1, 2, or 3 hydroxy groups), one or more -NH groups (such as 1, 2, or 3 -NH groups), one or more unsubstituted C 1~5an alkoxy group (such as one, two, or three alkyl groups), one or more unsubstituted -NH(unsubstituted 1~5 alkyl) group (one, two or three -NH(unsubstituted C 1~5 alkyl) groups), one or more -N (unsubstituted C 1~5 alkyl)2 (e.g., 1, 2, or 3 -N(unsubstituted C 1~5 one or more -C(=O)NH2 (e.g., one or two -C(=O)NH2 groups), one or more -OP(=O)(OH)2 (e.g., one or two -OP(=O)(OH)2 groups), one or more unsubstituted 5- or 6-membered monocyclic heterocyclyls (e.g., 1, 2, or 3 unsubstituted 5- or 6-membered monocyclic heterocyclyls), and / or one or more unsubstituted C 1~4 one or more 5- or 6-membered monocyclic heterocyclyls (e.g., each independently, 1, 2, or 3 unsubstituted C 1~4 Exemplary C substituted with one or more hydroxy groups are 5- or 6-membered monocyclic heterocyclyls (1, 2, or 3 substituted with alkyl groups). 1~5 Alkyl includes -CHCHOH, -CHCH(CH)OH, and -CHCH(OH)CH(OH). As provided herein, R A1 C 1~5 Alkyl may be one or more -NH groups, one or more -NH(unsubstituted C 1~5 alkyl) groups, and / or one or more -N(unsubstituted C 1~5 For example, R A1 is -(CH 21-4 NH2, -(CH 21-4 NH(unsubstituted C 1~5 alkyl), or -(CH2) 1-4 N(unsubstituted C 1~5 alkyl)2. One or more unsubstituted C 1~5 Alkoxy-substituted C 1~5 Examples of alkyl include -CH2CH2OCH3 and -CH2CH(CH3)OCH3. C substituted with -C(=O)NH2 1~5 An example of an alkyl is -CH2-C(=O)NH2.1~5 An example of an alkyl is -CHCH(OP(=O)(OH))(CH). In some embodiments, R A1 is hydroxy, -NH2, unsubstituted C 1~5 Alkoxy, unsubstituted -NH(unsubstituted C 1~5 Alkyl), -N(unsubstituted C 1~5 C(=O)NH, and -OP(=O)(OH) 1~5 For example, R A1 is -(CH2) 1-4 OH, -(CH2) 1-2 CH(CH3)(OH), -CH2CH(OH)CH2(OH), -(CH2) 1-4 NH2, -(CH2) 1-4 NH(unsubstituted C 1~5 alkyl), or -(CH2) 1-4 N(unsubstituted C 1~5 alkyl)2, -(CH2) 1-4 OCH3, -(CH2) 1-4 C(=O)NH2, -(CH2) 1-4 (OP(=O)(OH)2), and -(CH) 1-2 CH(OP(=O)(OH)2)(CH3). Some embodiments may be A1 is an unsubstituted 5- or 6-membered monocyclic heterocyclyl and / or one or more unsubstituted C 1~4 C substituted with 5- or 6-membered monocyclic heterocyclyl substituted with an alkyl group 1~5 It can be alkyl. 1~5 Exemplary 5- or 6-membered monocyclic heterocyclyls that may be substituted on the alkyl include pyrrolidinyl, piperidinyl, morpholinyl, 1,2,4-oxadiazol-5(4H)-one, 2,4-dihydro-3H-1,2,4-triazol-3-onyl, pyrazolonyl, and piperazinyl. 2 teeth,

[0090] [ka] where R A1 is an unsubstituted monocyclic C 3~6 In still yet other embodiments, R of formula (I) can be cycloalkyl. 2 teeth,

[0091] [ka] where R A1 has one or more hydroxy groups (such as 1, 2, or 3 hydroxy groups), one or more -NH groups (such as 1, 2, or 3 -NH groups), one or more unsubstituted C 1~5 an alkoxy group (such as one, two, or three alkyl groups), one or more unsubstituted -NH(unsubstituted 1~5 alkyl) group (one, two or three -NH(unsubstituted C 1~5 alkyl) groups), one or more -N (unsubstituted C 1~5 alkyl)2 (e.g., 1, 2, or 3 -N(unsubstituted C 1~5 one or more -C(=O)NH2 (e.g., one or two -C(=O)NH2 groups), one or more -OP(=O)(OH)2 (e.g., one or two -OP(=O)(OH)2 groups), one or more unsubstituted 5- or 6-membered monocyclic heterocyclyls (e.g., 1, 2, or 3 unsubstituted 5- or 6-membered monocyclic heterocyclyls), and / or one or more unsubstituted C 1~4 one or more 5- or 6-membered monocyclic heterocyclyls (e.g., each independently, 1, 2, or 3 unsubstituted C 1~4 Substituted monocyclic C substituted with 1, 2, or 3 5- or 6-membered monocyclic heterocyclyl substituted with alkyl groups 3~6 It can be a cycloalkyl. 3~6 Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In some embodiments, R A1 is hydroxy, -NH2, unsubstituted C 1~5 Alkoxy, unsubstituted -NH(unsubstituted C 1~5 alkyl), and -N(unsubstituted C 1~5 substituted monocyclic C substituted with one moiety selected from alkyl)23~6 In some embodiments, R A1 is hydroxy, -NH2, unsubstituted -NH (unsubstituted C 1~5 alkyl), and -N(unsubstituted C 1~5 In some embodiments, R can be cyclobutyl substituted with a moiety selected from alkyl. A1 may be hydrogen.

[0092] In some embodiments, Y 1A , Y 2A , Y 3A , and Y 4A Each can be CH. In other embodiments, Y 1A , Y 2A , Y 3A and Y 4A may be N. In yet other embodiments, one of Y 1A , Y 2A , Y 3A , and Y 4A Two or three of Y may be N. In some embodiments, 1A can be C-CHF2, CF, or C-Cl; Y 2A , Y 3A , and Y 4A Each can be CH. In some embodiments, Y 2A can be a C-halogen. In other embodiments, Y 2A can be C-OCH. In some embodiments, Y 2A can be a C-halogen, Y 1A , Y 3A , and Y 4A Each can be CH. In some embodiments, Y 2A is C(NH2), C(NH(unsubstituted C 1~5 alkyl)), or C(N(unsubstituted C 1~5 In another embodiment, Y 2A can be C-OCH3, and Y 1A , Y 3A , and Y 4A Each can be CH. In other embodiments, Y 2A is C(NH2), C(NH(unsubstituted C1~5 alkyl)), or C(N(unsubstituted C 1~5 alkyl)2, Y 1A , Y 3A , and Y 4A Each of R can be CH. 2 Examples of this are:

[0093] [ka] Examples include:

[0094] In another embodiment, R of formula (I) 2 teeth,

[0095] [ka] In various embodiments, Y 1B can be CH, C-Cl, or N; Y 2B are CH, C-Cl, C-OCH3, C(NH2), C(NH(unsubstituted C 1~5 alkyl)), or C(N(unsubstituted C 1~5 alkyl)2) or N; Y 3B can be CH or N, Y 4B can be CH or N, R A2 can be -CH3 or -CD3. In some embodiments, Y 1B , Y 2B , Y 3B , and Y 4B can each be CH 。 In another embodiment, Y 1B , Y 3B , and Y 4B At least one of Y may be N (nitrogen). 1B , Y 3B , and Y 4B One of them is

[0096] [ka] can be N, such that the ring of Y can be pyridinyl. 1B, Y 3B and Y 4B Other examples of rings where at least one of Y is nitrogen include pyridazine, pyrimidine, and pyrazine. In some embodiments, Y 1B , Y 2B , Y 3B , and Y 4B Each can be CH. In other embodiments, Y 1B , Y 2B , Y 3B , and Y 4B may be N. In yet other embodiments, one of Y 1B , Y 2B , Y 3B , and Y 4B Two or three of Y may be N. In some embodiments, 1B can be C-CHF2, CF, or C-Cl; Y 2B , Y 3B , and Y 4B Each can be CH. In some embodiments, Y 2B can be a C-halogen. In other embodiments, Y 2B can be C-OCH. In yet other embodiments, Y 2B is C(NH2), C(NH(unsubstituted C 1~5 alkyl)), or C(N(unsubstituted C 1~5 In some embodiments, Y 2B can be a C-halogen (such as C-Cl), and Y 1B , Y 3B , and Y 4B Each can be CH. In other embodiments, Y 2B can be C-OCH3, and Y 1B , Y 3B , and Y 4B Each can be CH. In still other embodiments, Y 2B is C(NH2), C(NH(unsubstituted C 1~5 alkyl)), or C(N(unsubstituted C 1~5 alkyl)2, Y 1B , Y 3B , and Y 4B Each can be CH. Exemplary R 2As a base,

[0097] [ka] Examples include:

[0098] In another embodiment, R of formula (I) 2 teeth,

[0099] [ka] In some embodiments, Y 1C , Y 2C , Y 3C , and Y 4C may each independently be CH or N (nitrogen); R A3 is -NH2, -NH(unsubstituted or substituted C 1~5 alkyl), -N(unsubstituted or substituted C 1~5 alkyl)2, -NH(unsubstituted or substituted C 3~6 monocyclic cycloalkyl), unsubstituted or substituted 5-membered monocyclic heteroaryl, unsubstituted or substituted 6-membered monocyclic heteroaryl, or unsubstituted or substituted 4-6-membered monocyclic heterocyclyl. A3 can be -NH2. In other embodiments, R A3 is NH(unsubstituted C 1~5 In still other embodiments, R A3 is -NH(substituted C 1~5 In still yet other embodiments, —N(unsubstituted C 1~5 In some embodiments, R A3 is -N(substitution C 1~5 C may be alkyl. 1~5 Examples of alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, or branched pentyl. 1~5 If the alkyl is substituted, C 1~5The alkyl may be substituted with one or more hydroxy groups, for example, one, two, or three hydroxy groups. For example, -NH(CH2) 1-5 OH, -NH(CH2) 1-4 CH(OH)(CH3), -NH(CH2) 1-3 CH(OH)CH2(CH3), -NH(CH2) 1-3 CH(OH)CH2(OH), or -NH((CH2) 1-5 OH). As provided herein, R A3 can be unsubstituted or substituted 5-6 membered heteroaryl. In some embodiments, R A3 can be an unsubstituted or substituted 5-membered monocyclic heteroaryl. In other embodiments, R A3 can be an unsubstituted or substituted 6-membered monocyclic heteroaryl. In some cases, the 5- and / or 6-membered monocyclic heteroaryl can contain 1, 2, or 3 heteroatoms such as N (nitrogen), O (oxygen), and / or S (sulfur). In some embodiments, R A3 can be an unsubstituted or substituted 5- or 6-membered monocyclic heteroaryl containing one or two nitrogens. Non-limiting examples of suitable 5-membered monocyclic heteroaryls include pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and tetrazolyl. Examples of 6-membered monocyclic heteroaryls include pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl. In some embodiments, R A3 can be an unsubstituted or substituted 4-membered monocyclic heterocyclyl. In other embodiments, R A3 can be an unsubstituted or substituted 5-membered monocyclic heterocyclyl. In still other embodiments, R A3 can be an unsubstituted or substituted 6-membered monocyclic heterocyclyl. In some cases, the 4- to 6-membered monocyclic heterocyclyl can contain 1, 2, or 3 heteroatoms N (nitrogen), O (oxygen), and / or S (sulfur). In some embodiments, R A3R may be an unsubstituted or substituted 4- or 6-membered monocyclic heterocyclyl containing one or two nitrogens. Non-limiting examples of suitable 4- to 6-membered monocyclic heterocyclyls include azetidinyl, pyrrolidinyl, morpholinyl, 1,2,4-oxadiazol-5(4H)-onyl, 2,4-dihydro-3H-1,2,4-triazol-3-onyl, pyrazolonyl, and piperazinyl. A3 -NH(substituted C 3~6 Possible substituents which may be present on the monocyclic cycloalkyl, substituted monocyclic heteroaryl, and / or substituted monocyclic heterocyclyl include halogen, hydroxy, amino, unsubstituted C 1~6 Alkyl and unsubstituted C 1~6 Haloalkyl is mentioned.

[0100] In some embodiments, Y 1C , Y 2C , Y 3C , and Y 4C is R 2 but,

[0101] [ka] In another embodiment, Y 1C , Y 2C , Y 3C , and Y 4C At least one of Y may be N (nitrogen). 1C , Y 2C , Y 3C , and Y 4C If at least one of is N,

[0102] [ka] Exemplary rings of include pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl. In some embodiments, Y 1C , Y 2C , Y 3C , and Y 4C Each can be CH. In other embodiments, Y 1C , Y2C , Y 3C , and Y 4C may be N. In yet other embodiments, one of Y 2C is CH, CF, or C-Cl. 1C , Y 2C , Y 3C , and Y 4C Two or three of Y may be N. In some embodiments, 1C , Y 2C , Y 3C , and Y 4C One of R can be C-(halogen). 2 Examples of this are:

[0103] [ka] Examples include:

[0104] In another embodiment, R of formula (I) 2 teeth,

[0105] [ka] In yet another embodiment, R of formula (I) may be 2 teeth,

[0106] [ka] In various embodiments, Y 1D can be CH, C-CH3, C-OCH3, C-(halogen), C-CHF2, C-CF3, or N; Y 2D can be CH, C-CH3, C-OCH3, C-(halogen), C-CHF2, C-CF3, or N; Y 3D can be CH, C-(halogen), or N; R A4 is unsubstituted or substituted C 1~5 Alkyl, unsubstituted C 1~5 Haloalkyl, or unsubstituted or substituted monocyclic C 3~6 may be cycloalkyl, C1~5 Alkyl and monocyclic C 3~6 If cycloalkyl is substituted, C 1~5 Alkyl and C 3~6 Cycloalkyl may be substituted with one or more groups selected from hydroxy, -C(=O)OH, and -C(=O)NH2; R A5 are hydrogen, halogens, -CN, -OH, -NH2, -C(=O)OH, -CH=CH2, unsubstituted C 1~5 Alkyl, and unsubstituted or substituted monocyclic C 3~6 cycloalkyl, monocyclic C 3~6 When cycloalkyl is substituted, C 3~6 The cycloalkyl may be substituted with one or more hydroxy groups.

[0107] In some embodiments, Y 1D , Y 2D , and Y 3D Each can be CH. In other embodiments, Y 1D and Y 2D One of the groups may be CH, and Y 1D and Y 2D The other of the groups may be C-CH3, C-OCH3, C-(halogen), C-CHF2, or C-CF3, and Y 3D can be CH. In still other embodiments, Y 1D and Y 2D One of the groups may be CH, and Y 1D and Y 2D The other of the groups may be C-CH3, C-OCH3, C-(halogen), C-CHF2, or C-CF3, and Y 3D can be N (nitrogen). The halogen in C-(halogen) can be F, Cl, Br, or I. In some embodiments, Y 2D can be N. In some embodiments, Y 3D can be N. In some embodiments, Y 2D and Y 3D may each be N. In some embodiments, Y 1D and / or Y 2D The C-(halogen) in R can be CF or C-Cl.A4 is unsubstituted C 1~5 In other embodiments, R A4 is a substitution C 1~5 In still other embodiments, R A4 is unsubstituted C 1~5 In still yet other embodiments, R A4 can be unsubstituted cyclopropyl, unsubstituted cyclobutyl, unsubstituted cyclopentyl, or unsubstituted cyclohexyl. In some embodiments, R A4 is a substituted monocyclic C substituted with one or more (such as 1, 2, or 3) hydroxy groups; 3~6 R can be cycloalkyl. A4 C 1~5 Examples of alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, or branched pentyl. A4 C 1~5 The alkyl may be substituted with one or more hydroxy groups (such as 1, 2, or 3 hydroxy groups), one or more -C(=O)OH groups (e.g., 1, 2, or 3 -C(=O)OH groups), and / or one or more -C(=O)NH groups, such as 1, 2, or 3 -C(=O)NH groups. Exemplary C(=O) alkyl groups substituted with one or more hydroxy groups, one or more -C(=O)OH groups, and / or one or more -C(=O)NH groups are: 1~5 Alkyl groups include -CH2CH2OH, -CH(CH3)OH, -CH2CH(CH3)OH, -CH2C(=O)NH2, -CH2CH2C(=O)NH2, -CH(CH3)C(=O)NH2, -CH2CH(CH3)C(=O)NH 2、 -CH2C(=O)OH, -CH2CH2C(=O)OH, -CH(CH3)C(=O)OH, and -CH2CH(CH3)C(=O)OH. 1~5Examples of haloalkyls include -CF3, -CCl3, -CHF2, -C(CH3)F2, -CHCl2, -CH2F, -CH(CH3)F, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2Cl, -CH2CH2F, -CH2CH2Cl, -CH2CH2CH2F, and -CH2CH2CH2Cl.

[0108] In some embodiments, R A5 can be hydrogen. In some embodiments, R A5 can be halogen, -CN, -OH, or -NH. In still other embodiments, R A5 can be -C(=O)OH. In still yet other embodiments, R A5 can be -CH=CH2. In some embodiments, R A5 is an unsubstituted C alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, or branched pentyl. 1~5 In other embodiments, R A5 is unsubstituted C 3~6 In other embodiments, R A5 is a substituted monocyclic C substituted with one or more (e.g., 1, 2, or 3) hydroxy groups. 3~6 R can be cycloalkyl. A5 The cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0109] In another embodiment, R of formula (I) 2 teeth,

[0110] [ka] In various embodiments, Y 1E can be CH. In various other embodiments, Y 1E can be N (nitrogen). In some embodiments, R A4 is unsubstituted or substituted C 1~5 In other embodiments, RA4 is unsubstituted C 1~5 In still other embodiments, R A4 is an unsubstituted or substituted monocyclic C 3~6 For example, R A4 may be selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, branched pentyl, -CF3, -CCl3, -CHF2, -C(CH3)F2, -CHCl2, -CH2F, -CH(CH3)F, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2Cl, -CH2CH2F, -CH2CH2Cl, -CH2CH2CH2F, -CH2CH2CH2F, -CH2CH2CH2Cl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 3~6 Possible substituents which may be present on the cycloalkyl include halogen, hydroxy, unsubstituted C 1~6 Alkyl and unsubstituted C 1~6 Haloalkyl substituted C 1~5 Possible substituents that may be present on the alkyl include halogen, hydroxy, and unsubstituted C 1~6 Haloalkyl is mentioned.

[0111] In another embodiment, R of formula (I) 2 teeth,

[0112] [ka] In some embodiments, Y 1F can be CH. In other embodiments, Y 1F can be N (nitrogen).

[0113] In another embodiment, R of formula (I) 2 teeth,

[0114] [ka] In some embodiments, formula (I) can be:

[0115] [ka] In another embodiment, R of formula (I) may be 2 teeth,

[0116] [ka] It could be.

[0117] In another embodiment, R of formula (I) 2 teeth,

[0118] [ka] wherein Y 1H , Y 2H , Y 3H , Y 4H , Y 5H , and Y 6H are each independently CH, C- (halogen), or N (nitrogen). 1H and Y 2H may be N. In other embodiments, one of Y 1H and Y 2H Each of Y can be N. In some embodiments, including the embodiment of this paragraph, 3H , Y 4H , Y 5H , and Y 6H One of Y can be N. In other embodiments, including the embodiment of this paragraph, 3H , Y 4H , Y 5H , and Y 6H Two of Y can be N. In still other embodiments, including those of this paragraph, 3H , Y 4H , Y 5H and Y 6H Three or four of may be N.

[0119] [ka] Examples include:

[0120] [ka] Examples include:

[0121] In another embodiment, R of formula (I) 2

[0122] [ka] teeth,

[0123] [ka] wherein X 1A , X 1B , and X 1C are independently hydrogen, halogens (F, Cl, and Br), unsubstituted C 1~5 Alkyl (methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl (straight and branched chain versions), and unsubstituted C 1~5 haloalkyl (-CF3, -CCl3, -CHF2, -C(CH3)F2, -CHCl2, -CH2F, -CH(CH3)F, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2Cl, -CH2CH2F, -CH2CH2Cl, -CH2CH2CH2F, -CH2CH2CH2F, -CH2CH2CH2Cl). In some embodiments, R 2 teeth,

[0124] [ka] In another embodiment, R of formula (I) may be 2 teeth,

[0125] [ka] In another embodiment, R of formula (I) may be 2 teeth,

[0126] [ka] In another embodiment, R of formula (I) may be 2 teeth,

[0127] [ka] It could be.

[0128] In some embodiments, R 2 teeth,

[0129] [ka] wherein each is independently halogen, hydroxy, amino, unsubstituted C 1~6 Alkyl and unsubstituted C 1~6 In some embodiments, the hydrogen on the carbon can be optionally substituted with one or more moieties (1, 2, or 3 moieties) selected from halogen, hydroxy, amino, unsubstituted C 1~6 Alkyl or unsubstituted C 1~6 haloalkyl and / or the hydrogen of the NH group may be replaced by an unsubstituted C 1~6 Alkyl or unsubstituted C 1~6 Suitable halogens include unsubstituted C 1~6 Alkyl, and C 1~6 Haloalkyl is provided herein and includes F, Cl, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (linear or branched), hexyl (linear or branched), -CF3, -CCl3, -CHF2, -C(CH3)F2, -CHCl2, -CH2F, -CH(CH3)F, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2Cl, -CH2CH2F, -CH2CH2Cl, -CH2CH2CH2F, -CH2CH2CH2F, -CH2CH2CH2Cl. Exemplary R 2 As a base,

[0130] [ka]

[0131] [ka]

[0132] [ka]

[0133] [ka]

[0134] [ka] Examples include:

[0135] In some embodiments, the compound of formula (I) or a pharma- ceutical acceptable salt thereof can be: 1 but,

[0136] [ka] R 2 but,

[0137] [ka] X may be selected from 1A , X 1B , and X 1C are independently hydrogen, halogen, or unsubstituted C 1~5 Alkyl and unsubstituted C 1~5 haloalkyl; Y 1A can be CH, C-CHF2, CF, C-Cl, or N; Y 2A can be CH, C-halogen, C-OCH3, or N; Y 3A can be CH or N, Y4A can be CH or N, Y 1B can be CH, C-CHF2, CF, C-Cl, or N (nitrogen); Y 2B can be CH, C-halogen, C-OCH3, or N (nitrogen), and Y 3B can be CH or N (nitrogen), and Y 4B can be CH or N (nitrogen), and Y 1C , Y 2C , Y 3C , and Y 4C may each independently be CH, C- (halogen), or N (nitrogen); Y 1D can be CH, C-CH3, C-OCH3, C-(halogen), C-CHF2, C-CF3, or N (nitrogen); Y 2D can be CH, C-CH3, C-OCH3, C-(halogen), C-CHF2, C-CF3, or N (nitrogen); Y 3D can be CH or N (nitrogen), and Y 1E , Y 1F , and Y 1G may each independently be CH, C- (halogen), or N (nitrogen); R A1 is unsubstituted or substituted C 1~5 Alkyl, or unsubstituted or substituted monocyclic C 3~6 may be cycloalkyl, C 1~5 Alkyl and monocyclic C 3~6 If cycloalkyl is substituted, C 1~5 Alkyl and C 3~6 Cycloalkyl is selected from hydroxy and unsubstituted C 1~5 alkoxy; R A2 can be -CH3 or -CD3, R A3 may be unsubstituted or substituted 5-membered monocyclic heteroaryl or unsubstituted or substituted 5-membered monocyclic heterocyclyl; R A4 is unsubstituted or substituted C 1~5 Alkyl, unsubstituted C 1~5 Haloalkyl, or unsubstituted or substituted monocyclic C 3~6 may be cycloalkyl, C 1~5 Alkyl and monocyclic C 3~6If cycloalkyl is substituted, C 1~5 Alkyl and C 3~6 Cycloalkyl may be substituted with one or more groups selected from hydroxy, -C(=O)OH, and -C(=O)NH2; R A5 are hydrogen, halogens, -CN, -OH, -NH2, -C(=O)OH, -CH=CH2, unsubstituted C 1~5 Alkyl, and unsubstituted or substituted monocyclic C 3~6 cycloalkyl, monocyclic C 3~6 When cycloalkyl is substituted, C 3~6 The cycloalkyl may be substituted with one or more hydroxy groups.

[0138] In some embodiments, the compound of formula (I) or a pharma- ceutical acceptable salt thereof can be: 1 but,

[0139] [ka] R 2 but,

[0140] [ka] X may be selected from 1A , X 1B , and X 1C are independently hydrogen, halogen, or unsubstituted C 1~5 Alkyl and unsubstituted C 1~5 haloalkyl; Y 1A CH, C-CHF2, CF, C-Cl, C(NH2), C(NH(unsubstituted C 1~5 alkyl), C(N(unsubstituted C 1~5 alkyl)2) or N; Y 2A CH, C-halogen, C-OCH3, C(NH2), C(NH(unsubstituted C 1~5 alkyl), C(N(unsubstituted C 1~5 alkyl)2) or N; Y 3A can be CH or N, Y 4Acan be CH or N, Y 1B CH, C-CHF2, CF, C-Cl, C(NH2), C(NH(unsubstituted C 1~5 alkyl), C(N(unsubstituted C 1~5 alkyl)2) or N; Y 2B CH, C-halogen, C-OCH3, C(NH2), C(NH(unsubstituted C 1~5 alkyl), C(N(unsubstituted C 1~5 alkyl)2) or N; Y 3B can be CH or N, Y 4B can be CH or N, Y 1C , Y 2C , Y 3C , and Y 4C may each independently be CH, C-(halogen), or N; Y 1D can be CH, C-CH3, C-OCH3, C-(halogen), C-CHF2, C-CF3, or N; Y 2D can be CH, C-CH3, C-OCH3, C-(halogen), C-CHF2, C-CF3, or N; Y 3D can be CH, C-(halogen), or N; Y 1E , Y 1F , and Y 1G may each independently be CH, C-(halogen), or N; R A1 is unsubstituted or substituted C 1~5 Alkyl, or unsubstituted or substituted monocyclic C 3~6 may be cycloalkyl, C 1~5 Alkyl and monocyclic C 3~6 If cycloalkyl is substituted, C 1~5 Alkyl and C 3~6 Cycloalkyl is hydroxy, unsubstituted C 1~5 R may be substituted with one or more groups selected from alkoxy, -C(=O)NH2, and -OP(=O)(OH)2; A2 can be -CH3 or -CD3, R A3 is -NH(unsubstituted or substituted C 1~5 alkyl), -N(unsubstituted or substituted C 1~5alkyl), unsubstituted or substituted 5-membered monocyclic heteroaryl, or unsubstituted or substituted 4-6-membered monocyclic heterocyclyl; R A4 is unsubstituted or substituted C 1~5 Alkyl, unsubstituted C 1~5 Haloalkyl, or unsubstituted or substituted monocyclic C 3~6 may be cycloalkyl, C 1~5 Alkyl and monocyclic C 3~6 If cycloalkyl is substituted, C 1~5 Alkyl and C 3~6 Cycloalkyl may be substituted with one or more groups selected from hydroxy, -C(=O)OH, and -C(=O)NH2; R A5 are hydrogen, halogens, -CN, -OH, -NH2, -C(=O)OH, -CH=CH2, unsubstituted C 1~5 Alkyl, and unsubstituted or substituted monocyclic C 3~6 cycloalkyl, monocyclic C 3~6 When cycloalkyl is substituted, C 3~6 The cycloalkyl may be substituted with one or more hydroxy groups.

[0141] In some embodiments, the compound of formula (I) or a pharma- ceutical acceptable salt thereof can be: 1 but,

[0142] [ka] R 2 but,

[0143] [ka] Y 1A can be CH or N, Y 2A can be CH or N, Y 3A is CH or N, and Y 4A is CH or N, and R A1 But substitution C 1~5 Alkyl or substituted monocyclic C 3~6In some embodiments of this paragraph, Y can be cycloalkyl. 1A can be CH, and Y 2A can be CH, and Y 3A is CH and Y 4A In another embodiment of this paragraph, Y is CH. 1A can be CH, and Y 2A can be N and Y 3A is CH and Y 4A In still other embodiments of this paragraph, Y is CH. 1A can be N and Y 2A can be CH, and Y 3A is N and Y 4A is CH. In some embodiments of this paragraph, R A1 is a substitution C 1~5 In some embodiments of this paragraph, R A1 is hydroxy-N(unsubstituted C 1~5 alkyl), -C(=O)NH, -OP(=O)(OH), unsubstituted 5- or 6-membered monocyclic heterocyclyl, or one or more unsubstituted C 1~4 C substituted with 5- or 6-membered monocyclic heterocyclyl substituted with alkyl group 1~5 In some embodiments of this paragraph, R A1 is a hydroxy-substituted C such as -CH2CH2OH, -CH2CH(CH3)OH, and -CH2CH(OH)CH2(OH). 1~5 In some embodiments of this paragraph, R A1 is a monocyclic C 3~6 In other embodiments of this paragraph, R A1 is hydroxy, -NH2, or -N(unsubstituted C 1~5 Substituted monocyclic C 3~6 It may be cycloalkyl (such as cyclobutyl).

[0144] In some embodiments, the compound of formula (I) or a pharma- ceutical acceptable salt thereof can be: 1 but,

[0145] [ka] R 2 but,

[0146] [ka] R A3 can be,R A3 is -NH2, -NH(unsubstituted or substituted C 1~5 alkyl), -NH(unsubstituted or substituted C 3~6 monocyclic cycloalkyl), unsubstituted or substituted 5-membered monocyclic heteroaryl, or unsubstituted or substituted 4-6-membered monocyclic heterocyclyl. In some embodiments of this paragraph, R A3 can be -NH2. In other embodiments of this paragraph, R A3 is -NH(unsubstituted C 1~5 In still other embodiments of this paragraph, R A3 For example, -NH(hydroxy-substituted C 1~5 R can be any alkyl group. A3 is -NH(substituted C 1~5 In still yet other embodiments of this paragraph, R A3 is -NH(unsubstituted C 3~6 In some embodiments of this paragraph, R A3 is -NH(hydroxy-substituted C 3~6 Monocyclic cycloalkyl) and the like -NH (substituted C 3~6 In other embodiments of this paragraph, R A3 can be an unsubstituted or substituted 5-membered monocyclic heteroaryl. For example, R A3 is unsubstituted C 1~4 In still other embodiments of this paragraph, R A3 can be an unsubstituted 4-6 membered monocyclic heterocyclyl. In still yet other embodiments of this paragraph, R A3can be a substituted 4-6 membered monocyclic heterocyclyl. In some embodiments of this paragraph, R A3 is hydroxy and / or unsubstituted C 1~4 It may be a 4-6 membered monocyclic heterocyclyl substituted by alkyl.

[0147] In some embodiments, the compound of formula (I) or a pharma- ceutical acceptable salt thereof can be: 1 but,

[0148] [ka] R 2 but,

[0149] [ka] In some embodiments of this paragraph, Y 1D can be CH or C-(halogen), Y 2D can be CH, C-(halogen), or C-CH3; Y 3D In other embodiments of this paragraph, Y can be CH. 1D can be CH, and Y 2D can be CH, and Y 3D can be N. In still other embodiments of this paragraph, Y 1D can be CH, and Y 2D can be N and Y 3D In still yet other embodiments of this paragraph, Y can be CH. 1D can be CH, and Y 2D can be N and Y 3D can be N. In some embodiments of this paragraph, R A4 is unsubstituted C 1~5 In other embodiments of this paragraph, R A4 is unsubstituted C 1~5 In some embodiments of this paragraph, R A5 can be hydrogen.

[0150] In some embodiments, the compound of formula (I) or a pharma- ceutical acceptable salt thereof can be: 1 but,

[0151] [ka] R 2 but,

[0152] [ka] In some embodiments of this paragraph, Y 1D can be CH or C-(halogen), Y 2D can be CH, C-(halogen), or C-CH3; Y 3D In some embodiments of this paragraph, Y can be CH. 1D can be CH, and Y 2D can be CH, C-(halogen), or C-CH3; Y 3D In some embodiments of this paragraph, Y can be CH. 1D can be CH, and Y 2D can be C-(halogen), Y 3D can be CH.

[0153] In some embodiments, the compound of formula (I) or a pharma- ceutical acceptable salt thereof can be: 1 but,

[0154] [ka] R 2 but,

[0155] [ka] In some embodiments of this paragraph, Y 1E can be CH. In some embodiments of this paragraph, R A4 is unsubstituted C 1~5 It may be alkyl.

[0156] In some embodiments, the compound of formula (I) or a pharma- ceutical acceptable salt thereof can be: 1 but,

[0157] [ka] R 2 but,

[0158] [ka] In some embodiments of this paragraph, Y 2H , Y 4H , and Y 5H are CH, and Y 1H , Y 3H , and Y 6H may each be N.

[0159] In some embodiments, the compound of formula (I) or a pharma- ceutical acceptable salt thereof can be: 1 but,

[0160] [ka] R 2 but,

[0161] [ka] In some embodiments of this paragraph, Y 1B can be CH or N, Y 2B can be CH, C-halogen, C-(NH2), or N; Y 3B can be CH, and Y 4B can be CH or N. In some embodiments of this paragraph, Y 1B can be CH, and Y 2B can be CH, C-halogen, or C-(NH), and Y 3B can be CH, and Y4B In other embodiments of this paragraph, Y can be CH. 1B can be N and Y 2B can be N and Y 3B can be CH, and Y 4B In still other embodiments of this paragraph, Y can be CH. 1B can be CH, and Y 2B can be CH, and Y 3B can be CH, and Y 4B can be N. In some embodiments of this paragraph, R A2 can be -CH3. In some embodiments of this paragraph, R A2 can be -CD3.

[0162] In some embodiments, the compound of formula (I) or a pharma- ceutical acceptable salt thereof can be: 1 but,

[0163] [ka] R 2 but,

[0164] [ka] In some embodiments of this paragraph, X 1C can be hydrogen. In other embodiments of this paragraph, X 1C is unsubstituted C 1~5 It may be alkyl.

[0165] Examples of compounds of formula (I) include:

[0166] [ka]

[0167] [ka]

[0168] [ka]

[0169] [ka]

[0170] [ka] or a pharma- ceutically acceptable salt of any of the foregoing.

[0171] Additional examples of compounds of formula (I), including pharma- ceutically acceptable salts thereof, include:

[0172] [ka]

[0173] [ka]

[0174] [ka]

[0175] [ka]

[0176] [ka]

[0177] [ka]

[0178] [ka] or a pharma- ceutically acceptable salt of any of the foregoing.

[0179] In some embodiments, the compound of formula (I) has the following formula:

[0180] [ka] or a pharma- ceutically acceptable salt thereof.

[0181] synthesis Compounds of formula (I) can be prepared in various ways, together with the compounds described herein. The general synthetic route for preparing compounds of formula (I) is shown and described herein, together with some examples of starting materials used to synthesize the compounds described herein. The routes shown and described herein are merely exemplary, and are not intended to limit the scope of the claims in any way, and should not be interpreted as such. Those skilled in the art can recognize modifications of the disclosed synthesis and devise alternative routes based on the disclosure of this specification, and all such modifications and alternative routes are within the scope of the claims.

[0182] [ka]

[0183] Compounds of formula (I) (including pharma- ceutically acceptable salts thereof) can be prepared from intermediates of formula (II) in which PG represents an amino protecting group such as Boc. The PG group can be cleaved from compounds of formula (II) using methods known in the art. For example, when PG represents a Boc group, PG can be cleaved using acidic conditions, for example in the presence of HCl in a suitable solvent (such as 1,4-dioxane) or in the presence of copper triflate. Compounds of formula (I) together with pharma- ceutically acceptable salts thereof can be obtained by coupling intermediates of formula (III) with a suitable agent. As an example, compounds of formula (I) together with pharma- ceutically acceptable salts thereof can be prepared by reacting compounds of formula (III) with a general formula R 1 As an alternative example, compounds of formula (I) and pharma- ceutically acceptable salts thereof can be obtained by reacting a compound of formula (III) with an acyl chloride of -C(=O)-Cl in the presence of a suitable base (e.g., triethylamine) in a suitable solvent (e.g., acetonitrile). 1 -COOH with a carboxylic acid in the presence of a suitable base (e.g., triethylamine) using a suitable amino acid coupling agent (e.g., HATU or EDC) in a suitable solvent (e.g., acetonitrile or DMF). Further compounds of formula (I), together with their pharma- ceutically acceptable salts, can be prepared from compounds of formula (III) using methods known in the art.

[0184] [ka]

[0185] Compounds of formula (I), including pharma- ceutically acceptable salts thereof, can also be prepared from intermediates of formula (IV) in which LG represents a leaving group, such as sulfhydryl, methylsulfoxide, or halogen (e.g., Cl or Br). Compounds of formula (I) can be prepared from compounds of formula (IV) in which LG represents -SO2CH3 by reacting 3,5-dimethyl-1H-pyrazole in the presence of a base, such as diisopropylethylamine (DIPEA) or NaH, in a suitable solvent, such as THF, DMF, or acetonitrile. Compounds of formula (I) can be prepared from compounds of formula (IV) in which LG represents chloro by reacting 3,5-dimethyl-1H- in the presence of a base, such as triethylamine, DBU, or DIPEA, in a suitable solvent, such as acetonitrile, DMF, or THF, optionally in the presence of a catalyst, such as DMAP.

[0186] [ka]

[0187] R 2 Compounds of formula (I) in which represents phenyl or heteroaryl, together with their pharma- ceutically acceptable salts, can be prepared from compounds of formula (Va) and formula (Vb). Formula (Va) and formula (Vb) can in turn be prepared by reacting the corresponding heteroaryl halide (such as bromo or iodo) with a palladium catalyst (e.g., Pd(PPh 34 ) in the presence of a base (e.g., Cs2CO3) and pinacoldiborane in a suitable solvent or solvent mixture (e.g., 1,4-dioxane / H2O). Alternatively, other methods known to those skilled in the art may be used to generate the boronic acid or boronic ester (e.g., Leermann et al., Org. Lett. (2011) 13, 4479-4481; Zhang et al., J. Am. Chem. Soc. (2019) 141, 9124-9128; Mfuh et al., J. Am. Chem. Soc. (2016) 138, 2985-2988).

[0188] [ka]

[0189] The compound of formula (I), together with its pharma- ceutically acceptable salts, can be prepared from the intermediate of formula (VI) and 3,5-dimethylpyrazole in the presence of t-butyl hydroperoxide (TBHP) in a suitable solvent (e.g., acetonitrile).

[0190] [ka]

[0191] R 2 Compounds of formula (I), including pharma- ceutical acceptable salts thereof, in which R represents an amide substituted phenyl or heteroaryl, can be prepared by reacting an acid intermediate of formula (VIIa) with an intermediate of formula NH2-R A2 can be prepared from the amine of R using a peptide coupling agent (such as HATU) in the presence of a base (e.g., diisopropylethylamine) in a suitable solvent such as acetonitrile or DMF. 2 represents an amide-substituted phenyl, or R 2 Compounds of formula (I) wherein represents an amide substituted heteroaryl, together with pharma- ceutical acceptable salts thereof, can be prepared by the synthesis of ester intermediates of formula (VIIb) and of the general formula NH2-R A2 can be prepared from the amine of formula (I) in a suitable solvent (such as acetonitrile), optionally at elevated temperature.

[0192] [ka]

[0193] R 2Compounds of formula (I) or a pharma- ceutically acceptable salt thereof, in which R represents phenyl or heteroaryl substituted with an amine, can be prepared from intermediates of formula (VIII) and an amine via Buchwald-Hartwig amination using a catalyst (e.g., XantPhos Pd G3) in a suitable solvent (such as 1,4-dioxane) in the presence of a base (e.g., Cs2CO3). 2 Compounds of formula (I), or pharma- ceutically acceptable salts thereof, in which represents phenyl or heteroaryl substituted with monocyclic heteroaryl, can be prepared from intermediates of formula (VIII) and boronic acids or boronic acid esters (e.g., optionally substituted 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-ylheteroaryl) in the presence of a base (e.g., Cs2CO3) using a catalyst such as Pd(PPh3)4 in a suitable solvent such as 1,4-dioxane / H2O. Examples of this reaction in the literature are described, and the following references are examples: Fan, et al., Org. Lett. (2015) 17, 5934-5937, Sheng et al. Org. Lett. (2008) 10, 4109-4112.

[0194] [ka]

[0195] The intermediate of formula (IIb) can be prepared from the compound of formula (IX) using ammonium acetate in a suitable solvent (such as ethanol) to give the intermediate of formula (X). The intermediate of formula (X) can be treated with a base such as NaH in a suitable solvent (such as THF) followed by conversion of the intermediate of general formula R 2 Subsequent addition of the isothiocyanate of -NCS can provide the intermediate of formula (XI), which can then be alkylated with iodomethane or any alkyl halide in the presence of a base (such as DBU) in a suitable solvent (such as DMF) to provide the compound of formula (IIb).

[0196] [ka]

[0197] The intermediate of formula (III) can be prepared from the compound of formula (XI) using methyl iodide or methyl bromide in a suitable solvent such as DMF in the presence of a base such as DBU to obtain the intermediate of formula (IIb). The oxidation of the intermediate of formula (IIb) to the sulfoxide intermediate of formula (IIc) can be achieved by treating with an oxidizing agent (such as m-CPBA) in the presence of MgSO4 and NaOAc in a suitable solvent such as dichloromethane. The intermediate of formula (III) can be obtained by treating the intermediate of formula (IIc) with 3,5-dimethylpyrazole in the presence of a base (such as DIPEA) and optionally in the presence of a catalyst (for example DMAP) in a suitable solvent such as DMF.

[0198] [ka]

[0199] Intermediates of formula (IV), in which the leaving group LG represents methyl sulfoxide, can be prepared from intermediates of formula (VI) using methyl iodide or methyl bromide in the presence of a base (e.g. DBU) in a suitable solvent such as DMF to give intermediates of formula (XIV). Oxidation of intermediates of formula (XIV) to sulfoxide intermediates of formula (IV, LG is sulfoxide) can be achieved using an oxidizing agent such as m-CPBA in the presence of MgSO4 and NaOAc in a suitable solvent such as dichloromethane.

[0200] [ka]

[0201] Intermediates of formula (IV) in which the leaving group LG is chloro may be prepared from intermediates of formula (VI) using thiophosgene or sulfuryl chloride in a suitable solvent (such as THF).

[0202] [ka]

[0203] Intermediates of formula (VI) can be prepared from intermediates of formula (XV) in the presence of a base such as NaH in a suitable solvent (e.g., THF), followed by reaction with intermediates of general formula R 2 The isothiocyanate of -NCS can then be added to give the intermediate of formula (XVI). The Boc group of the intermediate of formula (XVI) can be deprotected in the presence of an acid (e.g., HCl or TFA) in a suitable solvent (e.g., 1,4-dioxane) to give the intermediate of formula (XVII). The intermediate of formula (VI) can be prepared from the intermediate of formula (XVII) according to several conditions known to those skilled in the art.

[0204] Further compounds of formula (VI) can be prepared by reacting a compound of formula (XVII) with the general formula R 1 Compounds of formula (VI) can be obtained by reacting a compound of formula (XVII) with an acyl chloride of general formula R in the presence of an amide coupling agent (such as HATU) in a suitable solvent, including bases and solvents known to those skilled in the art (e.g., DMF). 1 Additional compounds of formula (VI) may be prepared from compounds of formula (XVII) using methods known in the art.

[0205] [ka]

[0206] The intermediate of formula (VI) can be prepared from the intermediate of formula (XVIII) according to conditions known in the art, such as the conditions used to convert the intermediate of formula (XVII) to the intermediate of formula (VI). For example, the intermediate of formula (XIX) can be prepared by reacting a compound of formula (XVIII) with a compound of general formula R 1Additional compounds of formula (XIX) can be obtained by reacting a compound of formula (XVIII) with an acyl chloride of general formula R in the presence of an amide coupling agent (such as HATU) in a suitable solvent. 1 The carboxylic acid may be obtained by reacting with a carboxylic acid of -C(=O)-OH. Suitable solvents are known to those skilled in the art and / or described herein.

[0207] The intermediate of formula (XX) may be prepared from the intermediate of formula (XI) in the presence of ammonium acetate in a suitable solvent (such as ethanol). The intermediate of formula (VI) may be prepared from the intermediate of formula (XI) in the presence of a base (such as NaH) in a suitable solvent (such as THF) by subsequent reaction with the intermediate of general formula R 2 The intermediate of formula (XX) can be prepared by addition of an isothiocyanate of -NCS. The intermediate of formula (XX) can be treated with thiophosgene / NMM in a suitable solvent such as dichloromethane to give an intermediate isothiocyanate, which can be converted to an isothiocyanate of general formula NH2-R in a suitable solvent (such as acetonitrile) in the presence of a base such as triethylamine. 2 can be converted to an intermediate of formula (VI) by using an amine of the formula:

[0208] [ka]

[0209] The intermediate of formula (II), where PG is a protecting group such as Boc, can be prepared from the intermediate of formula (XXI) using a guanidine derivative of formula (XXII) in a suitable solvent (such as CHCN) in the presence of a base such as DBU to give the intermediate of formula (XXIII). The intermediate of formula (XXIII) can be used to give the intermediate of formula (II) using methods known in the art. As an example, the intermediate of formula (XXIII) can be converted to a compound of general formula R in the presence of TMEDA and Cu(OAc) 2 -B(OH)2 with an aryl or heteroaryl boronic acid to form R 2Intermediates of formula (II) can be obtained in which R represents a phenyl, a monocyclic heteroaryl, or a fused bicyclic heteroaryl.

[0210] [ka]

[0211] The intermediate of formula (XI) can be obtained from the intermediate of formula (XV) using methods known in the art, for example by treating the intermediate of formula (XV) with thiophosgene and NMM in a suitable solvent, such as THF. 2 Treatment with an amine of -NH2 gives intermediates of formula (XI) in which PG represents a Boc group.

[0212] [ka]

[0213] The intermediate of formula (III) can be prepared from the chloro-N-Boc-aminopyridine carboxylic acid intermediate of formula (I1) using a base (such as triethylamine) in the presence of 2-chloro-N-methylpyridinium iodide in a suitable solvent (e.g., acetonitrile) to give the intermediate of formula (I2). The intermediate of formula (I2) can be prepared by reacting the intermediate of formula R 2 The intermediate of formula (XXV) can be converted to an intermediate of formula (XXV) using an amine of -NH2. The intermediate of formula (XXV) can be reacted with 1,1'-thiocarbonyldiimidazole (TCDI) in DMF to give a thio intermediate of formula (XXVI), which can be converted to an intermediate of formula (XXVII) using thiophosgene or sulfuryl chloride in a suitable solvent (such as 1,4-dioxane). The intermediate of formula (XXVII) can be treated with 3,5-dimethylpyrazole to give an intermediate of formula (XXVIII). The intermediate of formula (XXVIII) can be reacted with 1,1'-thiocarbonyldiimidazole (TCDI) in a suitable solvent (such as dioxane / water) using a Pd catalyst (e.g. Pd(Ph34 ) with methylboronic acid to give an intermediate of formula (XXIXa). The intermediate of formula (XXIXa) can be converted to an intermediate of formula (III) by catalytic hydrogenation using H2 in the presence of a catalyst (e.g., Pt / C) in a suitable solvent (e.g., acetic acid / THF / ethanol).

[0214] [ka]

[0215] The intermediate of formula (Va) can be prepared from an intermediate of formula (XXIX) in which LG represents a leaving group, such as sulfhydryl, methylsulfoxide, or halogen, such as chloro or bromo. The intermediate of formula (XXIX) can be reacted with 3,5-dimethyl-1H-pyrazole in the presence of a base, such as diisopropylethylamine, in a suitable solvent, such as acetonitrile, to give the intermediate of formula (XXX). Conversion of the bromo intermediate formula (XXX) to the boronate intermediate of formula (Va) can be achieved using bis(pinacolato)diboron in the presence of a base, such as KOAc, in the presence of a catalyst, such as Pd(dppf)Cl2, in a suitable solvent, such as 1,4-dioxane.

[0216] [ka]

[0217] The intermediate of formula (Vb) can be prepared from the intermediate of formula (XXX) using bis(pinacolato)diboron in the presence of a base (e.g., KOAc) and Pd(dppf)Cl in a suitable solvent such as 1,4-dioxane and water to give the intermediate of formula (Vb).

[0218] [ka]

[0219] The intermediate of formula (XXXI) can be prepared from the intermediate of formula (IV) using hydrazine monohydrate in a suitable solvent (such as ethanol). Subsequent formation of the compound of formula (I), including its pharma-ceutically acceptable salts, can be achieved by reacting the intermediate of formula (XXXI) with acetylacetone in a polar solvent (e.g., ethanol) at elevated temperature.

[0220] [ka]

[0221] Alternatively, intermediates of formula (XXXI) can be prepared from intermediates of formula (VI) using an oxidizing agent such as AcOOH 35% in acetic acid or urea peroxide in the presence of hydrazine monohydrate in a suitable solvent (such as isopropanol). Subsequent formation of compounds of formula (I), including pharma-ceutically acceptable salts thereof, can be achieved by reacting intermediates of formula (XXXI) with acetylacetone in a polar solvent (e.g., isopropanol) at elevated temperatures.

[0222] Pharmaceutical Compositions Some embodiments described herein relate to pharmaceutical compositions that can include an effective amount of a compound described herein (e.g., a compound described herein or a pharma- ceutically acceptable salt thereof) and a pharma- ceutically acceptable carrier, excipient, or combination thereof. The pharmaceutical compositions described herein are suitable for human and / or veterinary use.

[0223] As used herein, "carrier" refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, and without limitation, dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.

[0224] As used herein, "diluent" refers to an ingredient in a pharmaceutical composition that is not pharmacologically active, but may be medicamentally necessary or desirable. For example, a diluent may be used to bulk a potent drug whose mass is too small for manufacture and / or administration. A diluent may also be a liquid for dissolving a drug to be administered by injection, ingestion, or inhalation. A common form of diluent in the art is a buffered aqueous solution, such as, but not limited to, phosphate buffered saline, which mimics the composition of human blood.

[0225] As used herein, "excipient" refers to an inert substance added to a pharmaceutical composition to provide the composition with, but not limited to, bulk, consistency, stability, binding ability, lubrication, disintegration ability, etc. A "diluent" is a type of excipient.

[0226] Appropriate formulation depends on the route of administration selected.The techniques for formulating and administering the compounds described herein are known to those skilled in the art.There are multiple techniques for administering compounds in the art, including but not limited to oral, rectal, topical, aerosol, injection, and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injection, intrathecal, direct intraventricular, intraperitoneal, intranasal, and intraocular injection.The pharmaceutical composition is generally adjusted to the specific intended route of administration.

[0227] The compounds can also be administered locally rather than systemically, for example, by injecting the compound directly into the site of infection, often in a depot or sustained release formulation. Additionally, the compounds can be administered in targeted drug delivery systems, for example, in liposomes coated with tissue-specific antibodies. Liposomes can be targeted to and taken up selectively by organs.

[0228] The pharmaceutical compositions disclosed herein may be manufactured in a manner known per se, for example by conventional mixing, dissolving, granulating, dragee-making, elutriating, emulsifying, encapsulating, entrapping or tabletting processes. As described herein, the compounds used in the pharmaceutical compositions may be provided as salts with pharma- ceutically compatible counterions.

[0229] How to use Some embodiments described herein relate to methods of treating HBV and / or HDV infection, which may include administering to a subject identified as suffering from HBV and / or HDV infection an effective amount of a compound described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharma- ceutically acceptable salt thereof. Other embodiments described herein relate to the use of a compound described herein or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating HBV and / or HDV infection. Still other embodiments described herein relate to the use of a compound described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharma- ceutically acceptable salt thereof, for the treatment of HBV and / or HDV infection.

[0230] Some embodiments disclosed herein relate to methods of treating HBV and / or HDV infection, which may include contacting a cell infected with HBV and / or HDV with an effective amount of a compound described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharma- ceutically acceptable salt thereof. Other embodiments described herein relate to the use of a compound described herein or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating HBV and / or HDV infection. Still other embodiments described herein relate to the use of a compound described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharma- ceutically acceptable salt thereof, for the treatment of HBV and / or HDV infection.

[0231] Some embodiments disclosed herein relate to methods of inhibiting HBV and / or HDV replication, which may include contacting a cell infected with HBV and / or HDV with an effective amount of a compound described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharma- ceutically acceptable salt thereof. Other embodiments described herein relate to the use of a compound described herein or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for inhibiting HBV and / or HDV replication. Still other embodiments described herein relate to the use of a compound described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharma- ceutically acceptable salt thereof, for inhibiting HBV and / or HDV replication.

[0232] In some embodiments, the HBV infection can be an acute HBV infection. In some embodiments, the HBV infection can be a chronic HBV infection.

[0233] Some embodiments disclosed herein relate to a method for treating cirrhosis of the liver, which may include administering to a subject suffering from cirrhosis an effective amount of a compound described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharma- ceutically acceptable salt thereof, and / or contacting a cell infected with HBV and / or HDV in a subject suffering from cirrhosis with the compound. Other embodiments described herein relate to the use of a compound described herein or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating cirrhosis of the liver with an effective amount of the compound or a pharma- ceutically acceptable salt thereof. Still other embodiments described herein relate to the use of a compound described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharma- ceutically acceptable salt thereof, for treating cirrhosis of the liver.

[0234] Some embodiments disclosed herein relate to a method for treating liver cancer (such as hepatocellular carcinoma) developed for HBV and / or HDV infection, which may include administering to a subject suffering from liver cancer an effective amount of a compound described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharma- ceutically acceptable salt thereof, and / or contacting cells infected with HBV and / or HDV in a subject suffering from liver cancer with the compound. Other embodiments described herein relate to the use of a compound described herein or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating liver cancer (such as hepatocellular carcinoma). Still other embodiments described herein relate to the use of a compound described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharma- ceutically acceptable salt thereof, for treating liver cancer (such as hepatocellular carcinoma).

[0235] Some embodiments disclosed herein relate to a method for treating liver failure developed for HBV and / or HDV infection, which may include administering to a subject suffering from liver failure an effective amount of a compound described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharma- ceutically acceptable salt thereof, and / or contacting cells infected with HBV and / or HDV in a subject suffering from liver failure with the compound. Other embodiments described herein relate to the use of a compound described herein or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating liver failure. Still other embodiments described herein relate to the use of a compound described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharma- ceutically acceptable salt thereof, for treating liver failure.

[0236] Various indicators for determining the effectiveness of a method for treating HBV and / or HDV infection are also known to those skilled in the art. Examples of suitable indicators include viral load (or burden) as indicated by a reduction in HBV DNA (e.g., <10 in serum). 5 These include, but are not limited to, reduction in HBV infection (reduced HBV copies / mL), reduction in HBV surface antigen (HBsAg) and HBV e-antigen (HBV e-antigen, HBeAg), reduction in plasma viral load, reduction in viral replication, shortening the time to seroconversion (undetectable virus in patient serum), increasing the rate of sustained viral response to therapy, improving liver function, and / or reducing morbidity or mortality in clinical outcomes.

[0237] As used herein, the terms "treat," "treating," "treatment," "therapeutic," and "therapy" do not necessarily mean a complete cure or elimination of a disease or condition. Any alleviation, to any extent, of any undesirable signs or symptoms of a disease or condition may be considered treatment and / or therapy. Additionally, treatment may include actions that may worsen a subject's overall feeling of health or appearance.

[0238] As used herein, "subject" refers to an animal that is the object of treatment, observation, or experiment. "Animals" include cold-blooded and warm-blooded vertebrates and invertebrates, such as fish, crustaceans, reptiles, and especially mammals. "Mammals" include, but are not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and especially humans. In some embodiments, the subject is a human.

[0239] The term "effective amount" is used to indicate the amount of an active compound or drug that induces the indicated biological or pharmaceutical response. For example, an effective amount of a compound may be the amount necessary to alleviate or ameliorate the symptoms of a disease or prolong the survival of the subject being treated. This response may occur in a tissue, system, animal, or human, and includes alleviating the signs or symptoms of the disease being treated. Determination of an effective amount is well within the capabilities of one of ordinary skill in the art in light of the disclosure provided herein. The effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including humans, being treated, and the physical characteristics of the particular animal under consideration. Dosages may be adjusted to achieve the desired effect, but will depend on factors such as body weight, diet, concomitant medications, and other factors that one of ordinary skill in the medical field would recognize.

[0240] In some embodiments, an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, is an amount effective to achieve a sustained viral response, e.g., a sustained viral response 12 months after completion of treatment.

[0241] Subjects clinically diagnosed with HBV and / or HDV infection include "naive" subjects (e.g., subjects not previously treated for HBV and / or HDV) and subjects who have failed prior HBV and / or HDV treatment ("treatment failure" subjects). Treatment failure subjects include "non-responders" (subjects who have not achieved a sufficient reduction in ALT (alanine aminotransferase) levels, e.g., subjects who have not achieved a greater than 1 log10 reduction from baseline within 6 months of starting anti-HBV and / or anti-HDV therapy) and "relapsers" (subjects previously treated for HBV and / or HDV who have increased ALT levels, e.g., ALT >2x upper normal limit and detectable serum HBV DNA by hybridization assay). Further examples of subjects include subjects with HBV and / or HDV infection who are asymptomatic.

[0242] In some embodiments, the compounds described herein or pharma- ceutically acceptable salts thereof may be provided to treatment-failed subjects suffering from HBV and / or HDV. In some embodiments, the compounds described herein or pharma- ceutically acceptable salts thereof may be provided to non-responder subjects suffering from HBV and / or HDV. In some embodiments, the compounds described herein or pharma- ceutically acceptable salts thereof may be provided to relapser subjects suffering from HBV and / or HDV. In some embodiments, the subject may have HBeAg-positive chronic hepatitis B. In some embodiments, the subject may have HBeAg-negative chronic hepatitis B. In some embodiments, the subject may have cirrhosis. In some embodiments, the subject may be asymptomatic, e.g., the subject may be infected with HBV and / or HDV but does not show any symptoms of viral infection. In some embodiments, the subject may be immunocompromised. In some embodiments, the subject may be undergoing chemotherapy.

[0243] Examples of drugs that have been used to treat HBV and / or HDV include immunomodulators and nucleosides / nucleotides. Examples of immunomodulators include interferons (IFN-α and PEGylated interferons, including PEG-IFN-α-2a), and examples of nucleosides / nucleotides include lamivudine, telbivudine, adefovir dipivoxil, clevudine, entecavir, tenofovir alafenamide, and tenofovir disoproxil. However, some of the drawbacks associated with interferon therapy are adverse side effects, the need for subcutaneous administration, and high cost. Potential advantages of the compound of formula (I), or a pharma- ceutically acceptable salt of any of the foregoing, may be fewer adverse side effects, delayed onset of adverse side effects, and / or reduced severity of adverse side effects. A drawback with nucleoside / nucleotide therapy may be the development of resistance, including cross-resistance.

[0244] Resistance may be a cause of treatment failure. As used herein, the term "resistance" refers to a virus strain that shows delayed, attenuated, and / or ineffective response to an antiviral agent. In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof can be provided to a subject infected with an HBV and / or HDV strain that is resistant to one or more anti-HBV and / or anti-HDV agents. Examples of antiviral agents to which resistance may develop include lamivudine, telbivudine, adefovir dipivoxil, clevudine, entecavir, tenofovir alafenamide, and tenofovir disoproxil. In some embodiments, when a subject is treated with a compound described herein or a pharmaceutically acceptable salt thereof, the development of resistant HBV and / or HDV strains is delayed compared to the development of HBV and / or HDV strains resistance to other HBV and / or HDV antiviral agents, such as those described.

[0245] Combination therapy In some embodiments, the compounds described herein or pharma- ceutically acceptable salts thereof can be used in combination with one or more additional agents for treating and / or inhibiting replicating HBV and / or HDV. Additional agents include, but are not limited to, interferons, nucleoside / nucleotide analogs, sequence-specific oligonucleotides (such as antisense oligonucleotides and siRNAs), nucleic acid polymers (NAPs, e.g., nucleic acid polymers that reduce HBsAg levels), entry inhibitors, and / or small molecule immunomodulators. Examples of additional agents include recombinant interferon alpha 2b, IFN-α, PEG-IFN-α-2a, lamivudine, telbivudine, adefovir dipivoxil, clevudine, entecavir, tenofovir alafenamide, and tenofovir disoproxil. Examples of NAPs include, but are not limited to, STOPS™ compounds such as REP2139, REP2165, and the modified oligonucleotides identified as numbers 1-392 described in U.S. Patent Application Publication No. 2020 / 0147124(A1), which is incorporated by reference herein for purposes of describing the STOPS™ compounds provided in this disclosure.

[0246] In some embodiments, the compounds described herein or pharma- ceutically acceptable salts thereof may be administered together with one or more additional agents in a single pharmaceutical composition. In some embodiments, the compounds or pharma- ceutically acceptable salts thereof may be administered together with one or more additional agents as two or more separate pharmaceutical compositions. Furthermore, the order of administration of the compounds described herein or pharma- ceutically acceptable salts thereof with one or more additional agents may be different. EXAMPLES

[0247] Further embodiments, which are not intended to limit the scope of the claims in any way, are disclosed in more detail in the following examples.

[0248] [Table 1]

[0249] 4-[(6R)-7-[4-bromo-3-(trifluoromethyl)benzoyl]-2-chloro-6-methyl-4-oxo-3H,4H,5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-3-yl]-N-methylbenzamide

[0250] [ka]

[0251] To a solution of oxalyl dichloride (181 g, 1.43 mol) in CH2Cl2 (1.5 L) at -65°C was added DMSO (111 mL) in CH2Cl2 (500 mL). After stirring for 1 h, t-butyl (R)-(1-hydroxypropan-2-yl)carbamate (250 g, 1.43 mol) in CH2Cl2 (500 mL) was added dropwise. After stirring for 2 h, Et3N (144 g, 1.43 mol, 198 mL) was added dropwise. The mixture was gradually warmed to 25°C and then stirred at 25°C for 4 h. The reaction was quenched by the addition of NH4Cl (sat. aq., 2.5 L) and then extracted with CH2Cl2 (2 x 2.5 L). The combined organic layers were dried over Na2SO4. The solids were removed by filtration and the filtrate was concentrated under reduced pressure to give the crude product t-butyl (R)-(1-oxopropan-2-yl)carbamate (450 g, 2.60 mol, 91% yield) as a colorless oil, which was used in the next step without further purification.

[0252] To a solution of t-butyl (R)-(1-oxopropan-2-yl)carbamate (225 g, 1.30 mol) in CHCl (2.25 L) was added (carbethoxymethylene)triphenylphosphorane (429 g, 1.23 mol). The mixture was stirred at 25° C. for 12 h. The mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (PE:EA=15:1 to 5:1) to give ethyl (R)-4-((t-butoxycarbonyl)amino)pent-2-enoate (500 g, 2.06 mol, 79.1% yield) as a colorless oil.1 HNMR(400MHz,CDCl3)δ6.86(dd,J=15.76,4.88Hz,1H)5.89(dd,J=15.70,1.56Hz,1H) 4.58(brs,1H)4.39(brs,1H)4.18(q,J=7.13Hz,2H)1.44(s,9H)1.24-1.29(m,6H)ppm.

[0253] To a solution of ethyl (R)-4-((t-butoxycarbonyl)amino)pent-2-enoate (125 g, 513 mmol) in CH3OH (1.25 L) was added 10% Pd / C (6.00 g) and Pd(OH)2 (6.06 g) under N2. The suspension was degassed under vacuum and purged several times with H2 (1.04 g, 514 mmol). The mixture was stirred under H2 (50 psi) at 50 °C for 12 h. The solids were removed by filtration under N2 and the filtrate was evaporated to dryness to give ethyl (R)-4-((t-butoxycarbonyl)amino)pentanoate (480 g, 1.96 mol, 95% yield) as a colorless oil. 1 HNMR(400MHz,CDCl3)δ4.29-4.45(m,1H)4.13(q,J=7.13Hz,2H)3.57-3.75(m,1H)2.35(t,J= 7.69Hz,2H)1.66-1.84(m,3H)1.43(s,9H)1.25(t,J=7.13Hz,3H)1.14(d,J=6.50Hz,3H)ppm.

[0254] To a solution of ethyl (R)-4-((t-butoxycarbonyl)amino)pentanoate (480 g, 1.96 mol) in EA (2 L) was added HCl in EA (4 M, 2.5 L). The mixture was stirred at 25° C. for 2 h. The mixture was concentrated under reduced pressure to give ethyl (R)-4-aminopentanoate HCl (450 g, crude) as a yellow oil, which was used directly in the next step without purification.

[0255] To a mixture of ethyl (R)-4-aminopentanoate HCl (225 g, 1.24 mol) in THF (4 L) and HO (1 L) was added KCO (427 g, 3.10 mol) at 25° C. After the addition, the yellow solution was stirred at 25° C. for 30 min. A solution of ethyl 2-bromoacetate (206 g, 1.24 mol, 137 mL) was added dropwise over 30 min at 25° C. The yellow solution was stirred at 25° C. for 11 h. The crude product ethyl (R)-4-((2-ethoxy-2-oxoethyl)amino)pentanoate (400 g, 1.73 mol, 70% yield) was obtained as a colorless oil, which was used in the next step without workup or purification.

[0256] A solution of (Boc)2O (189 g, 865 mmol, 199 mL) was added dropwise to ethyl (R)-4-((2-ethoxy-2-oxoethyl)amino)pentanoate (200 g, 865 mmol) over 30 min. The yellow solution was stirred at 25 °C for 6 h and then pumped onto the filter. The filter cake was washed with EA (1 L) and the filtrate was collected. To the filtrate was added H2O (3 L). The mixture was extracted with EA (2 x 5 L). The combined organic layers were washed with brine (2 L) and dried over Na2SO4. The solids were removed by filtration. The filtrate was concentrated under reduced pressure to give the crude product ethyl (R-4-((t-butoxycarbonyl)(2-ethoxy-2-oxoethyl)amino)pentanoate (400 g, 1.21 mol, 70% yield) as a yellow oil, which was used in the next step without purification. 1 HNMR(400MHz,CDCl3)δ4.06-4.22(m,4H)3.54-3.93(m,2H)2.26-2.55(m,2H)1. 71(qd,J=7.48,3.69Hz,2H)1.45-1.55(m,6H)1.42(s,4H)1.22-1.35(m,6H)ppm.

[0257] To a mixture of ethyl (R)-4-((t-butoxycarbonyl)(2-ethoxy-2-oxoethyl)amino)pentanoate (200 g, 603 mmol) in THF (2 L) at 0° C. under N2 was added t-BuOK (135 g, 1.21 mol). The mixture was stirred at 25° C. under N2 for 12 h. The reaction was quenched by addition of aqueous citric acid (250 g in 3 L H2O) below 10° C. The mixture was extracted with EA (3×2.5 L). The combined organic layers were washed with brine (2 L×1) and dried over Na2SO4. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (PE:EA=15:1-10:1) to give 1-(t-butyl) 4-ethyl 5-oxo-2-(R)-methyl-3,6-dihydropyridine-1,4(2H)-dicarboxylate (210 g, 736 mmol, 61% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ12.06(s,1H),4.54(brs,1H),4.33(brd,J=19.39Hz,1H),4.23(dtt,J=10.62,7.07,7.07,3.63,3.63Hz,2H),3. 64(brd,J=19.26Hz,1H),2.45-2.55(m,1H),2.18(d,J=15.63Hz,1H),1.47(s,9H)1.31(t,J=7.13Hz,3H),1.11(d,J=6.88Hz,3H)ppm.

[0258] To a solution of 1-(t-butyl) 4-ethyl 5-oxo-2-(R)-methyl-3,6-dihydropyridine-1,4(2H)-dicarboxylate (210 g, 736 mmol) in EA (1 L) was added a solution of HCl:EA (4 M, 2 L) dropwise at 25° C. The mixture was stirred at 25° C. for 3 h and then concentrated under reduced pressure. The crude product was triturated with EA (500 mL) at 25° C. for 30 min to give ethyl (R)-5-hydroxy-2-methyl-1,2,3,6-tetrahydropyridine-4-carboxylate HCl (140 g, 631 mmol, 86% yield, 100% purity) as a white solid. 1H NMR (400 MHz, methanol-d4) δ 4.29 (q, J = 6.96 Hz, 2H), 3.92-4.01 (m, 1H), 3.77-3.87 (m, 1H), 3.42-3.54 (m, 1H), 2.66-2.76 (m, 1H), 2.23-2.39 (m, 1H), 1.43 (d, J = 6.50 Hz, 3H), 1.32 (t, J = 7.07 Hz, 3H) ppm.

[0259] A solution of ethyl (R)-5-hydroxy-2-methyl-1,2,3,6-tetrahydropyridine-4-carboxylate HCl (115 g, 519 mmol) in DMF (1 L) was cooled to 0° C. DIPEA (268 g, 2.08 mol, 361 mL) and T3P (495 g, 778 mmol, 463 mL, 50% purity) were added. The mixture was stirred at 25° C. for 12 h. The reaction was quenched by addition of 2 L of water at 25° C. The mixture was diluted with EA (1.5 L) and extracted with EA (3×1 L). The combined organic layers were washed with brine (500 mL) and dried over Na2SO4. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% EA:PE gradient) to give ethyl (R)-1-(4-bromo-3-(trifluoromethyl)benzoyl)-5-hydroxy-2-methyl-1,2,3,6-tetrahydropyridine-4-carboxylate (130 g, 259 mmol, 50% yield, 87% purity) as a yellow oil. 1 H NMR(CDCl3400MHz),δ12.10(brs,1H),7.80(d,J=8.13Hz,1H),7.74(d,J=1.88H z,1H),7.42(dd,J=8.13,1.88Hz,1H),4.64-5.30(m,1H),4.19-4.34(m,2H),4.0 8-4.17(m,1H),3.81(brdd,J=12.13,2.75Hz,1H),2.58(brd,J=14.76Hz,1H),2 .24(brd,J=16.01Hz,1H),1.32(t,J=7.13Hz,3H),1.25(brt,J=3.13Hz,3H)ppm.

[0260] To a solution of ethyl (R)-1-(4-bromo-3-(trifluoromethyl)benzoyl)-5-hydroxy-2-methyl-1,2,3,6-tetrahydropyridine-4-carboxylate (90.0 g, 206 mmol) in ethanol (900 mL) was added NHOAc (79.5 g, 1.03 mol). The mixture was stirred at 60° C. for 2 h. The mixture was concentrated under reduced pressure, diluted with water (200 mL) and extracted with EA (3×200 mL). The combined organic layers were washed with brine (200 mL) and dried over NaSO. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-50% EA:PE gradient) to give ethyl (R)-5-amino-1-(4-bromo-3-(trifluoromethyl)benzoyl)-2-methyl-1,2,3,6-tetrahydropyridine-4-carboxylate (55.0 g, 125 mmol, 61% yield, 99% purity) as a yellow solid. 1 H-NMR (DMSO-d6,400MHz)δ7.98(d,J=8.13Hz,1H),7.84(d,J=1.75Hz,1H),7.63(dd,J=8.19,1.56Hz,1H),6.74-7.47(m,2H),4.63-4.91(m ,1H),4.00-4.08(m,2H),3.80-3.95(m,1H),3.59-3.75(m,1H),2.45(brd,J=5.75Hz,1H),2.14(brd,J=1.25Hz,1H),1.06-1.20(m,6H)ppm.

[0261] To a solution of ethyl R-5-amino-1-(4-bromo-3-(trifluoromethyl)benzoyl)-2-methyl-1,2,3,6-tetrahydropyridine-4-carboxylate (100 g, 230 mmol) and NMM (102 g, 1.01 mol, 111 mL) in CHCl (1 L) was added SCCl (55.5 g, 483 mmol, 37.0 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction was quenched by the addition of ice water (100 mL) at 0 °C. The mixture was diluted with CHCl (150 mL) and extracted with CHCl (3 x 500 mL). The combined organic layers were washed with brine (500 mL) and dried over NaSO. The solids were removed by filtration and the filtrate's solvent was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-20% EA:PE gradient) to give ethyl (R)-1-(4-bromo-3-(trifluoromethyl)benzoyl)-5-isothiocyanato-2-methyl-1,2,3,6-tetrahydropyridine-4-carboxylate (100 g, 163 mmol, 71% yield, 78% purity) as a yellow oil. 1 H-NMR(CDCl3,400MHz)δ7.74(d,J=8.13Hz,1H),7.66(d,J=1.75Hz,1H),7.34(dd,J=8.13,2.00Hz,1H),4.55-5.18(m,1H),4.14- 4.26(m,3H),3.67-3.85(m,2H),2.51-2.70(m,1H),2.31-2.47(m,1H),1.29(t,J=7.13Hz,3H),1.18(dd,J=7.00,3.38Hz,4H)ppm.

[0262] To a solution of ethyl (R)-1-(4-bromo-3-(trifluoromethyl)benzoyl)-5-isothiocyanato-2-methyl-1,2,3,6-tetrahydropyridine-4-carboxylate (100 g, 210 mmol) in CH3CN (1 L) was added 4-amino-N-methylbenzamide (31.5 g, 210 mmol) and Et3N (53.0 g, 524 mmol, 72.9 mL). The mixture was stirred at 95° C. for 12 h to give a yellow suspension. The mixture was concentrated under reduced pressure. The crude product was triturated with EA (500 mL) at 25 °C for 1 h to give (R)-4-(7-(4-bromo-3-(trifluoromethyl)benzoyl)-6-methyl-4-oxo-2-thioxo-1,4,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-3(2H)-yl)-N-methylbenzamide (80.0 g, 119 mmol, 57% yield, 86% purity) as a white solid. 1 H-NMR(DMSO-d6,400MHz)δ8.49-8.57(m,1H),8.02(brd,J=7.63Hz,1H),7.88(m,3H),7.69(brd,J=7.63Hz,1H),7.29(brd,J=8.88Hz,1H),7.25(brs ,1H),5.08-5.27(m,1H),4.18-4.35(m,1H),4.05-4.14(m,1H),2.80(d,J= 4.50Hz, 3H), 2.53-2.62 (m, 1H), 2.17-2.36 (m, 1H), 1.18-1.20 (m, 3H)ppm.

[0263] To a solution of (R)-4-(7-(4-bromo-3-(trifluoromethyl)benzoyl)-6-methyl-4-oxo-2-thioxo-1,4,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-3(2H)-yl)-N-methylbenzamide (80.0 g, 138 mmol) in dioxane (880 mL) was added SCCl2 (31.6 g, 275 mmol, 21.1 mL). The mixture was stirred at 100° C. for 2 h and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-80% EA:PE gradient) to give 4-[(6R)-7-[4-bromo-3-(trifluoromethyl)benzoyl]-2-chloro-6-methyl-4-oxo-3H,4H,5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-3-yl]-N-methylbenzamide (49.0 g, 81.5 mmol, 59% yield, 97% purity) as an off-white solid. 1 H-NMR(CD3OD,400MHz)δ7.94-8.03(m,3H),7.90(d,J=1.75Hz,1H),7.61-7.68(m,1H),7.42-7.54(m,2H),5.02-5 .49(m,1H),4.13-4.56(m,2H),2.95(s,3H),2.72-2.86(m,1H),2.56(brd,J=17.89Hz,1H),1.24-1.38(m,3H)ppm.

[0264] Example 1

[0265] [ka]

[0266] Triethylamine (159 mg, 1.57 mmol) was added to a solution of ethyl-(R)-1-(4-bromo-3-(trifluoromethyl)benzoyl)-5-isothiocyanato-2-methyl-1,2,3,6-tetrahydropyridine-4-carboxylate (500 mg, 1.048 mmol) and 1-methyl-1H-1,3-benzodiazol-5-amine (185 mg, 1.26 mmol) in anhydrous CHCN (10 mL) under N. The mixture was stirred at 95° C. for 1 h. The mixture was evaporated to dryness and purified by chromatography on silica gel (0-5% CHOH in CHCl) to give (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-6-methyl-3-(1-methyl-1H-benzo[d]imidazol-5-yl)-2-thioxo-2,3,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-4(1H)-one (414 mg, 68%) as a yellow solid. 1 H-NMR(DMSO,400MHz,80℃)δ1.25(d,J=7.8Hz,3H),2.28-2.37(m,1H),2.54- 2.63(m,1H),3.87(s,3H),4.04-4.15(m,1H),4.39-4.64(m,1H),4.70-4.97 (m,1H),6.98-7.09(m,1H),7.42(d,J=15.7Hz,1H),7.59(d,J=8.8Hz,1H),7 .65-7.70(m,1H),7.88(s,1H),8.0(m,1H),8.18(s,1H),12.33(brs,1H)ppm. LC-MS:C 24 H 19 BrF3N5O2S[M+H] + :578.

[0267] SO2Cl2 (0.14 mL, 1.73 mmol) was added to a solution of (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-6-methyl-3-(1-methyl-1H-benzo[d]imidazol-5-yl)-2-thioxo-2,3,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-4(1H)-one (500 mg, 0.86 mmol) in CHCl3 (10 mL) under N2. The mixture was stirred at room temperature for 1 h. The mixture was evaporated to dryness to give (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-chloro-6-methyl-3-(1-methyl-1H-benzo[d]imidazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one as crude product, which was used directly in the next step.

[0268] Hydrazine monohydrate (55.4 mg, 0.86 mmol) was added to a solution of (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-chloro-6-methyl-3-(1-methyl-1H-benzo[d]imidazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (500 mg, 0.86 mmol) in EtOH (7 mL). The mixture was stirred at 100° C. for 1 h and then concentrated to dryness to give (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-hydrazineyl-6-methyl-3-(1-methyl-1H-benzo[d]imidazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one as crude product, which was used directly in the next step.

[0269] Acetylacetone (0.089 mL, 0.87 mmol) was added to a solution of (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-hydrazinyl-6-methyl-3-(1-methyl-1H-benzo[d]imidazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d[pyrimidin-4(3H)-one (500 mg, 0.87 mmol) in EtOH (8.52 mL). The mixture was stirred and heated at 100 °C for 18 h. The mixture was evaporated to dryness to give the crude product, which was purified by flash chromatography on silica gel (0-10% CH3OH in DCM) to give a yellow solid. The corresponding solid was purified by reverse phase chromatography (5-100% CHOH in water (+0.1% formic acid)) to give (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-methyl-3-(1-methyl-1H-benzo[d]imidazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (1) (110 mg, 20%) as a white solid. 1 H-NMR(DMSO-d6,400MHz,80℃)δ1.26(d,J=6.9Hz,3H),1.81(s,3H),2.28(s,3H),2.52 -2.58(m,1H),2.72-2.82(m,1H),2.83(s,3H),4.27(d,J=20.3Hz,1H),4.56(br.s.,1 H),4.78(br.s.,1H),5.73(s,1H),7.11(d,J=9.0Hz,1H),7.45-7.51(m,2H),7.71(dd ,J=8.4Hz,2.1Hz,1H),7.89(d,J=1.9Hz,1H),8.00(d,J=8.2Hz,1H),8.14(s,1H)ppm. LC-MS:C 29 H 25 BrF3N7O2[M+H] + :640 / 642.

[0270] Example 2

[0271] [ka]

[0272] NEt3 (0.57 mL, 4.08 mmol) was added to a solution of ethyl-(R)-1-(4-bromo-3-(trifluoromethyl)benzoyl)-5-isothiocyanato-2-methyl-1,2,3,6-tetrahydropyridine-4-carboxylate (1.3 g, 2.72 mmol) and 4-amino-2-chloro-N-methylbenzamide (0.55 g, 3 mmol) in anhydrous CH3CN (20 mL) under N2. The mixture was stirred at 80 °C for 22 h. The reaction mixture was then evaporated to dryness and purified by chromatography on silica gel (0-2.5% CHOH in CH2Cl2) to give (R)-4-(7-(4-bromo-3-(trifluoromethyl)benzoyl)-6-methyl-4-oxo-2-thioxo-1,4,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-3(2H)-yl)-2-chloro-N-methylbenzamide (660 mg, 39%) as a yellow solid. 1 H-NMR(DMSO-d6,400MHz)δ1.21(br.s,3H),2.27(br.s,1H),2.44(br.s,1H),2.76(d,J=4.6Hz,3H),3.99-4.08(br.s,1H),4.23(br.s,1H),5 .10(br.s,1H),7.25(m,1H),7.45(m,1H),7.5(m,1H),7.68(m,1H),7.90(br.s,1H),8.02(d,J=8.0Hz,1H),8.52(m,1H),12.89(br.s,1H)ppm. LC-MS:C 24 H 19 BrF3N4O3S[M+H] + :615.

[0273] Thiophosgene (0.045 mL, 0.49 mmol) was added to a solution of (R)-4-(7-(4-bromo-3-(trifluoromethyl)benzoyl)-6-methyl-4-oxo-2-thioxo-1,4,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-3(2H)-yl)-2-chloro-N-methylbenzamide (300 mg, 0.49 mmol) in anhydrous dioxane (10 mL) under N2. The mixture was stirred at 100° C. for 0.5 h and then evaporated to dryness to give (R)-4-(7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-chloro-6-methyl-4-oxo-5,6,7,8-tetrahydropyrido[3,4-d[pyrimidin-3(4H)-yl-2-chloro-N-methylbenzamide] as crude product, which was used directly in the next step.

[0274] Hydrazine monohydrate (31.1 mg, 0.49 mmol) was added to a solution of (R)-4-(7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-chloro-6-methyl-4-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)-2-chloro-N-methylbenzamide (300 mg, 0.49 mmol) in EtOH (4 mL). The mixture was stirred at 100° C. for 1 h. The mixture was evaporated to dryness to give the crude product, which was purified by reverse phase chromatography (C18 column, 5-100% CH3CN in water (+0.1% formic acid)) to give (R)-4-(7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-hydrazinyl-6-methyl-4-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-3(4H-yl)-2-chloro-N-methylbenzamide (270 mg, 90%) as a white solid. LC-MS: C 24 H 21 BrClF3N6O3[M+H] + :613 / 615.

[0275] Acetylacetone (0.045 mL, 0.44 mmol) was added to a solution of (R)-4-(7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-hydrazinyl-6-methyl-4-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)-2-chloro-N-methylbenzamide (270 mg, 0.44 mmol) in EtOH (4.5 mL). The mixture was stirred and heated at 100° C. for 2 days. The mixture was evaporated to dryness to give the crude product, which was purified by reverse phase chromatography C18 (5-100% CH3CN in water (+0.1% formic acid)) to give (R)-4-(7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-methyl-4-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)-2-chloro-N-methylbenzamide (2) (98 mg, 33%) as a white solid. 1 H-NMR(CDCl3,400MHz)δ1.26(d,J=6.7Hz,3H),1.91(s,3H),2.33(s,3H),2.51-2.5 7(m,1H),2.71-2.79(m,4H),4.26(d,J=17.7Hz,1H),4.55(br.s.,1H),4.77(br.s., 1H),5.88(s,1H),7.22(dd,J=8.1Hz,1.5Hz,1H),7.36-7.43(m,2H),7.69(dd,J=8.1 Hz,1.5Hz,1H),7.88(d,J=1.8Hz,1H),8.00(d,J=8.1Hz,1H),8.10-8.17(m,1H)ppm. LC-MS:C 29 H 25 BrClF3N6O3[M+H] + :677 / 679.

[0276] Example 3

[0277] [ka]

[0278] MeI (1.1 eq., 0.14 mL, 2.28 mmol) and DBU (1.2 eq., 0.38 g, 0.37 mL, 2.49 mmol) were added to a solution of (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-6-methyl-3-(1-methyl-1H-imidazo[4,5-b]pyridin-5-yl)-2-thioxo-2,3,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-4(1H)-one (1 eq., 1.2 g, 2.071 mmol) in anhydrous DMF (15 mL) cooled at 0° C. The mixture was stirred at room temperature for 1 h, followed by addition of water (50 mL) and EA (50 mL) to the mixture. The aqueous phase was extracted with EA (2×50 mL). The combined organic layers were washed with 1N HCl (1×25 mL), water (2×25 mL), and brine (1×25 mL) and dried over Na2SO4. The solids were removed by filtration and the filtrate was evaporated to dryness to give (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-6-methyl-3-(1-methyl-1H-imidazo[4,5-b]pyridin-5-yl)-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (1.2 g, 99%) as a brown solid. LCMS: C 24 H 20 BrF3N6O2S[M+H] + :593 / 595.

[0279] mCPBA (1.2 equiv., 0.77 g, 2.47 mmol) was added to a solution of (R)-7-(4-bromo-3-trifluoromethyl)benzoyl)-6-methyl-3-(1-methyl-1H-imidazo[4,5-b]pyridin-5-yl)-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (1 equiv., 1.22 g, 2.056 mmol) in anhydrous DCM (100 mL) at 0° C. The mixture was stirred at room temperature for 1 h, then saturated aqueous NaHCO3 was added. The aqueous phase was extracted with DCM (3×25 mL). The combined organic layers were washed with brine (1×25 mL) and dried over Na2SO4. The solids were removed by filtration and the filtrate was evaporated to dryness to give (6R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-6-methyl-3-(1-methyl-1H-imidazo[4,5-b]pyridin-5-yl)-2-(methylsulfinyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (1.25 g, 99%) as a beige solid. LCMS: C 24 H 20 BrF3N6O3S[M+H] + :609 / 611.

[0280] Hydrazine monohydrate (3 eq., 0.39 g, 6.15 mmol) was added to a solution of (6R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-6-methyl-3-(1-methyl-1H-imidazo[4,5-b]pyridin-5-yl)-2-(methylsulfinyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (1 eq., 1.25 g, 2.05 mmol) in EtOH (12 mL). The mixture was stirred at 100° C. for 1 h. The mixture was evaporated to dryness to give the crude product. The crude product was purified by flash chromatography on silica gel (0-100% EA in CyH, then 0-10% MeOH in DCM) to give (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-hydrazinyl-6-methyl-3-(1-methyl-1H-imidazo[4,5-b]pyridin-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (905 mg, 76%) as a beige solid. LCMS: C 23 H 20 BrF3N8O2[M+H] + :577 / 579.

[0281] Acetylacetone (1 equiv., 0.16 mL, 1.56 mmol) was added to a solution of (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-hydrazinyl-6-methyl-3-(1-methyl-1H-imidazo[4,5-b]pyridin-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (1 equiv., 900 mg, 1.56 mmol) in EtOH (15 mL). The mixture was stirred and heated at 100° C. for 18 h. The mixture was evaporated to dryness and purified by flash chromatography on silica gel (0-100% EA in CyH, then 0-10% MeOH in DCM) to give a yellow solid. The solid was purified by reverse phase chromatography (5-100% MeCN in HO (+0.1% FA)) to give (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-methyl-3-(1-methyl-1H-imidazo[4,5-b]pyridin-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (405 mg, 41%) as a white solid. 1 H-NMR(DMSO-d6,400MHz,80℃)δ1.27(d,J=6.7Hz,3H),1.72(s,3H),2.38(s,3H),2.52 -2.58(m,1H),2.73-2.84(m,1H),3.88(s,3H),4.29(d,J=19.4Hz,1H),4.56(br.s.,1H) ),4.80(br.s.,1H),5.76(s,1H),7.37(d,J=8.3H,1H),7.72(dd,J=8.1Hz,1.6Hz,1H) ,7.91(d,J=1.5Hz,1H),7.99(d,J=8.2Hz,1H),8.08(d,J=8.2Hz,1H),8.37(s,1H)ppm. LCMS:C 28 H 24 BrF3N8O2[M+H] + :641 / 643.

[0282] Example 4

[0283] [ka]

[0284] Hydrazine monohydrate (10 equiv., 0.42 mL, 6.65 mmol) was added to a solution of crude (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-chloro-3-(4-hydroxyphenyl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (1 equiv., 361 mg, 0.67 mmol) in EtOH (5 mL) under N2. The mixture was stirred at 25° C. for 18 h. The mixture was evaporated to dryness to give a yellow solid, which was purified by flash chromatography on silica gel (DCM / MeOH 100:0 to 90:10) to give (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-hydrazinyl-3-(4-hydroxyphenyl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (210 mg, 59%) as a yellow solid. LCMS: C 22 H 19 BrF3N5O3[M+H] + :538 / 540.

[0285] A solution of (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-hydrazineyl-3-(4-hydroxyphenyl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (1 equiv., 210 mg, 0.39 mmol) and acetylacetone (2 equiv., 0.0801 mL, 0.78 mmol) in EtOH (4 mL) was heated to 100° C. for 1 h. The mixture was evaporated to dryness to give a yellow oil, which was purified by flash chromatography on silica gel (DCM:MeOH 100:0 to 90:10) to give (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-3-(4-hydroxyphenyl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (170 mg, 72%) as a pale yellow solid. LCMS: C 27 H 23 BrF3N5O3[M+H]+ :602 / 604. 1 H-NMR(DMSO-d6,400MHz,80℃)δ1.25(d,J=6.7Hz,3H),1.91(s,3H),2.24(s, 3H),2.52-2.59(m,1H),2.69-2.80(m,1H),4.19-4.30(m,1H),4.39-4.90(m ,2H),5.80(s,1H),6.63-6.69(m,2H),6.91-6.91(m,2H),7.69(dd,J=8.2Hz ,1.8Hz,1H),7.88(d,J=1.8Hz,1H),7.99(d,J=8.3Hz,1H),9.36(s,1H)ppm.

[0286] Example 5

[0287]

change

[0288] K2CO3 (3 eq., 117.004 mg, 0.85 mmol) was added to a solution of (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-3-(4-hydroxyphenyl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (1 eq., 170 mg, 0.28 mmol) and 2-bromoacetamide (2 eq., 77.87 mg, 0.56 mmol) in anhydrous MeCN (10 mL). The mixture was heated at 75° C. for 19 h and then diluted with EA / iPrOH (85:15). The mixture was washed with saturated aqueous NaHCO3 and brine and dried over Na2SO4. The solids were removed by filtration and the filtrate was evaporated to dryness to give a white solid which was purified by flash chromatography on silica gel (DCM:MeOH 100:0 to 90:10) to give (R)-2-(4-(7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-methyl-4-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)phenoxy)acetamide (126 mg, 68%) as a white solid. LCMS: C 29 H 26 BrF3N6O4[M+H] + :659 / 661. 1 H-NMR(DMSO-d6,400MHz,80℃)δ1.26(d,J=6.9Hz,3H),1.90(s,3H),2.27(s,3H),2 .51-2.58(m,1H),2.70-2.80(m,1H),4.18-4.31(m,1H),4.40(s,2H),4.44-4.92(m ,2H),5.81(s,1H),6.90(d,J=8.7Hz,2H),7.10(d,J=8.7Hz,2H),7.08-7.31(m,2H ),7.69(dd,J=8.2Hz,1.8Hz,1H),7.88(d,J=1.8Hz,1H),7.99(d,J=8.1Hz,1H)ppm.

[0289] Example 6

[0290] [ka]

[0291] K2CO3 (3 eq., 206 mg, 1.49 mmol) was added to a solution of (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-3-(4-hydroxyphenyl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (1 eq., 300 mg, 0.5 mmol) and (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate 2 (2 eq., 285 mg, 1 mmol) in anhydrous MeCN (15 mL). The mixture was heated at 100° C. for 4 days and then diluted with EA:iPrOH (85:15). The mixture was washed with saturated aqueous NaHCO3 and brine and dried over Na2SO4. The solids were removed by filtration and the filtrate was evaporated to dryness to give a white solid which was purified by flash chromatography on silica gel (DCM / MeOH 100:0 to 90:10) to give (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-3-(4-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (334 mg, 94%) as a white solid. 1 H-NMR(DMSO-d6,400MHz)δ1.18-1.36(m,3H),1.29(s,3H),1.34(s,3H),1.88(s3H) ,2.12-2.37(m,4H),2.68-2.80(m,1H),3.67-3.74(m,1H),3.90-4.26(m,5H),4.33 -4.42(m,1H),4.93-5.30(m,1H),5.83(s,1H),6.82-6.94(m,2H),6.98-7.22(m,2H) ),7.71(dd,J=8.3Hz,1.4Hz,1H),7.91(d,J=1.6Hz,1H),8.01(d,J=8.4Hz,1H)ppm. LCMS:C 33 H 33BrF3N5O5[M+H]+:716 / 718.

[0292] HCl (10 equiv., 4.66 mL, 4.66 mmol) was added to a solution of (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-3-(4-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (1 equiv., 334 mg, 0.47 mmol) in THF (16 mL). The mixture was stirred at room temperature for 18 h, diluted with EA / iPrOH (85:15) and neutralized by addition of saturated aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with EA:iPrOH (85:15). The combined organic layers were washed with brine and dried over Na2SO4. The solids were removed by filtration and the filtrate was evaporated to dryness to give a yellow sticky solid, which was purified by flash chromatography on silica gel (DCM / MeOH 100:0 to 90:10) to give (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-3-(4-((S)-2,3-dihydroxypropoxy)phenyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (151 mg, 48%) as a white solid. 1H-NMR(DMSO-d6,400MHz,80℃)δ1.26(d,J=6.8Hz,3H),1.91(s,3H),2.25(s,3H),2.51-2.58(m,1H),2.70-2.8 0(m,1H),3.46(t,J=5.5Hz,2H),3.73-3.82(m,1H),3.83-3.90(m,1H),3.99(dd,J=10.0Hz,4.3Hz,1H),4.25(d ,J=19.1Hz,1H),4.35(t,J=5.7Hz,1H),4.43-4.90(m,2H),4.63(d,J=4.7Hz,1H),5.80(s,1H),6.86(d,J=9.1H) ppm. LCMS:C 30 H 29 BrF3N5O5[M+H] + :676 / 678.

[0293] Example 7

[0294] [ka]

[0295] (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-3-(4-((R)-2,3-dihydroxypropoxy)phenyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one was synthesized according to the route described for the synthesis of compound 24, using (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate instead of (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate in the penultimate step. 11H-NMR (DMSO-d6, 400 MHz, 80 °C) δ 1.26 (d, J = 6.8 Hz, 3H), 1.91 (s, 3H), 2.25 (s, 3H), 2.51 - 2.57 (m, 1H), 2.71 - 2.80 (m, 1H), 3.46 (t, J = 5.7 Hz, 2H), 3.74 - 3.83 (m, 1H), 3.84 - 3.90 (m, 1H), 3.99 (dd, J = 10.0 Hz, 4.3 Hz, 1H), 4.25 (d, J = 19.4 Hz, 1H), 4.36 (t, J = 5.7 Hz, 1H), 4.44 - 4.92 (m, 2H), 4.63 (d, J = 5.0 Hz, 1H), 5.80 (s, 1H), 6.86 (d, J = 9.3 Hz, 2H), 7.07 (d, J = 8.6 Hz, 2H), 7.69 (dd, J = 7.9 Hz, 1.4 Hz, 1H), 7.88 (d, J = 1.4 Hz, 1H), 7.99 (d, J = 8.3 Hz, 1H) ppm. LCMS: C 30 H 29 BrF3N5O5 [M+H] + : 676 / 678。

[0296] Example 8

[0297]

Chem.

[0298] 35% AcOOH in AcOH (4 eq., 24 mL, 1.27 mmol) was added to a solution of (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-3-(6-(((R)-2-hydroxypropyl)amino)pyridin-3-yl)-6-methyl-2-thioxo-2,3,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-4(1H)-one (1 eq., 190 mg, 0.32 mmol) and hydrazine monohydrate (10 eq., 0.15 mL, 3.17 mmol) in isopropanol (10 mL). The mixture was stirred at room temperature for 16 h, then pentane-2,4-dione (20 eq., 0.65 mL, 6.35 mmol) was added. The mixture was stirred at 100° C. for 2 h. The mixture was evaporated to dryness and purified by flash chromatography on silica gel (0-100% EA in DCM then 0-10% MeOH) to give a yellow solid which was purified by reverse flash chromatography (5-100% MeCN in water (+0.1% FA)) to give (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-3-(6-(((R)-2-hydroxypropyl)amino)pyridin-3-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (105 mg, 50%) as a white solid. 1 H-NMR(DMSO-d6,400MHz,80℃)δ1.07(d,J=6.3Hz,3H),1.25(d,J=6.8Hz,3H),1.94(s,3H),2.27(s,3H),2 .50-2.55(m,1H),2.71-2.79(m,1H),3.10-3.26(m,2H),3.77(hept,J=5.8Hz,1H),4.25(d,J=19.5Hz,1H) ,4.35-4.97(m,3H),5.85(s,1H),6.35-6.42(m,1H),6.44(d,J=8.9Hz,1H),7.18(dd,J=8.9Hz,2.4Hz,1H ),7.66(d,J=2.3Hz,1H),7.69(dd,J=8.1Hz,1.5Hz,1H),7.88(d,J=1.5Hz,1H),7.99(d,J=8.1Hz,1H)ppm. LCMS:C 29 H 29BrF3N7O3[M+H] + :660 / 662.

[0299] Example 9

[0300] [ka]

[0301] Urea hydrogen peroxide (10 eq., 770.5 mg, 8.19 mmol) was added to a solution of (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-3-(6-((R)-3-hydroxypyrrolidin-1-yl)pyridin-3-yl)-6-methyl-2-thioxo-2,3,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-4(1H)-one (1 eq., 500 mg, 0.82 mmol) and hydrazine monohydrate (10 eq., 409.53 mg, 8.19 mmol) in isopropanol (7 mL). The mixture was stirred at room temperature for 18 hours, then pentane-2,4-dione (20 eq., 1.68 mL, 16.38 mmol) was added. The mixture was stirred at 100° C. for 2 hours. Saturated Na2S2O3 was added to the mixture. Isopropanol was removed under vacuum and the resulting aqueous phase was extracted with EtOAc (3x). The combined organic layers were washed with brine and dried over Na2SO4. The solids were removed by filtration and the filtrate was evaporated to dryness to give the crude product. The crude product was purified by flash chromatography on silica gel (0-100% EA in DCM, then 0-10% MeOH) to give a yellow solid, which was purified by reverse flash chromatography (5-100% MeCN in water (+0.1% FA)) to give (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-3-(6-((R)-3-hydroxypyrrolidin-1-yl)pyridin-3-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (204 mg, 37%) as a white solid. 11H-NMR (DMSO-d6, 400 MHz, 80 °C) δ 1.24 (d, J = 6.4 Hz, 3H), 1.83 - 1.92 (m, 1H), 1.95 (s, 3H), 1.98 - 2.09 (m, 1H), 2.27 (s, 3H), 2.52 - 2.59 (m, 1H), 2.70 - 2.81 (m, 1H), 3.27 (d, J = 10.5 Hz, 1H), 3.37 - 3.52 (m, 3H), 4.25 (d, J = 20.3 Hz, 1H), 4.39 (br.s., 1H), 4.45 - 4.92 (m, 3H), 5.85 (s, 1H), 6.34 (d, J = 8.9 Hz, 1H), 7.31 (dd, J = 8.6 Hz, 1.9 Hz, 1H), 7.69 (d, J = 8.3 Hz, 1H), 7.79 (s, 1H), 7.88 (s, 1H), 7.99 (d, J = 7.6 Hz, 1H) ppm. LCMS: C 30 H 29 BrF3N7O3 [M+H] + : 672 / 674。

[0302] Example 10

[0303]

Chem.

[0304] Urea hydrogen peroxide (10 eq., 1.3 g, 14.09 mmol) was added to a solution of tert-butyl (R)-4-(5-(7-(4-bromo-3-(trifluoromethyl)benzoyl)-6-methyl-4-oxo-2-thioxo-1,4,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-2-yl)piperazine-1-carboxylate (1 eq., 1 g, 1.40 mmol) and hydrazine monohydrate (10 eq., 705 mg, 14.09 mmol) in isopropanol (20 mL). The mixture was stirred at room temperature for 18 h and pentane-2,4-dione (20 eq., 2.89 mL, 28.19 mmol) was added. The mixture was stirred at 100° C. for 2 h. Saturated aqueous NaHCO3 (100 mL) and EtOAc (50 mL) were added to the mixture. The layers were separated and the aqueous layer was extracted using EtOAc (3 x 80 mL). The combined organic layers were washed with 1N HCl (100 mL), brine (100 mL) and dried over Na2SO4. The solids were removed by filtration and the filtrate was evaporated to dryness to give the crude product. The crude mixture was purified by flash chromatography on silica gel (0% to 100% EA in DCM, then 0% to 10% MeOH) to give tert-butyl (R)-4-(5-(7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(3.5-dimethyl-1H-pyrazol-1-yl)-6-methyl-4-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)pyridin-2-yl)piperazine-1-carboxylate (820 mg, 75%) as a white solid. 1 H-NMR(DMSO-d6,400MHz)δ1.21-1.26(m,3H),1.41(s,9H),1.90(s,3H),2.26-2. 35(m,3H),2.44-2.50(m,1H),2.66-2.78(m,1H),3.35-3.42(m,4H),3.43-3.51( m,4H),4.08-4.61(m,2H),4.95-5.33(m,1H),5.88(s,1H),6.78(d,J=8.7Hz,1H) ,7.32-7.56(m,1H),7.66-7.73(m,1H),7.78-7.94(m,2H),7.98-8.04(m,1H)ppm. LCMS:C35 H 38 BrF3N8O4[M+H] + :771 / 773.

[0305] 4N HCl in dioxane (40 eq., 10.6 mL, 42.4 mmol) was added to tert-butyl (R)-4-(5-(7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-methyl-4-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)pyridin-2-yl)piperazine-1-carboxylate (1 eq., 0.82 g, 1.06 mmol). The mixture was stirred at room temperature for 1 h. The mixture was evaporated to dryness, then saturated aqueous NaHCO3 (100 mL) and EtOAc (50 mL) were added to the mixture. The layers were separated and the aqueous layer was extracted using EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL) and dried over Na2SO4. The solids were removed by filtration and the filtrate was evaporated to dryness to give (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-methyl-3-(6-(piperazin-1-yl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (609 mg, 86%) as a yellow solid. LCMS: C 30 H 30 BrF3N8O2[M+H] + :671 / 673.

[0306] In a sealed microwave tube equipped with molecular sieves under N2, 4N HCl in dioxane (5 eq., 0.16 mL, 0.65 mmol) was added to a solution of (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-methyl-3-(6-(piperazin-1-yl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (1 eq., 87 mg, 0.13 mmol) in 1,4-dioxane (2 mL). The mixture was stirred at room temperature for 1 h. The mixture was evaporated to dryness, triturated with DCM and co-evaporated with MeCN (3×) to give (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-methyl-3-(6-(piperazin-1-yl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one hydrochloride (60 mg, 65%) as a beige solid 1 H-NMR(DMSO-d6,400MHz,80℃)δ1.26(br.s.,3H);2.92(br.s.,3H);2.30(br.s.,3H); 2.53-2.60(m,1H);2.67-2.82(m,1H);3.14(br.s.,4H);4.25(d,J=18.3Hz,1H);4.57 (br.s.,1H);4.75(br.s.,1H),5.87(s,1H);6.85(d,J=6.0Hz,1H);7.45(d,J=5.8Hz, 1H);7.69(d,J=5.8Hz,1H);7.89(m,2H);7.99(d,J=5.4Hz,1H);9.44(br.s.,2H)ppm. LCMS:C 30 H 31 BrClF3N8O2[M+H] + :671 / 673.

[0307] Example 11

[0308] [ka]

[0309] Et3N (4 eq., 0.25 mL, 1.79 mmol) was added to a solution of (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-methyl-3-(6-(piperazin-1-yl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (1 eq., 300 mg, 0.45 mmol) in EtOH (10 mL). The mixture was stirred at room temperature for 30 min, then 37% formaldehyde in water (5 eq., 0.17 mL, 2.23 mmol) and acetic acid (6 eq., 0.15 mL, 2.68 mmol) were added. The mixture was stirred at room temperature for 1 h. NaBH3CN (2 eq., 56.15 mg, 0.89 mmol) was added to the mixture, which was then further stirred at room temperature for 1 h. Saturated aqueous NaHCO3 (20 mL) and DCM (20 mL) were added. The layers were separated and the aqueous layer was extracted with DCM (3 x 30 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (20 mL) and brine (30 mL) and dried over Na2SO4. The solids were removed by filtration and the filtrate was evaporated to dryness and purified by flash chromatography on silica gel (0-100% EA in DCM, then 0-10% MeOH) to give a yellow solid. The solid was purified by reverse phase chromatography (5-100% MeCN in water (+0.1)% FA). The tubes containing products were combined and MeCN was evaporated. Saturated aqueous NaHCO3 (20 mL) and EtOAc (30 mL) were added to the solution and the layers were separated. EtOAc (3 x 30 mL) was used to extract the aqueous layer. The combined organic phases were washed with saturated aqueous NaHCO3 (30 mL) and water (30 mL) and dried over Na2SO4. The solid was filtered and the filtrate was evaporated to dryness to give (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-methyl-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (128 mg, 41%) as a white solid. 11H-NMR (DMSO-d6, 400 MHz, 80 °C) δ 1.25 (d, J = 6.9 Hz, 3H); 1.93 (s, 3H); 2.22 (s, 3H); 2.29 (s, 3H); 2.34 - 2.39 (m, 4H); 2.52 - 2.57 (m, 1H); 2.70 - 2.81 (m, 1H); 3.44 - 3.52 (m, 4H); 4.25 (d, J = 19.1 Hz, 1H); 4.36 - 5.10 (m, 2H); 5.86 (s, 1H); 6.72 (d, J = 9.1 Hz, 1H); 7.34 (dd, J = 9.0 Hz, 2.6 Hz, 1H); 7.69 (dd, J = 8.3 Hz, 1.6 Hz, 1H); 7.83 (d, J = 2.5 Hz, 1H); 7.88 (d, J = 1.9 Hz, 1H); 7.99 (d, J = 8.3 Hz, 1H) ppm. LCMS: C 31 H 32 BrF3N8O2 [M + H] + : 685 / 687.

[0310] Example 12

[0311] [Chemical formula]

[0312] POCl3 (3 eq., 0.42 mL, 4.54 mmol) and pyridine (10 eq., 1.22 mL, 15.14 mmol) were added to a solution of (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-3-(4-((S)-2-hydroxypropoxy)phenyl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (1 eq., 1 g, 1.51 mmol) in anhydrous THF (14 mL) cooled at 0° C. The mixture was allowed to warm slowly to room temperature and stirred for 1 h. The mixture was filtered and the filtrate was cooled to 0° C. Water was added and the pH was adjusted to pH ∼2 with 1N HCl. DCM was added and the layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were combined and dried over Na2SO4. The solids were removed and the filtrate was evaporated to dryness under reduced pressure using a 30°C water bath to give a yellow oil, which was purified by reverse phase chromatography (water (0.5% FA):MeCN 95:5 to 0:100). The fractions were combined, the pH was adjusted to pH ∼2 by addition of 1N HCl, and extracted with DCM:iPrOH (95:5). The organic layer was dried over Na2SO4 and evaporated under reduced pressure using a 30 °C water bath to give (S)-1-(4-((R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-methyl-4-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)phenoxy)propan-2-yl dihydrogen phosphate (409 mg, 36%) as a white solid. 1 H-NMR(DMSO-d6,600MHz,80℃)δ1.26(d,J=6.9Hz,3H),1.33(d,J=5.9Hz,3H),1.9 0(s,3H),2.25(s,3H),2.48-2.57(m,1H),2.69-2.80(m,1H),3.93-4.07(m,2H), 4.20-4.31(m,1H),4.45-4.97(m,3H),5.81(s,1H),6.89(d,J=8.7Hz,2H),7.09( d,J=8.7Hz,2H),7.66-7.73(m,1H),7.85-7.89(m,1H),7.99(d,J=8.7Hz,1H)ppm. LCMS:C30 H 30 BrF3N5O7P[M+H] + :740 / 742.

[0313] Example 13 Synthesis of compounds 13-44 Compounds 14-35 were synthesized using the protocols and intermediates described herein, as well as methods known in the art. Different methods described in Schemes 2, 4, 10, 17, and 18 were used to introduce the 3,5-dimethylpyrazole moiety and are listed in Table 1.

[0314] Table 1. Description of methods 1-6 used to synthesize compounds 13-44 of formula (I) from compounds of formula (VI).

[0315] [ka]

[0316] [Table 2]

[0317] Compounds 13-44, as well as the methods used to synthesize them, are listed in Table 2.

[0318] [Table 3-1]

[0319] [Table 3-2]

[0320] [Table 3-3]

[0321] [Table 3-4]

[0322] [Table 3-5]

[0323] [Table 3-6]

[0324] [Table 3-7]

[0325] [Table 3-8]

[0326] [Table 3-9]

[0327] [Table 3-10]

[0328] [Table 3-11]

[0329] Additional Compounds Additional compounds, such as those described herein, can be prepared using similar materials and methods described herein.

[0330] [ka]

[0331] [ka]

[0332] [ka] (including pharma- ceutically acceptable salts of any of the foregoing).

[0333] Example 14 Intermediates I1-I24

[0334] [ka]

[0335] NaHMDS 2M in THF (1.5 eq., 24.42 mL, 48.84 mmol) was added dropwise to a solution of 5-chloro-1H-imidazo[4,5-b]pyridine (1 eq., 5 g, 32.56 mmol) in anhydrous THF (162 mL) at 0° C. MeI (3 eq., 6.081 mL, 97.68 mmol) was added and the mixture was stirred at room temperature for 1 h. Saturated aqueous NH4Cl was added to the mixture and THF was evaporated under vacuum. The aqueous phase was extracted with DCM (3×). The combined organic layers were washed with brine and dried over MgSO4. The solids were removed by filtration and the filtrate was evaporated to dryness to give the crude mixture as a brown solid. The solid was purified by flash chromatography on silica gel (0-10% MeOH in DCM) to give 5-chloro-1-methyl-1H-imidazo[4,5-b]pyridine (3.65 g, 67%) as a colorless oil. 1 H-NMR (DMSO-d6,400MHz) δ3.88(s,3H),7.37(d,J=8.2Hz,1H),8.13(d,J=8.4Hz,1H),8.50(s,1H)ppm.

[0336] Pd2(dba)3 (0.1 equiv., 0.55 g, 0.6 mmol), (+ / -)-BINAP (0.2 equiv., 0.74 g, 1.19 mmol), benzophenone imine (1.5 equiv., 1.502 mL, 8.95 mmol), and Cs2CO3 (2.5 equiv., 4.86 g, 14.92 mmol) were added to a solution of 5-chloro-1-methyl-1H-imidazo[4,5-b]pyridine (1 equiv., 1 g, 5.97 mmol) in DME (50 mL). The mixture was purged with N2 and stirred at 120 °C for 18 h. The mixture was evaporated to dryness to give the crude product, which was purified by flash chromatography on silica gel (0-100% EA in CyH, then 0-10% MeOH in DCM) to give N-(1-methyl-1H-imidazo[4,5-b]pyridin-5-yl)-1,1-diphenylmethanimine (1.49 g, 80%) as a beige solid. 1 H-NMR(DMSO-d6,400MHz)δ3.77(s,3H),6.60(d,J=8.2Hz,1H),7.13-7.18(m,2H),7.23-7.29(m,3H) ),7.46-7.52(m,2H),7.54-7.60(m,1H),7.67-7.73(m,2H),7.80(d,J=8.2Hz,1H),8.23(s,1H)ppm.

[0337] 1M HCl (1.5 eq., 8.64 mL, 8.64 mmol) was added to a solution of N-(1-methyl-1H-imidazo[4,5-b]pyridin-5-yl)-1,1-diphenylmethanimine (1 eq., 1.8 g, 5.76 mmol) in THF (55 mL). The mixture was stirred at room temperature for 18 h. THF was evaporated under vacuum and the resulting aqueous phase was extracted with Et2O (3 x 20 mL). The aqueous phase was evaporated to dryness to give 1-methyl-1H-imidazo[4,5-b]pyridin-5-amine hydrochloride (1.05 g, 99%) as a beige solid. LCMS: C7H8N4, [M+H] + :149.

[0338] [ka]

[0339] Ethyl L(-)-lactate (5 g, 42.33 mmol) in anhydrous CHCl (30 mL) was added to a solution of DBU (8.85 mL, 59.26 mmol) and triphenylmethyl chloride (11.8 g, 42.33 mmol) in anhydrous CHCl (30 mL) under N. The mixture was stirred at room temperature for 3 days. The mixture was diluted with cold water (20 mL), extracted with EtO (3×50 mL), washed with brine, and dried over NaSO. The solids were removed by filtration and the filtrate was evaporated to dryness to give the crude product, which was purified by chromatography on silica gel (0–10% EA in CyH) to give ethyl (S)-2-(trityloxy)propanoate (15.9 g, 99%) as a colorless oil. 1 H-NMR(DMSO-d6,400MHz)δ0.98(t,J=7.0Hz,3H),1.22(d,J=6.7Hz,3H),3.62(q,J=7.0Hz ,2H),4.01(q,J=6.7Hz,1H),7.24-7.29(m,3H),7.30-7.35(m,6H),7.37-7.41(m,6H)ppm.

[0340] LiAlH4 (1M) in THF (42.33 mL, 42.33 mmol) was added dropwise to a solution of ethyl (S)-2-(trityloxy)propanoate (15.26 g, 42.33 mmol) in anhydrous THF (200 mL) at -78 °C under N2. The mixture was stirred at -78 °C for 4 h. The mixture was diluted with Et2O (100 mL) and cooled to 0 °C. Water (42 mL) was added slowly, followed by NaOH (42 mL, aq., 15%) and water (170 mL), respectively. The mixture was stirred at room temperature for 15 min and MgSO4 was added. The mixture was stirred for 15 min. The salts were removed by filtration, washed with Et2O, and the filtrate was evaporated to dryness to give (S)-2-(trityloxy)propan-1-ol (9.3 g, 69%) as a white solid. 1H-NMR(DMSO-d6,400MHz)δ0.69(d,J=6.1Hz,3H),2.94-3.13(m,2H),3.43-3.54(m,1 H),4.46-4.49(m,1H),7.23-7.28(m,3H),7.30-7.36(m,6H),7.43-7.47(m,6H)ppm.

[0341] Cs2CO3 (697 mg, 2.14 mmol) was added to a solution of 4-fluoronitrobenzene (201 mg, 1.43 mmol) and (S)-2-(trityloxy)propan-1-ol (500 mg, 1.57 mmol) in anhydrous DMSO (6 mL) under N2. The mixture was stirred at 50 °C for 4 h. The mixture was diluted with NaHCO3 (20 mL) and extracted with EA (3 × 25 mL). The combined organic phase was washed with water and brine and dried over Na2SO4. The solids were removed by filtration and the filtrate was evaporated to dryness to give the crude product, which was purified by chromatography on silica gel (0-20% EA in CyH) to give (S)-(((1-(4-nitrophenoxy)propan-2-yl)oxy)methanetriyl)tribenzene (567 mg, 90%) as a white solid. 1 H-NMR(DMSO-d6,400MHz)δ0.89(d,J=6.2Hz,3H),3.65-3.76(m,2H),3.82-3.90(m,1H),6.94- 7.00(m,2H),7.24-7.28(m,3H),7.30-7.36(m,6H),7.42-7.50(m,6H),8.12-8.18(m,2H)ppm.

[0342] 10% Pd / C (1.04 g, 0.98 mmol) was added to a solution of (S)-(((1-(4-nitrophenoxy)propan-2-yl)oxy)methanetriyl)tribenzene (4.3 g, 9.78 mmol) in EtOH (170 mL). The mixture was purged with N2, then with H2, and stirred at room temperature for 3 days. The mixture was filtered over a pad of Celite and evaporated to dryness to give (S)-4-(2-(trityloxy)propoxy)aniline (3.8 g, 95%) as a colorless oil. LC-MS: C 28 H 27NO2[M+H] + :410.

[0343] (S)-4-(2-(trityloxy)propoxy)aniline (1.03 g, 2.51 mmol) was added to a solution of ethyl (R)-1-(4-bromo-3-(trifluoromethyl)benzoyl)-5-isothiocyanato-2-methyl-1,2,3,6-tetrahydropyridine-4-carboxylate (1 g, 2.095 mmol) and EtN (2.0 mL, 4.19 mmol) in anhydrous CHCN (8 mL) under N. The mixture was stirred at 110° C. for 4 h. The mixture was evaporated to dryness and purified by flash chromatography on silica gel (0-100% EA in CyH) to give (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-6-methyl-2-thioxo-3-(4-((S)-2-(trityloxy)propoxy)phenyl)-2,3,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-4(1H)-one (1.20 g, 68%) as a yellow solid. LC-MS: C 44 H 37 BrF3N3O4S[M+H] + :840 / 842.

[0344] [ka]

[0345] Intermediate I3 was synthesized following the procedure reported for the synthesis of intermediate I2, using D(+)-ethyl lactate instead of L(-)-ethyl lactate in the first step. LC-MS: 44 H 37 BrF3N3O4S[M+H] + :840 / 842.

[0346] [ka]

[0347] MeI (1 equiv., 1.49 mL, 23.99 mmol) and LiHMDS (1 M in THF, 1 equiv., 23.99 mL, 23.99 mmol) were added to a solution of 5-bromo-3-chloropyrazine-2-amine (1 equiv., 5 g, 23.99 mmol) in anhydrous DMF (150 mL) at 0° C. The mixture was stirred at room temperature for 2 h. Then water and EA were added. The aqueous phase was extracted with EA (3×). The combined organic layers were washed with water (2×) and brine (2×) and dried over Na2SO4. The solids were removed by filtration. The filtrate was evaporated to dryness to give the crude product, which was purified by flash chromatography on silica gel (0-50% EA in cyclohexane) to give 5-bromo-3-chloro-N-methylpyrazine-2-amine (2.72 g, 51%) as a colorless oil. 1 H-NMR (DMSO-d6, 400MHz) δ2.85 (d, J=4.5Hz, 3H), 7.25-7.31 (m, 1H), 8.18 (s, 1H) ppm.

[0348] A solution of 5-bromo-3-chloro-N-methylpyrazin-2-amine (1 equiv., 2.5 g, 11.24 mmol) in NHOH (33% in water, 50 equiv., 72.93 mL, 561.87 mmol) was stirred at 120° C. for 2 days. The mixture was evaporated to dryness to give the crude product, which was washed with CHCl (3×) and 5-bromo-N 2 -Methylpyrazine-2,3-diamine (2.36 g, 99%) was obtained as a beige powder. LCMS: C5H7BrN4, [M+H] + :203 / 205.

[0349] 5-Bromo-N in triethyl orthoformate (24.39 equiv., 102.2 mL, 613.74 mmol) 2 A solution of p-methylpyrazine-2,3-diamine (1 equiv, 5.11 g, 25.17 mmol) and p-TsOH (0.12 equiv, 0.51 g, 2.97 mmol) was stirred and heated at 130° C. for 2 h. The mixture was cooled to 0° C. The resulting solid was filtered to give 5-bromo-1-methyl-1H-imidazo[4,5-b]pyrazine (4.73 g, 88%) as a brown solid. 1H-NMR (DMSO-d6, 400MHz) δ3.87(s,3H),8.59(s,1H),8.80(s,1H)ppm. LCMS:C6H5BrN4,[M+H] + :213 / 215.

[0350] Pd2(dba)3 (0.1 equiv., 0.64 g, 0.704 mmol), (+ / -)-BINAP (0.2 equiv., 0.88 g, 1.408 mmol), benzophenone imine (1.5 equiv., 1.77 mL, 10.56 mmol), and Cs2CO3 (2.5 equiv., 5.74 g, 17.602 mmol) were added to a solution of 5-bromo-1-methyl-1H-imidazo[4,5-b]pyrazine (1 equiv., 1.5 g, 7.041 mmol) in DME (59 mL). The mixture was purged with N2 (3x) and then stirred at 120 °C for 18 h. The mixture was evaporated to dryness to give the crude product, which was purified by flash chromatography on silica gel (0-100% EA in CyH, then 0-10% MeOH in DCM) to give N-(1-methyl-1H-imidazo[4,5-b]pyrazin-5-yl)-1,1-diphenylmethanimine (2.11 g, 96%). 1 H-NMR (DMSO-d6, 400MHz) δ3.78(s,3H),7.16-7.21(m,2H),7.28-7.32(m,3H),7.49-7.64(m,3H),7.71-7.76(m,2H),7.84(s,1H),8.54(s,1H)ppm.

[0351] 1N HCl (1.5 equiv., 10.1 mL, 10.1 mmol) was added to a solution of N-(1-methyl-1H-imidazo[4,5-b]pyrazin-5-yl)-1,1-diphenylmethanimine (1 equiv., 2.11 g, 6.73 mmol) in THF (60 mL). The mixture was stirred at room temperature for 18 h, then the THF was evaporated under vacuum. The resulting aqueous phase was extracted with Et2O. The aqueous phase was evaporated to dryness to give 1-methyl-1H-imidazo[4,5-b]pyrazin-5-amine hydrochloride (1.15 g, 92%) as an orange solid. 1H-NMR (DMSO-d6, 400MHz) δ3.90(s,3H),7.96(s,1H),9.23(s.,1H)ppm.

[0352] [ka]

[0353] Tetrabutylammonium hydrogen sulfate (0.1 equiv., 1.47 g, 4.33 mmol) and dimethyl sulfate (1.1 equiv., 4.51 mL, 47.609 mmol) were added to a solution of 4-bromo-2-methyl-6-nitroaniline (1 equiv., 10 g, 43.28 mmol) in toluene (80 mL) and a solution of NaOH 50% (24 equiv., 80 mL, 1040 mmol). The mixture was stirred at room temperature for 2 h, then water was added. The organic layer was separated, washed with water and brine, and dried over Na2SO4. The solids were removed by filtration. The filtrate was evaporated to dryness to give a red solid, which was triturated with n-pentane to give 4-bromo-N,2-dimethyl-6-nitroaniline (10.2 g, 96%) as a red solid. 1 H-NMR (DMSO-d6,400MHz) δ2.26(s,3H),2.70(d,J=5.2Hz,3H),6.45-6.54(m,1H),7.48(d,J=2.0Hz,1H),7.77(d,J=2.4Hz,1H)ppm. LCMS:C8H9BrN2O2,[M+H] + :245 / 247.

[0354] Fe (5 equiv., 5.7 g, 102.009 mmol) was added to a solution of 4-bromo-N,2-dimethyl-6-nitroaniline (1 equiv., 5 g, 20.402 mmol) and AcOH (10 equiv., 11.69 mL, 204.018 mmol) in EtOH (130 mL) and water (70 mL). The mixture was stirred at 80° C. for 2 h. The mixture was filtered through a pad of Celite and washed with EtOAc. The filtrate was concentrated to remove EtOH, then saturated aqueous NaHCO3 was added. The aqueous phase was extracted with EtOAc (3×). The combined organic layers were washed with brine and dried over Na2SO4. The solids were removed by filtration. The filtrate was evaporated to dryness to give 4-bromo-N1,6-dimethylbenzene-1,2-diamine (5.54 g, crude) as a brown oil. A solution of 4-bromo-N1,6-dimethylbenzene-1,2-diamine (1 equiv., 4.5 g, 20.92 mmol) and p-TsOH (0.1 equiv., 0.36 g, 2.092 mmol) in trimethyl orthoformate (25 equiv., 57.22 mL, 523.027 mmol) was heated at 80° C. for 1 h. The mixture was evaporated to dryness and purified by flash chromatography on silica gel (0-100% EA in CyH, then 0-10% MeOH in DCM) to give 5-bromo-1,7-dimethyl-1H-benzo[d]imidazole (3.59 g, 72%) as a beige solid. 1 H-NMR (DMSO-d6, 400MHz) δ2.69(s,3H),4.03(s,3H),7.10-7.15(m,1H),7.60-7.65(m,1H),8.11(s,1H)ppm. LCMS:C6H9BrN2,[M+H] + :225 / 227.

[0355] Pd2(dba)3 (0.1 equiv., 1.38 g, 1.51 mmol), (+ / -)-BINAP (0.2 equiv., 1.88 g, 3.021 mmol), benzophenone imine (1.5 equiv., 3.802 mL, 22.66 mmol), and Cs2CO3 (2.5 equiv., 12.304 g, 37.76 mmol) were added to a solution of 5-bromo-1,7-dimethyl-1H-benzo[d]imidazole (1 equiv., 3.4 g, 15.105 mmol) in DME (126 mL). The mixture was purged with N2 and stirred at 100 °C for 24 h. The mixture was filtered through a pad of Celite. The filtrate was evaporated to dryness and purified by flash chromatography on silica gel (0-100% EA in CyH, then 0-10% MeOH in DCM) to give N-(1,7-dimethyl-1H-benzo[d]imidazol-5-yl)-1,1-diphenylmethanimine (4.08 g, 83%) as an orange oil. 1 H-NMR(DMSO-d6,400MHz)δ2.56(s,3H),3.94(s,3H),6.48(br.s.,1H),6.65(d,J=1.9Hz,1H), 7.13-7.20(m,2H),7.25-7.34(m,3H),7.42-7.54(m,3H),7.62-7.69(m,2H),7.90(s,1H)ppm. LCMS:C 22 H 19 N3, [M+H] + :326.

[0356] [1N HCl (1.5 eq., 19.96 mL, 19.96 mmol) was added to a solution of N-(1,7-dimethyl-1H-benzo[d]imidazol-5-yl)-1,1-diphenylmethanimine (1 eq., 4.33 g, 13.306 mmol) in THF (125 mL). The mixture was stirred at room temperature for 2 days. THF was evaporated under vacuum. The resulting aqueous phase was extracted with Et2O (2x) and AcOEt (2x). The aqueous phase was evaporated to dryness to give 1,7-dimethyl-1H-benzo[d]imidazol-5-amine hydrochloride (2.96 g, 99%) as a beige solid. LCMS: C9H 11 N3, [M+H] + :162.

[0357] [ka]

[0358] MeI (1.5 eq, 1.74 mL, 27.904 mmol) and isopropylmagnesium chloride 2M in THF (1.5 eq, 13.95 mL, 27.904 mmol) were added to a solution of 5-bromo-7-fluoro-1H-1,3-benzodiazole (1 eq, 4 g, 18.602 mmol) in anhydrous THF (160 mL) at 0° C. The mixture was stirred for 5 min and then heated at 50° C. for 18 h. Saturated aqueous NaHCO3 was added to the mixture. The aqueous layer was extracted with EA (3×). The combined organic layers were washed with brine and dried over Na2SO4. The solids were removed by filtration. The filtrate was evaporated to dryness and purified by flash chromatography on silica gel (0–10% MeOH in DCM) to give a mixture of 5-bromo-7-fluoro-1-methyl-1H-benzo[d]imidazole / 6-bromo-4-fluoro-1-methyl-1H-benzo[d]imidazole (1.85 g, 43%, 2 / 2′3:1) as a brown solid. 1 H-NMR (DMSO-d6,400MHz) δ2.26(s,3H),2.70(d,J=5.2Hz,3H),6.45-6.54(m,1H),7.48(d,J=2.0Hz,1H),7.77(d,J=2.4Hz,1H)ppm. LCMS:C8H6BrN2,[M+H] + :229 / 231.

[0359] Pd2(dba)3 (0.1 equiv., 0.68 g, 0.74 mmol), (+ / -)-BINAP (0.2 equiv., 0.92 g, 1.48 mmol), benzophenone imine (1.5 equiv., 1.87 mL, 11.13 mmol), and Cs2CO3 (2.5 equiv., 6.045 g, 18.55 mmol) were added to a solution of 5-bromo-7-fluoro-1-methyl-1H-benzo[d]imidazole / 6-bromo-4-fluoro-1-methyl-1H-benzo[d]imidazole (1 equiv., 1.7 g, 7.42 mmol) in DME (62 mL). The mixture was purged with N2 (3x) and stirred at 100 °C for 35 h. The mixture was filtered through a pad of Celite. The filtrate was evaporated to dryness and purified by flash chromatography on silica gel (0-100% EA in CyH, then 0-10% MeOH in DCM) to give N-(7-fluoro-1-methyl-1H-benzo[d]imidazol-5-yl)-1,1-diphenylmethanimine / N-(4-fluoro-1-methyl-1H-benzo[d]imidazol-6-yl)-1,1-diphenylmethanimine (4.08 g, 83%, 3:1 ratio) as a yellow solid. LCMS: C 21 H 16 FN3, [M+H] + :330.

[0360] 1N HCl (1.5 eq., 12.3 mL, 12.3 mmol) was added to a solution of N-(7-fluoro-1-methyl-1H-benzo[d]imidazol-5-yl)-1,1-diphenylmethanimine / N-(4-fluoro-1-methyl-1H-benzo[d]imidazol-6-yl)-1,1-diphenylmethanimine (1 eq., 2.7 g, 8.02 mmol) in THF (80 mL). The mixture was stirred at room temperature for 2 days and the THF was evaporated under vacuum. The aqueous phase was extracted with Et2O (2x) and then evaporated to dryness to give 7-fluoro-1-methyl-1H-benzo[d]imidazol-5-amine hydrochloride / 4-fluoro-1-methyl-1H-benzo[d]imidazol-6-amine hydrochloride (1.60 g, 99% in a 3:1 ratio) as a beige solid. LCMS: C8H8FN3, [M+H] + :166.

[0361] [ka]

[0362] Et3N (2 eq., 6.32 mL, 45.46 mmol) was added to a solution of 4-bromo-1-fluoro-2-nitrobenzene (1 eq., 2.8 mL, 22.73 mmol) and 2,2-difluoroethan-1-amine (1.5 eq., 2.76 g, 34.091 mmol) in anhydrous THF (50 mL). The mixture was heated to 70° C. for 2 h. The mixture was evaporated to dryness, dissolved in AcOEt and washed with 1N HCl. The organic layer was dried over Na2SO4 and evaporated to dryness to give 4-bromo-N-(2,2-difluoroethyl)-2-nitroaniline (6.3 g, 99%) as an orange solid. 1 H-NMR(CDCl3,400MHz)δ3.67-3.77(m,2H),5.96(tt,J=55.2Hz,3.7Hz,1H),6.82(d,J=9 .2Hz,1H),7.54(dd,J=9.0Hz,2.3Hz,1H),8.08-8.17(m,1H),8.32(d,J=2.5Hz,1H)ppm. LCMS:C8H7BrF2N2O2[M+H] + :281 / 283.

[0363] Iron (5 equiv., 6.04 g, 108.16 mmol) was added to a solution of 4-bromo-N-(2,2-difluoroethyl)-2-nitroaniline (1 equiv., 6.08 g, 21.63 mmol) and NH4Cl (10 equiv., 11.57 g, 216.33 mmol) in EtOH (20 mL) and water (20 mL). The mixture was stirred at 70 °C for 22 h. The mixture was filtered through a celite pad and concentrated to remove EtOH. EA (150 mL) and saturated NaHCO3 (120 mL) were added to the resulting suspension. The layers were separated and the aqueous layer was extracted using EA (3 x 150 mL). The combined organic layers were washed with water (100 mL) and brine (2 x 100 mL) and dried over Na2SO4. The solids were removed by filtration and the filtrate was evaporated to dryness to give 4-bromo-N1-(2,2-difluoroethyl)benzene-1,2-diamine (5.7 g, quantitative) as a black wax, which was used directly in the next step without purification. LCMS: C8H9BrF2N2[M+H] + :251 / 253.

[0364] pTsOH·HO (0.1 equiv., 0.43 g, 2.27 mmol) was added to a solution of 4-bromo-N1-(2,2-difluoroethyl)benzene-1,2-diamine (1 equiv., 5.7 g, 22.70 mmol) in trimethyl orthoformate (60 mL). The mixture was heated to 100 °C for 1 h. The mixture was evaporated to dryness to give the crude product, which was purified by flash chromatography on silica gel (0-100% AcOEt in CyH, then 0-5% MeOH in DCM) to give 5-bromo-1-(2,2-difluoroethyl)-1H-benzo[d]imidazole (4.72 g, 83% over two steps) as a yellow solid. 1 H-NMR(DMSO-d6,400MHz)δ4.83(td,J=16.4Hz,3.0Hz,2H),5.46(tt,J=54.4Hz,3.0Hz,1H),7 .45(dd,J=8.7Hz,2.0Hz,1H),7.66(d,J=8.7Hz,1H),7.89(d,J=1.7Hz,1H),8.28(s,1H)ppm. LCMS:C9H7BrF2N2[M+H] + :261 / 263.

[0365] Pd 2( dba)3 (0.1 equiv., 0.702 g, 0.77 mmol), (+ / -)-BINAP (0.2 equiv., 0.95 g, 1.53 mmol), and Cs2CO3 (4 equiv., 9.98 g, 30.64 mmol) were added to a solution of 5-bromo-1-(2,2-difluoroethyl)-1H-benzo[d]imidazole (1 equiv., 2.0 g, 7.66 mmol) and benzophenone imine (1.5 equiv., 1.93 mL, 11.49 mmol) in DME (30 mL). The mixture was heated and stirred at 100 °C for 16 h. The mixture was filtered through a pad of Celite and the filtrate was concentrated to dryness and purified by flash chromatography on silica gel (0-100% EA in CyH over 5 CV, then 0-10% MeOH in DCM) to give N-(1-(2,2-difluoroethyl)-1H-benzo[d]imidazol-5-yl)-1,1-diphenylmethanimine (2.48 g, 90%) as an orange solid. 1 H-NMR(CDCl3,400MHz)δ4.70(td,J=15.9Hz,3.0Hz,2H),6.22-6.60(m,1H),6.73(dd,J=8.6Hz,1.5Hz,1H),6.92 (d,J=1.5Hz,1H),7.16-7.20(m,2H),7.24-7.33(m,3H),7.38-7.56(m,4H),7.63-7.70(m,2H),8.09(s,1H)ppm. LCMS:C 22 H 17 F2N3[M+H] + :362.

[0366] 1M HCl (1.5 equiv., 10.29 mL, 10.29 mmol) was added to a solution of N-(1-(2,2-difluoroethyl)-1H-benzo[d]imidazol-5-yl)-1,1-diphenylmethanimine (1 equiv., 2.48 g, 6.86 mmol) in THF (65 mL). The mixture was stirred at room temperature and then the THF was evaporated under reduced pressure. The resulting solution was filtered and washed with Et2O (3×20 mL). The aqueous solution was evaporated to dryness to give 1-(2,2-difluoroethyl)-1H-benzo[d]imidazol-5-amine hydrochloride (1.35 g, 84%) as a red solid. 1 H-NMR(CDCl3,400MHz)δ5.07(td,J=15.9Hz,3.1Hz,2H),6.58(tt,J=54.2Hz,2.9Hz,1H),7.46(dd,J= 6.6Hz,1.6Hz,1H),7.78(d,J=1.5Hz,1H),7.97(d,J=8.8Hz,1H),8.06-8.94(m,3H),9.36(s,1H)ppm. LCMS:C9H 10 ClF2N3[M+H] + :198.

[0367] [ka]

[0368] A solution of sulfuric acid (1.87 equiv., 5.6 mL, 102.52 mmol) in MeOH (56 mL) was added to a solution of 4-nitroanthranilic acid (1 equiv., 10 g, 54.9 mmol) in MeOH (110 mL) under N2. The mixture was stirred at 70 °C for 2 days. The mixture was diluted with a saturated solution of NaHCO3. The precipitate was filtered and washed with water (3x) to give methyl 2-amino-4-nitrobenzoate (10 g, 93%) as a yellow solid, which was used directly in the next step. 1 H-NMR (DMSO-d6,400MHz) δ3.84(s,3H),7.13(br.s,2H),7.26(dd,J=8.9Hz,2.4Hz,1H),7.67(d,J=2.4Hz,1H),7.92(d,J=8.8Hz,1H)ppm. LCMS:C8H8N2O4[M+H] +:197.

[0369] Boc2O (1.5 equiv., 8.34 g, 38.23 mmol) and Et3N (1.5 equiv., 5.31 mL, 38.23 mmol) were added to a solution of methyl 2-amino-4-nitrobenzoate (1 equiv., 5 g, 25.49 mmol) and DMAP (0.1 equiv., 0.31 g, 2.55 mmol) in anhydrous THF (120 mL) under N2. The mixture was stirred at room temperature for 4 h, then water was added. The resulting solution was extracted with EA (3x). The combined organic layers were washed with brine (2x) and dried over Na2SO4. The solids were removed by filtration and the filtrate was evaporated to dryness. The crude mixture was purified by flash chromatography on silica gel (0-100% EA in PE) to give methyl 2-(bis(tert-butoxycarbonyl)amino)-4-nitrobenzoate (4.54 g, 45%) as a beige solid. 1 H-NMR (DMSO-d6,400MHz) δ1.33(s,18H),3.85(s,3H),8.13(d,J=8.6Hz,1H),8.28(d,J=2.3Hz,1H),8.32(dd,J=8.5Hz,2.4Hz,1H)ppm.

[0370] A solution of methyl 2-(bis(tert-butoxycarbonyl)amino)-4-nitrobenzoate (1 equiv., 4.2 g, 10.6 mmol) in 2 M methylamine in THF (15 equiv., 79.5 mL, 158.93 mmol) was stirred for 3 days at 60° C. The mixture was evaporated under reduced pressure to give tert-butyl (2-(methylcarbamoyl)-5-nitrophenyl)carbamate (3.13 g, 99%) as a brown solid, which was used directly in the next step. 1 H-NMR (DMSO-d6,400MHz) δ1.36(s,6H),1.48(s,9H),2.81(d,J=4.5Hz,3H),6.64(br.s,1H),7.88-7.93(m,2H),9.02-9.05(m,2H)ppm. LCMS:C 13 H 17 N3O5[M+H] + :296.

[0371] A solution of (2-(methylcarbamoyl)-5-nitrophenyl)carbamate (1 equiv., 2.9 g, 9.82 mmol) in EtOH (145 mL) was purged with N2 (3x). Pd / C (0.1 equiv., 1.04 g, 0.98 mmol) was added. The mixture was purged with N2 and then with H2 (3x). The mixture was stirred at room temperature for 20 h. The mixture was filtered through a pad of Celite with the aid of EA and evaporated to dryness to give tert-butyl (5-amino-2-(methylcarbamoyl)phenyl)carbamate (2.6 g, 99%) as an orange solid which was used as such in the next step. 1 H-NMR(DMSO-d6,400MHz)δ1.45(s,9H),2.69(d,J=4.5Hz,3H),5.73(br.,s,2H),6.15(dd,J=8.6Hz ,2.3Hz,1H),7.4(d,J=8.7Hz,1H),7.49(d,J=2.3Hz,1H),8.16(q,J=4.6Hz,1H),11.38(s,1H)ppm. LCMS:C 13 H 19 N3O3[M+H] + :266.

[0372] [ka]

[0373] Isopropylamine (1.2 equiv., 1.809 mL, 21.11 mmol) was added to a solution of 2-fluoro-5-nitropyridine (1 equiv., 2.5 g, 17.59 mmol) and Cs2CO3 (1.5 equiv., 8.6 g, 26.39 mmol) in anhydrous DMSO (50 mL). The mixture was stirred at 50° C. for 3 h, then water was added. The aqueous layer was extracted with EA (3×50 mL). The organic layers were combined, washed with 10% citric acid solution in water (2×50 mL) and brine (4×50 mL), dried over Na2SO4, filtered and evaporated to dryness to give N-isopropyl-5-nitropyridin-2-amine (3.015 g, 95%) as a yellow solid. 1H-NMR(CDCl3,400MHz)δ1.27(d,J=6.5Hz,6H),3.96-4.13(m,1H),5.08-5.27(m,1 H),6.30(d,J=8.8Hz,1H),8.15(dd,J=9.3,2.6Hz,1H),8.98(d,J=2.8Hz,1H)ppm. LCMS:C8H 11 N3O2[M+H] + :182.

[0374] Boc2O (1.2 equiv., 2.3 g, 10.53 mmol) and DMAP (1.2 equiv., 1.29 g, 10.53 mmol) were added to a solution of N-isopropyl-5-nitropyridin-2-amine (1 equiv., 1.59 g, 8.78 mmol) in anhydrous MeCN (46 mL). The mixture was stirred for 3 h. The mixture was diluted in EA (100 mL), washed with 20% citric acid solution (3×50 mL), saturated NaHCO3 solution (50 mL), and brine (50 mL), and dried over Na2SO4. The solids were removed by filtration and the filtrate was evaporated to dryness to give the crude product, which was purified by flash chromatography on silica gel (0-30% EA in CyH) to give tert-butyl isopropyl(5-nitropyridin-2-yl)carbamate (1.76 g, 71%) as a colorless oil. 1 H-NMR(CDCl3,400MHz)δ1.37(d,J=7.0Hz,6H),1.50(s,9H),4.82(heptet,J=6.8Hz ,1H),7.59(d,J=9.1Hz,1H),8.33(dd,J=9.1,2.8Hz,1H),9.2(d,J=2.8Hz,1H)ppm. LCMS:C 13 H 19 N3O4[M+H] + :282.

[0375] Pd / C 10% (0.05 equiv., 320 mg, 0.30 mmol) was added to a solution of tert-butyl isopropyl(5-nitropyridin-2-yl)carbamate (1 equiv., 1.76 g, 6.26 mmol) in MeOH (40 mL). The mixture was purged with N2 and then with H2 (3x). The mixture was stirred at room temperature for 3 h. The mixture was filtered through a pad of Celite with EA and evaporated to dryness to give tert-butyl(5-aminopyridin-2-yl)(isopropyl)carbamate (1.57 g, 95%) as a white solid. 1 H-NMR(CDCl3,400MHz)δ1.14(d,J=6.6Hz,6H),1.36(s,9H),3.67(bs,2H),4.42(heptet,J= 6.7Hz,1H),6.86(d,J=7.8Hz,1H),6.96(dd,J=7.8Hz,2.8Hz,1H),7.92(d,J=2.8Hz,1H)ppm. LCMS:C 13 H 21 N3O2[M+H] + :252.

[0376] [ka]

[0377] Ethyl L(-)-lactate (1 equiv., 5 g, 42.33 mmol) in anhydrous CHCl (30 mL) was added to a solution of DBU (1.4 equiv., 8.85 mL, 59.26 mmol) and triphenylmethyl chloride (1 equiv., 11.8 g, 42.33 mmol) in anhydrous CHCl (30 mL) under N. The mixture was stirred at room temperature for 3 days. The mixture was diluted with cold water (20 mL), extracted with EtO (3×50 mL), washed with brine, and dried over NaSO. The solids were removed by filtration and the filtrate was evaporated to dryness to give the crude product, which was purified by flash chromatography on silica gel (0–10% EA in CyH) to give ethyl (S)-2-(trityloxy)propanoate (15.9 g, 99%) as a colorless oil. 1H-NMR(DMSO-d6,400MHz)δ0.98(t,J=7.0Hz,3H),1.22(d,J=6.7Hz,3H),3.62(q,J=7.0Hz ,2H),4.01(q,J=6.7Hz,1H),7.24-7.29(m,3H),7.30-7.35(m,6H),7.37-7.41(m,6H)ppm.

[0378] LiAlH4 1M in THF (1 equiv., 42.33 mL, 42.33 mmol) was added dropwise to a solution of ethyl (S)-2-(trityloxy)propanoate (1 equiv., 15.26 g, 42.33 mmol) in anhydrous THF (200 mL) under N2 at -78 °C. The mixture was stirred at -78 °C for 4 h. The mixture was diluted with Et2O (100 mL) and cooled at 0 °C. Water (42 mL) was added slowly, followed by aqueous NaOH (15%) (42 mL) and a second portion of water (170 mL). The mixture was stirred at room temperature for 15 min, then MgSO4 was added. The mixture was stirred for 15 min. The salts were removed by filtration and washed with Et2O. The filtrate was evaporated to dryness to give (S)-2-(trityloxy)propan-1-ol (9.3 g, 69%) as a white solid. 1 H-NMR(DMSO-d6,400MHz)δ0.69(d,J=6.1Hz,3H),2.94-3.13(m,2H),3.43-3.54(m,1 H),4.46-4.49(m,1H),7.23-7.28(m,3H),7.30-7.36(m,6H),7.43-7.47(m,6H)ppm.

[0379] (S)-2-(trityloxy)propan-1-ol (1.2 equiv., 12.33 g, 38.7 mmol) was added to a solution of 2-fluoro-5-nitropyridine (1 equiv., 5.5 g, 38.7 mmol) and Cs2CO3 (1.5 equiv., 18.9 g, 58.06 mmol) in anhydrous DMSO (100 mL). The mixture was stirred at 50° C. for 3 h, then water was added. The aqueous layer was extracted with EA:iPrOH (85:15) (3×). The organic layers were combined, washed with water (2x) and brine (4x), dried over Na2SO4, filtered and evaporated to dryness to give the crude product, which was purified by flash chromatography on silica gel (0-30% EtOAc in CyH) to give (S)-5-nitro-2-(2-(trityloxy)propoxy)pyridine (6.95 g, 41%). 1 H-NMR(DMSO-d6,400MHz)δ0.85(d,J=6.2Hz,3H),3.84-3.95(m,1H),4.07-4.11(m,2H),6.98(d,J=9.2H) z,1H),7.17-7.35(m,11H),7.41-7.47(m,4H),8.45(dd,J=9.2Hz,3.0Hz,1H),8.99(d,J=3.0Hz,1H)ppm.

[0380] Pd / C 10% (0.1 equiv., 1.65 g, 1.57 mmol) was added to a solution of (S)-5-nitro-2-(2-(trityloxy)propoxy)pyridine (1 equiv., 6.9 g, 15.66 mmol) in AcOEt (100 mL). The mixture was purged with N2 and then with H2 (3x). The mixture was stirred at room temperature for 18 h. The mixture was filtered through a pad of Celite with the aid of EA and evaporated to dryness to give (S)-6-(2-(trityloxy)propoxy)pyridin-3-amine (6.33 g, 98%) as a beige solid. 1 H-NMR(DMSO-d6,400MHz)δ0.70(d,J=5.5Hz,3H),3.77-3.88(m,3H),4.70(s,2H),6.48(d ,J=8.7Hz,1H),6.97(dd,J=8.8Hz,2.8Hz,1H),7.17-7.35(m,12H),7.38-7.50(m,4H)ppm.

[0381] [ka]

[0382] (S)-(-)-1-amino-2-propanol (1.2 equiv., 1 mL, 12.67 mmol) was added to a solution of 2-fluoro-5-nitropyridine (1 equiv., 1.5 g, 10.56 mmol) and Cs2CO3 (1.5 equiv., 5.16 g, 15.84 mmol) in anhydrous DMSO (30 mL). The mixture was stirred at 50° C. for 2 h, then water was added. The aqueous layer was extracted with EA (3×50 mL). The organic layers were combined, washed with 10% citric acid solution in water (2×50 mL) and brine (4×50 mL), dried over Na2SO4, filtered and evaporated to dryness to give (S)-1-((5-nitropyridin-2-yl)amino)propan-2-ol (1.76 g, 85%) as a yellow solid. 1 H-NMR(DMSO-d6,400MHz)δ1.08(d,J=6.0Hz,3H),3.76-3.84(m,1H),3.22-3.30(m,1H),4 .82(d,J=4.3Hz,1H),6.63(d,J=9.5Hz,1H),8.00-8.23(m,2H),8.89(d,J=2.7Hz,1H)ppm. LCMS:C8H 11 N3O3[M+H] + :198.

[0383] Pd / C 10% (0.1 equiv., 0.95 g, 0.89 mmol) was added to a solution of (S)-1-((5-nitropyridin-2-yl)amino)propan-2-ol (1 equiv., 1.76 g, 8.93 mmol) in EtOH (60 mL). The mixture was purged with N2 and then H2 (3x). The mixture was stirred at room temperature for 18 h. The mixture was filtered through a pad of Celite with EA and evaporated to dryness to give (S)-1-((5-aminopyridin-2-yl)amino)propan-2-ol (1.42 g, 95%) as a beige solid. 1H-NMR(DMSO-d6,400MHz)δ1.04(d,J=6.4Hz,3H),2.94-3.13(m,2H),3.71-3.78(m,1H),5.45- 5.54(m,1H),6.33(d,J=8.5Hz,1H),6.82(dd,J=8.5Hz,2.8Hz,1H),7.42(d,J=2.8Hz,1H)ppm. LCMS:C8H 13 NO[M+H] + :168.

[0384] [ka]

[0385] (R)-1-((5-aminopyridin-2-yl)amino)propan-2-ol was synthesized according to the protocol described for the synthesis of (S)-1-((5-aminopyridin-2-yl)amino)propan-2-ol, using (L)-(+)-1-amino-2-propanol instead of (S)-(-)-1-amino-2-propanol in the first step. LCMS: C8H 13 NO[M+H] + :168.

[0386] [ka]

[0387] (2S)-3-amino-1,2-propanediol (1 eq., 1.22 g, 13.37 mmol) was added to a solution of 2-fluoro-5-nitropyridine 1 (1 eq., 1.9 g, 13.37 mmol) and Et3N (2 eq., 3.72 mL, 26.74 mmol) in anhydrous THF (40 mL). The mixture was stirred at 70° C. for 3 h and then concentrated to dryness to give a yellow oil. DCM was added and the resulting precipitate was filtered to give (S)-3-((5-nitropyridin-2-yl)amino)propane-1,2-diol (1.75 g, 61%) as a yellow solid. LCMS: C8H 11 N3O4[M+H] + :214.

[0388] A solution of (S)-3-((5-nitropyridin-2-yl)amino)propane-1,2-diol (1 eq., 1.75 g, 8.20 mmol) in MeOH (60 mL) was purged with N2 (3x). Pd / C (0.1 eq., 870 mg, 0.82 mmol) was added. The mixture was purged with N2 (3x) and then with H2 (3x). The mixture was stirred at room temperature for 18 h. The mixture was filtered through a pad of Celite with MeOH and evaporated to dryness to give (S)-3-((5-aminopyridin-2-yl)amino)propane-1,2-diol (1.50 g, quant.) as a red oil, which was used directly in the next step. 1 H-NMR(DMSO-d6,400MHz)δ3.01-3.07(m,1H),3.22-3.25(m,5H),3.51-3.55(m,1H),4.2 5(br.s.,2H),5.57(m,1H),6.35(d,J=8.7Hz,1H),6.83(m,1H),7.4(d,J=2.6Hz,1H)ppm. LCMS:C8H 13 N3O2[M+H] + :183.

[0389] [ka]

[0390] (R)-3-((5-aminopyridin-2-yl)amino)propane-1,2-diol was synthesized following the route reported for the synthesis of (S)-3-((5-aminopyridin-2-yl)amino)propane-1,2-diol, using (2R)-3-amino-1,2-propanediol instead of (2S)-3-amino-1,2-propanediol. LCMS: C8H 13 N3O2[M+H] + :183.

[0391] [ka]

[0392] (3R)-3-pyrrolidinol (1.1 equiv., 0.97 mL, 11.6 mmol) was added to a solution of 2-fluoro-5-nitropyridine (1 equiv., 1.5 g, 10.56 mmol) and Cs2CO3 (1.5 equiv., 5.1 g, 15.84 mmol) in anhydrous DMSO (30 mL). The mixture was stirred at 50° C. for 3 h. Water was added and the aqueous layer was extracted with EA (3×50 mL). The organic layers were combined, washed with 10% citric acid solution in water (2×50 mL) and brine (4×50 mL), dried over Na2SO4, filtered and evaporated to dryness to give (R)-1-(5-nitropyridin-2-yl)pyrrolidin-3-ol (1.9 g, 86%) as a yellow solid. 1 H-NMR(DMSO-d6,400MHz)δ1.83-2.12(m,2H),3.45-3.82(m,4H),4.42(d,J=19.5Hz,1H),5.09( d,J=29.7Hz,1H),6.52-6.62(m,1H),8.20(dd,J=9.3Hz,1.8Hz,1H),8.97(d,J=2.7Hz,1H)ppm. LCMS:C9H 11 N3O3[M+H] + :210.

[0393] Pd / C 10% (0.1 equiv., 1.1 g, 1.06 mmol) was added to a solution of (R)-1-(5-nitropyridin-2-yl)pyrrolidin-3-ol (1 equiv., 2.2 g, 10.56 mmol) in EtOH (110 mL). The mixture was purged with N2 and then with H2 (3x). The mixture was stirred at room temperature for 18 h. The mixture was filtered through a pad of Celite with EA and evaporated to dryness to give (R)-1-(5-aminopyridin-2-yl)pyrrolidin-3-ol (1.45 g, 77%) as a beige solid. 1H-NMR(DMSO-d6,400MHz)δ1.74-1.91(m,1H),1.92-2.03(m,1H),3.10-3.19(m,1H),3.26-3.33(m,2H),3.39-3.51(m, 1H),4.21-4.44(m,3H),4.86(s,1H),6.23(d,J=8.7Hz,1H),6.90(dd,J=8.5Hz,2.5Hz,1H),7.55(d,J=2.1Hz,1H)ppm. LCMS:C9H 13 N3O1[M+H] + :180.

[0394] [ka]

[0395] Cs2CO3 (1.5 equiv., 5.57 g, 17.1 mmol) was added to a solution of 2-fluoro-5-nitropyridine (1 equiv., 1.62 g, 11.4 mmol) and azetidin-3-ol (1.2 equiv., 1.0 g, 13.7 mmol) in anhydrous DMSO (30 mL). The mixture was stirred at 50 °C for 20 h. Water was added and the aqueous layer was extracted with EA (3 x 50 mL). The organic layers were combined, washed with 10% citric acid solution in water (2 x 50 mL) and brine (4 x 50 mL), dried over Na2SO4, filtered and evaporated to dryness to give 1-(5-nitropyridin-2-yl)azetidin-3-ol (1.4 g, 63%) as a yellow solid. 1 H-NMR(CDCl3,400MHz)δ3.86-3.90(m,2H),4.32-4.38(m,2H),4.59-4.67(m,1H),5.86(d,J =6.4Hz,1H),6.42(d,J=9.3Hz,1H),8.19(dd,J=9.3,2.8Hz,1H),8.93(d,J=2.7Hz,1H)ppm. LCMS:C8H9N3O3[M+H] + :196.

[0396] Pd / C 10% (0.1 equiv., 760 mg, 0.720 mmol) was added to a solution of 1-(5-nitropyridin-2-yl)azetidin-3-ol (1 equiv., 1.4 g, 7.17 mmol) in MeOH (30 mL). The mixture was purged with N2 and then H2 (3x). The mixture was stirred at room temperature for 18 h. The mixture was filtered through a pad of Celite and evaporated to dryness to give 1-(5-aminopyridin-2-yl)azetidin-3-ol (1.16 g, 98%) as a black wax. 1 H-NMR(CDCl3,400MHz)δ3.50-3.55(m,2H),3.99-4.05(m,2H),4.46-4.53(m,1H),5.56(b r.s.,2H),6.29(d,J=8.5Hz,1H),6.99(dd,J=8.8,2.8Hz,1H),7.52(d,J=2.6Hz,1H)ppm. LCMS:C8H 11 NO[M+H] + :166.

[0397] [ka]

[0398] Cs2CO3 (4.0 equiv., 18.34 g, 56.30 mmol) was added to a solution of 2-fluoro-5-nitropyridine (1 equiv., 2.0 g, 14.08 mmol) and cis-3-aminocyclobutanol hydrochloride (1.1 equiv., 1.91 g, 15.48 mmol) in anhydrous DMSO (60 mL). The mixture was stirred at room temperature for 1 h. NaHCO3 (sat. aq., 50 mL) was added and the aqueous layer was extracted with EA (3×50 mL). The organic layers were combined, washed with water (4×50 mL), brine (50 mL) and dried over Na2SO4. The solids were removed by filtration and the filtrate's solvent was evaporated to dryness to give (1s,3s)-3-((5-nitropyridin-2-yl)amino)cyclobutan-1-ol (2.46 g, 84%) as a yellow solid. 1H-NMR(CDCl3,400MHz)δ1.73-1.84(m,2H),2.59-2.68(m,2H),3.82-3.92(m,1H),3.94-4.03(m,1H),5.14( d,J=5.8Hz,1H),6.50(d,J=8.3Hz,1H),8.04-8.13(m,1H),8.33(d,J=6.7Hz,1H),8.88(d,J=2.6Hz,1H)ppm LCMS:C9H 11 N3O3[M+H] + :210.

[0399] Pd / C 10% (0.1 equiv., 1.25 g, 1.18 mmol) was added to a solution of (1s,3s)-3-((5-nitropyridin-2-yl)amino)cyclobutan-1-ol (1 equiv., 2.46 g, 11.76 mmol) in EA (125 mL). The mixture was purged with N2 and then H2 (3x). The mixture was stirred at room temperature for 3 h, then filtered through a pad of Celite and evaporated to dryness to give (1s,3s)-3-((5-aminopyridin-2-yl)amino)cyclobutan-1-ol (1.87 g, 89%). 1 H-NMR(CDCl3,400MHz)δ1.56-1.65(m,2H),2.52-2.59(m,2H),3.48-3.58(m,1H),3.74-3.84(m,1H),4.24(bs,2) H),4.94(d,J=5.6Hz,1H),5.64(d,J=7.4Hz,1H),6.21(d,J=8.2Hz,1H),6.79(m,1H),7.43(d,J=2.8Hz,1H)ppm. LCMS:C9H 13 NO[M+H] + :180.

[0400] [ka]

[0401] Cs2CO3 (2.5 equiv., 11.47 g, 35.19 mmol) was added to a solution of 2-fluoro-5-nitropyridine (1 equiv., 2.0 g, 14.08 mmol) and trans-3-aminocyclobutanol HCl (1.2 equiv., 2.09 g, 16.89 mmol) in anhydrous DMSO (40 mL). The mixture was stirred at 50 °C for 3 h. Water (50 mL) was added and the aqueous layer was extracted with EA (3 x 50 mL). The organic layers were combined, washed with 10% citric acid (aq) (2 x 50 mL) and brine (4 x 50 mL) and dried over Na2SO4. The solids were removed by filtration and the filtrate's solvent was evaporated to dryness to give (1r,3r)-3-((5-nitropyridin-2-yl)amino)cyclobutan-1-ol (2.42 g, 82%) as a yellow solid. 1 H-NMR(CDCl3,400MHz)δ2.14-2.25(m,4H),4.27-4.35(m,1H),4.45(bs,1H),5.09(d,J=4 .4Hz,1H),6.51(bs,1H),8.09(bs,1H),8.39(d,J=5.1Hz,1H),8.90(d,J=2.7Hz,1H)ppm. LCMS:C9H 11 N3O3[M+H] + :210.

[0402] Pd / C 10% (0.1 equiv., 1.23 g, 1.15 mmol) was added to a solution of (1r,3r)-3-((5-nitropyridin-2-yl)amino)cyclobutan-1-ol (1 equiv., 2.42 g, 11.54 mmol) in MeOH (50 mL). The mixture was purged with N2 and then H2 (3x). The mixture was stirred at room temperature for 18 h. The mixture was filtered through a pad of Celite and the filtrate was evaporated to dryness to give (1r,3r)-3-((5-aminopyridin-2-yl)amino)cyclobutan-1-ol (2.02 g, 98%). 1H-NMR(CDCl3,400MHz)δ2.02-2.16(m,4H),3.98-4.06(m,1H),4.27(m,1H),4.73-5.36(m,2H) ),4.94(d,J=5.5Hz,1H),6.12(bs,1H),6.28(m,1H),6.91(m,1H),7.40(d,J=2.7Hz,1H)ppm. LCMS:C9H 13 NO[M+H] + :180.

[0403] [ka]

[0404] Cis-3-(benzyloxy)cyclobutanol (1.1 equiv., 1.0 g, 5.61 mmol) was added to a solution of 4-fluoronitrobenzene (1 equiv., 0.72 g, 5.10 mmol) and Cs2CO3 (1.5 equiv., 2.49 g, 7.65 mmol) in anhydrous DMSO (15 mL). The mixture was stirred at 80 °C for 18 h. Water was added and the aqueous layer was extracted with EA (3 x 50 mL). The organic layers were combined, washed with 10% citric acid (aq) (2 x 50 mL) and brine (4 x 50 mL) and dried over Na2SO4. The solids were removed by filtration and the filtrate's solvent was evaporated to dryness to give 1-((1s,3s)-3-(benzyloxy)cyclobutoxy)-4-nitrobenzene (1.53 g, 99%) as a yellow solid. 1 H-NMR(DMSO-d6,400MHz)δ1.95-2.04(m,2H),2.85-2.96(m,2H),3.82(m,1H),4.41 (s,2H),4.55(m,1H),7.04-7.08(m,2H),7.26-7.37(m,5H),8.16-8.22(m,2H)ppm.

[0405] Pd / C 10% (0.2 equiv., 1.1 g, 1.04 mmol) was added to a solution of 1-((1s,3s)-3-(benzyloxy)cyclobutoxy)-4-nitrobenzene (1 equiv., 1.4 g, 5.2 mmol) and 1N HCl in water (4.8 equiv., 25 mmol, 25 mL) in MeOH (25 mL). The mixture was purged with N2 then H2 (3x) and stirred at room temperature for 18 h. The mixture was filtered through a pad of Celite and the filtrate was evaporated to dryness to give (1s,3s)-3-(4-aminophenoxy)cyclobutan-1-ol hydrochloride (1.2 g, quant.) as a beige solid. 1 H-NMR (DMSO-d6, 400MHz) δ1.83-1.95(m,2H),2.77-2.86(m,2H),3.83(m,1H),4.25(m,1H),6.89(m,2H),7.28-7.33(m,2H),10.25(s,3H)ppm. LCMS:C 10 H 13 NO2[M+H] + :180.

[0406] [ka]

[0407] Trans-3-(benzyloxy)cyclobutanol (1.1 equiv., 1.0 g, 5.61 mmol) was added to a solution of 4-fluoronitrobenzene (1 equiv., 0.72 g, 5.10 mmol) and Cs2CO3 (1.5 equiv., 2.49 g, 7.65 mmol) in anhydrous DMSO (15 mL). The mixture was stirred at 80 °C for 18 h. Water was added and the aqueous layer was extracted with EA (3 x 50 mL). The organic layers were combined, washed with 10% citric acid (aq) (2 x 50 mL) and brine (4 x 50 mL) and dried over Na2SO4. The solids were removed by filtration and the filtrate's solvent was evaporated to dryness to give 1-((1r,3r)-3-(benzyloxy)cyclobutoxy)-4-nitrobenzene (1.53 g, 99%) as a yellow solid. 1H-NMR(DMSO-d6,400MHz)δ2.32-2.41(m,2H),2.53-2.60(m,2H),4.25-4.33(m,1H),4.42 (s,2H),4.98-5.05(m,1H),7.01-7.08(m,2H),7.26-7.37(m,5H),8.16-8.22(m,2H)ppm.

[0408] BBr3 (1M in DCM, 3.0 equiv., 16.4 mL, 16.14 mmol) was added to a solution of 1-((1r,3r)-3-(benzyloxy)cyclobutoxy)-4-nitrobenzene (1.0 equiv., 1.6 g, 5.38 mmol) in anhydrous DCM (50 mL) at -78 °C. The mixture was stirred for 1 h and then warmed to 0 °C. The mixture was stirred for 1 h. NH4Cl (sat. aq.) was added. The organic layer was collected and the aqueous layer was extracted with DCM (3x). The combined organic layers were dried over Na2SO4. The solids were removed by filtration and the filtrate's solvent was evaporated to dryness and purified by normal phase chromatography (0-70% EA in CyH) to give (1r,3r)-3-(4-nitrophenoxy)cyclobutan-1-ol (0.96 g, 85%) as a white solid. 1 H-NMR (DMSO-d6, 400MHz) δ2.35(m,4H),4.38(m,1H),4.98(m,1H),5.24(m,1H),6.99-7.04(m,2H),8.16-8.22(m,2H)ppm. LCMS:C 10 H 11 NO4[M+H] + :210.

[0409] Pd / C 10% (0.2 equiv., 0.98 g, 0.92 mmol) was added to a solution of (1r,3r)-3-(4-nitrophenoxy)cyclobutan-1-ol (1 equiv., 0.96 g, 4.59 mmol) in MeOH (25 mL). The mixture was purged with N2 and then H2 (3x). The mixture was stirred at room temperature for 18 h and then filtered through a pad of Celite. The filtrate was evaporated to dryness to give (1r,3r)-3-(4-aminophenoxy)cyclobutan-1-ol (0.80 g, 97%) as a beige solid. 1H-NMR (DMSO-d6, 400MHz) δ2.13-2.22(m,4H),4.27-4.37(m,1H),4.57(s,2H),4.59-4.67(m,1H),5.07(m,1H),6.44-6.55(m,4H)ppm. LCMS:C 10 H 13 NO2[M+H] + :180.

[0410] [ka]

[0411] Cis-3-(benzyloxy)cyclobutanol (1.1 equiv., 2.2 g, 12.34 mmol) was added to a solution of 2-fluoro-5-nitropyridine (1 equiv., 1.59 g, 11.22 mmol) and Cs2CO3 (1.5 equiv., 5.48 g, 16.83 mmol) in anhydrous DMSO (22 mL). The mixture was stirred at 80° C. for 2 h. Water was added and the aqueous layer was extracted with EA (3×). The organic layers were combined, washed with water (2×) and brine (2×) and dried over Na2SO4. The solids were removed by filtration and the filtrate's solvent was evaporated to dryness. The product was purified by normal phase chromatography (0-20% EA in CyH) to give 2-((1s,3s)-3-(benzyloxy)cyclobutoxy)-5-nitropyridine (2.2 g, 65%) as a colorless oil. 1 H-NMR(DMSO-d6,400MHz)δ1.99-2.09(m,2H),2.81-2.91(m,2H),3.85(m,1H),4.40(s,2) H),4.93(m,1H),7.03(d,J=9.1Hz,1H),7.24-7.39(m,5H),8.48(m,1H),9.05(m,1H)ppm. LCMS:C 16 H 16 N2O4[M+H] + :301.

[0412] BBr3 (1M in DCM, 3.0 equiv, 18.98 mL, 18.98 mmol) was added to a solution of 2-((1s,3s)-3-(benzyloxy)cyclobutoxy)-5-nitropyridine (1.0 equiv, 1.9 g, 6.33 mmol) in anhydrous DCM (50 mL) at -78 °C. The mixture was stirred for 1 h and then warmed to 0 °C. The mixture was stirred for 1 h. NH4Cl (sat. aq.) was added. The organic layer was collected. The aqueous layer was extracted with DCM (3x) and the combined organic layers were dried over Na2SO4. The solids were removed by filtration and the filtrate's solvent was evaporated to dryness. The product was purified by normal phase chromatography (0-70% EA in CyH) to give (1s,3s)-3-((5-nitropyridin-2-yl)oxy)cyclobutan-1-ol (1.25 g, 94%) as a white solid. 1 H-NMR(DMSO-d6,400MHz)δ1.90-2.00(m,2H),2.76-2.86(m,2H),3.87(m,1H),4.82 (m,1H),5.23(d,J=6.5Hz,1H),7.01(d,J=9.1Hz,1H),8.47(m,1H),9.04(m,1H)ppm. LCMS:C9H 10 N2O4[M+H] + :211.

[0413] Pd / C 10% (0.2 equiv., 1.27 g, 1.19 mmol) was added to a solution of (1s,3s)-3-((5-nitropyridin-2-yl)oxy)cyclobutan-1-ol (1 equiv., 1.25 g, 6.66 mmol) in MeOH (25 mL). The mixture was purged with N2 and then H2 (3x). The mixture was stirred at room temperature for 18 h. The mixture was filtered through a pad of Celite and the filtrate was evaporated to dryness to give (1s,3s)-3-((5-aminopyridin-2-yl)oxy)cyclobutan-1-ol (1.0 g, 93%) as a beige solid. 1H-NMR(DMSO-d6,400MHz)δ1.76-1.87(m,2H),2.65-2.75(m,2H),3.72-3.84(m,1H),4.5 3(m,1H),4.72(s,2H),5.07(s,1H),6.49(m,1H),6.97(m,1H),7.45(d,J=2.8Hz,1H)ppm. LCMS:C9H 12 N2O2[M+H] + :181.

[0414] [ka]

[0415] Trans-3-(benzyloxy)cyclobutanol (1.1 equiv., 2.4 g, 13.47 mmol) was added to a mixture of 2-fluoro-5-nitropyridine (1 equiv., 1.74 g, 12.24 mmol) and Cs2CO3 (1.5 equiv., 5.98 g, 18.36 mmol) in anhydrous DMSO (22 mL). The mixture was stirred at 80° C. for 2 h. Water was added and the aqueous layer was extracted with EA (3×). The organic layers were combined, washed with water (2×) and brine (2×) and dried over Na2SO4. The solids were removed by filtration and the filtrate's solvent was evaporated to dryness. The product was purified by normal phase chromatography (0-20% EA in CyH) to give 2-((1r,3r)-3-(benzyloxy)cyclobutoxy)-5-nitropyridine (2.86 g, 78%) as a colorless oil. 1 H-NMR(DMSO-d6,400MHz)δ2.30-2.40(m,2H),2.47-2.55(m,2H),4.25-4.33(m,1H),4.41 (s,2H),5.37-5.42(m,1H),7.03(d,J=8.9Hz,1H),8.47(m,1H),9.06(d,J=2.9Hz,1H)ppm. LCMS:C 16 H 16 N2O4[M+H] + :301.

[0416] BBr3 (1M in DCM, 3.0 equiv, 28.60 mL, 28.60 mmol) was added to a solution of 2-((1r,3r)-3-(benzyloxy)cyclobutoxy)-5-nitropyridine (1.0 equiv, 2.86 g, 9.52 mmol) in anhydrous DCM (110 mL) at -78 °C. The mixture was stirred for 1 h and then warmed to 0 °C. The mixture was stirred for 1 h. NH4Cl (sat. aq.) was added and the organic layer was collected. The aqueous layer was extracted with DCM (3x). The combined organic layers were dried over Na2SO4 and the solids were removed by filtration. The filtrate's solvent was evaporated to dryness and purified by normal phase chromatography (0-70% EA in CyH) to give (1r,3r)-3-((5-nitropyridin-2-yl)oxy)cyclobutan-1-ol (2.0 g, 99%) as a white solid. 1 H-NMR (DMSO-d6,400MHz)δ2.31-2.40(m,4H),4.34-4.44(m,1H),5.20(d,J=5.3Hz,1H),5.36-5.42(m,1H),7.01(m,1H),8.47(m,1H),9.06(m,1H). LCMS:C9H 10 N2O4[M+H] + :211.

[0417] Pd / C 10% (0.2 equiv., 1.01 g, 0.95 mmol) was added to a solution of (1r,3r)-3-((5-nitropyridin-2-yl)oxy)cyclobutan-1-ol (1 equiv., 2.0 g, 9.52 mmol) in MeOH (60 mL). The mixture was purged with N2 and then H2 (3x). The mixture was stirred at room temperature for 18 h. The mixture was filtered through a pad of Celite and the filtrate was evaporated to dryness to give (1r,3r)-3-((5-aminopyridin-2-yl)oxy)cyclobutan-1-ol (1.56 g, 91%) as a beige solid. 1 H-NMR (DMSO-d6,400MHz)δ2.17-2.25(m,4H),4.28-4.37(m,1H),4.70(s,2H),5.02-5.12(m,2H),6.49(d,J=8.5Hz,1H),6.97(m,1H),7.46(m,1H)ppm. LCMS:C9H 12 N2O2[M+H]+ :181.

[0418] [ka]

[0419] NaH 60% (2.2 equiv., 3.38 g, 84.58 mmol) was added to a solution of methyl 2-aminopyrimidine-5-carboxylate (1.1 equiv., 6.48 g, 42.29 mmol) in anhydrous DMF (140 mL) at 0° C. under N2. The mixture was stirred from 0° C. to room temperature for 30 min, then a solution of ethyl (R)-1-(4-bromo-3-(trifluoromethyl)benzoyl)-5-isothiocyanato-2-methyl-1,2,3,6-tetrahydropyridine-4-carboxylate (1 equiv., 18.35 g, 38.45 mmol) in anhydrous DMF (140 mL) was added. The mixture was stirred at room temperature for 1.5 h, then cooled to 0° C. Brine was added, followed by 1N HCl. The precipitate was collected by filtration and further dried under reduced pressure to give (R)-2-(7-(4-bromo-3-(trifluoromethyl)benzoyl)-6-methyl-4-oxo-2-thioxo-1,4,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-3(2H-yl)pyrimidine-5-carboxylic acid (14.53 g, 66%) as a brown solid which was used in the next step without further purification. LCMS: C 21 H 15 BrF3N5O4S[M+H] + :570 / 572.

[0420] Et3N (1.5 equiv., 6.59 mL, 47.45 mmol) and diphenylphosphoryl azide (1.5 equiv., 10.22 mL, 47.45 mmol) were added to a solution of (R)-2-(7-(4-bromo-3-(trifluoromethyl)benzoyl)-6-methyl-4-oxo-2-thioxo-1,4,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyrimidine-5-carboxylic acid (1 equiv., 18.04 g, 31.63 mmol) in anhydrous DMF (180 mL) under N2. The mixture was stirred at room temperature for 1.5 h. Water (35 mL) was added. The round-bottom flask was equipped with a condenser and the mixture was stirred at 100° C. for 30 min. The mixture was cooled to room temperature. Water was added. The precipitate was isolated by filtration and washed with water (3x). The crude mixture was purified by flash chromatography on silica gel (0-10% MeOH in DCM) to give (R)-3-(5-aminopyrimidin-2-yl)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-6-methyl-2-thioxo-2,3,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-4(1H)-one (8.15 g, 48%) as a beige solid, which was used in the next step without further purification. 1 H-NMR(DMSO-d6,400MHz,80℃)δ1.17-1.20(m,6H),2.22-2.30(m,1H),3.95-4.30(m,3H),5.07-5.15(m ,1H),5.82(br.s,2H),7.68-7.70(m,1H),7.91-7.93(m,1H),8.01-8.02(m,2H),8.12-8.15(m,2H)ppm. LCMS:C 20 H 16 BrF3N6O2S[M+H] + :541 / 543.

[0421] [ka]

[0422] 4-Methoxybenzylamine (1.5 equiv., 3.1 mL, 23.44 mmol) was added to a solution of 2-amino-5-bromo-3-nitropyridine (1 equiv., 3.41 g, 15.63 mmol), cesium acetate (3 equiv., 9 g, 46.89 mmol), Cu (0.1 equiv., 99 mg, 1.56 mmol) in anhydrous DMSO (23 mL) under N2. The mixture was stirred at 90°C for 16 h. The mixture was filtered through a pad of Celite and rinsed with EA. Water was added and the layers were separated. The aqueous layer was extracted with EA (2x). The organic phase was washed with water (3x) and brine and dried over Na2SO4. The solids were removed by filtration and the filtrate was evaporated to dryness. The crude mixture was purified by flash chromatography on silica gel (0-100% EA in CyH) to give N5-(4-methoxybenzyl)-3-nitropyridine-2,5-diamine (1.29 g, 30%) as a red solid, which was used directly in the next step. 1 H-NMR (DMSO-d6, 400MHz) δ3.72(s,3H),4.18(m,2H),6.19(m,1H),6.88-6.91(m,2H),7.28-7.33(m,4H),7.38(m,1H),8.12(m,1H)ppm. LCMS:C 13 H 14 N4O3[M+H] + :275.

[0423] TFA (50 equiv., 17.5 mL, 235.16 mmol) was added to a solution of N5-(4-methoxybenzyl)-3-nitropyridine-2,5-diamine (1 equiv., 1.29 g, 4.70 mmol) in anhydrous DCM (45 mL) under N2. The mixture was stirred at room temperature for 3 h. DCM was evaporated. Water was added and the aqueous layer was extracted with EA (3x). The combined organic layers were washed with brine and dried over Na2SO4. The solids were removed by filtration and the filtrate was evaporated to dryness. The crude mixture was purified by flash chromatography on silica gel (0-10% MeOH in DCM) to give 3-nitropyridine-2,5-diamine (420 mg, 58%) as a red solid, which was used in the next step without further purification. 1H-NMR (DMSO-d6, 400MHz) δ5.04 (br.s, 2H), 7.24 (br.s, 2H), 7.58 (m, 1H), 8.02 (m, 1H) ppm. LCMS:C5H6N4O2[M+H] + :155.

[0424] NEt3 (4 equiv., 1.38 mL, 9.91 mmol) was added to a solution of ethyl (R)-1-(4-bromo-3-(trifluoromethyl)benzoyl)-5-isothiocyanato-2-methyl-1,2,3,6-tetrahydropyridine-4-carboxylate (1 equiv., 1182.4 mg, 2.48 mmol) and 3-nitropyridine-2,5-diamine (1.1 equiv., 420 mg, 2.72 mmol) in anhydrous CH3CN (24 mL) under N2. The mixture was stirred at 100 °C for 3 h. The mixture was evaporated to dryness and purified by flash chromatography on silica gel (0-5% MeOH in DCM) to give (R)-3-(6-amino-5-nitropyridin-3-yl)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-6-methyl-2-thioxo-2,3,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-4(1H)-one (1.26 g, 87%) as a brown solid which was used directly in the next step. LCMS: C 21 H 16 BrF3N6O4S[M+H] + :586.

[0425] Fe (5 eq., 1.07 g, 19.22 mmol) was added to a solution of (R)-3-(6-amino-5-nitropyridin-3-yl)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-6-methyl-2-thioxo-2,3,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-4(1H)-one (1 eq., 2.25 g, 3.84 mmol) and NH4Cl (5 eq., 1.03 g, 19.22 mmol) in EtOH (15 mL) and water (15 mL) under N2. The mixture was stirred at 80° C. for 3 h. The mixture was diluted in EA and filtered over packed Celite. The organic layer was washed with brine (2×) and dried over Na2SO4. The solids were removed by filtration and the filtrate was evaporated to dryness to give (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-3-(5,6-diaminopyridin-3-yl)-6-methyl-2-thioxo-2,3,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-4(1H)-one (1.6 g, 75%) as a brown solid which was used in the next step without further purification. LCMS: C 21 H 18 BrF3N6O4S[M+H] + :555 / 557.

[0426] Glyoxal, 40% w / w in water (1.1 eq., 0.46 g, 3.17 mmol) was added to a solution of (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-3-(5,6-diaminopyridin-3-yl)-6-methyl-2-thioxo-2,3,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-4(1H)-one (1 eq., 1.6 g, 2.88 mmol) in EtOH (10 mL) under N2. The mixture was stirred at room temperature for 18 h and then poured into water. The precipitate was isolated by filtration and washed with water. The crude mixture was purified by reverse phase chromatography (5-100% CHCN in HO (+0.1% FA)) to afford (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-6-methyl-3-(pyrido[2,3-b]pyrazin-7-yl)-2-thioxo-2,3,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-4(1H)-one (638 mg, 38%) as a beige solid, which was used in the next step without further purification. 1 H-NMR(DMSO-d6,400MHz,80℃)δ1.26(m,3H),2.35-2.48(m,1H),2.58-2.64(m,1H),4.11-4.16(m,1H),4.5-4.85(m,2H), 7.67(m,1H),7.87(m,1H),8.0(m,1H),8.48(br.s,1H),9.01(br.s,1H),9.07(m,1H),9.17(m,1H),12.68(br.s,1H)ppm. LCMS:C 23 H 16 BrF3N6O2S[M+H] + :577 / 579.

[0427] [ka]

[0428] N,N-Dimethylethanolamine (1 equiv., 0.70 mL, 7.03 mmol) was added to a mixture of 2-fluoro-5-nitropyridine (1 equiv., 1.0 g, 7.03 mmol) and Cs2CO3 (1.5 equiv., 3.44 g, 10.56 mmol) in anhydrous DMSO (20 mL). The mixture was stirred at 50° C. for 1 h. Water was added and the aqueous layer was extracted with EA (3×). The organic layers were combined, washed with water (2×) and brine (2×) and dried over Na2SO4. The solids were removed by filtration and the filtrate's solvent was evaporated to dryness to give N,N-dimethyl-2-((5-nitropyridin-2-yl)oxy)ethan-1-amine (1.05 g, 67%) as a yellow solid. 1 H-NMR (DMSO-d6, 400MHz) δ2.21(s,6H),2.66(m,2H),4.49(t,J=5.8Hz,2H),7.03(m,1H),8.47(m,1H),9.08(m,1H)ppm. LCMS:C9H 13 N3O3[M+H] + :212.

[0429] Pd / C 10% (0.1 equiv., 0.50 g, 0.47 mmol) was added to a solution of N,N-dimethyl-2-((5-nitropyridin-2-yl)oxy)ethan-1-amine (1 equiv., 1.05 g, 4.73 mmol) in EtOH (35 mL). The mixture was purged with N2 and then H2 (3x). The mixture was stirred at room temperature for 2 days and then filtered through a pad of Celite. The filtrate was evaporated to dryness to give 6-(2-(dimethylamino)ethoxy)pyridin-3-amine (800 mg, 93%) as an orange oil. 1 H-NMR (DMSO-d6,400MHz) δ2.17(s,6H),2.54(m,2H),4.16(m,2H),4.72(s,2H),6.52(d,J=8.7Hz,1H),6.99(m,1H),7.48(m,1H)ppm. LCMS:C9H 15 NO[M+H] + :182.

[0430] Final step in the synthesis of compound 43

[0431] [ka]

[0432] Formaldehyde 37% (2 eq., 62 μL, 0.83 mmol) was added to a solution of (R)-3-(5-aminopyrimidin-2-yl)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one, compound 42 (1 eq., 250 mg, 0.41 mmol) in EtOH (2.5 mL), THF (2.5 mL), and AcOH (0.5 mL) under N2. The mixture was stirred at 85° C. for 6 h. NaCNBH3 (2 eq., 52 mg, 0.83 mmol) was then added and the mixture was stirred at room temperature for 16 h. This procedure was repeated three times. The mixture was poured into brine at 0°C and then extracted with EA (3x). The combined organic layers were washed with NaHCO3 (sat. aq., 2x), brine (1x) and dried over Na2SO4. The solids were removed by filtration and the filtrate was evaporated to dryness. The crude mixture was purified by flash chromatography on silica gel (0-100% EA in CyH, then 0-10% MeOH in DCM) followed by reverse phase chromatography (5-100% CH3CN in H2O (+0.1% FA)) and purified by preparative HPLC (Agilent 5 prep Further purification by C18, 5 μm, 30 mL / min over 30 min (2% to 100% CH3CN in HO (+0.4% NH4HCO3)) afforded (R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-methyl-3-(5-(methylamino)pyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one compound 43 (44 mg, 17%) as a white solid. 1H-NMR(DMSO-d6,400MHz,80℃)δ1.24(m,3H),1.84(s,3H),2.37(s,3H),2.50-5.54(m,1H),2.73-2.79(m,4H),4.22- 4.28(m,1H),4.41-4.84(m,2H),5.90(s,1H),6.12(m,1H),7.71(m,1H),7.9(d,J=2.2Hz,1H),7.98-8.01(m,3H)ppm. LCMS:C 26 H 24 BrF3N8O2[M+H] + :617 / 618.

[0433] Example A HBV-DNA antiviral assay using HepG2.117 cells The following assay procedure describes an HBV antiviral assay using HepG2.117 cells carrying a stably integrated genotype D HBV genome under the control of the Tet-off promoter and intracellular HBV DNA quantification as the endpoint. Cell viability is assessed in parallel by measuring intracellular ATP content using CellTiter-Glo2.0 (Promega).

[0434] On day 0, HepG2.117 cells (maintained in regular cell culture with doxycycline present in the medium at a final concentration of 1 μg / mL) were inoculated with 2.0 × 10 HBV in medium without doxycycline to induce transcription of pgRNA and subsequent formation of HBV particles. 4 Seed cells / well in 96-well plates (white with clear bottom) at a density of 0.1 mL / well. Incubate cells at 37° C. and 5% CO2.

[0435] On day 1, medium was removed from each well and test articles were diluted in culture medium without doxycycline and 100 μL was added to cell culture wells (9 concentrations, 4-fold dilutions). For each plate, 6 untreated (pure DMSO) wells are included. The final concentration of DMSO in the culture medium is 2%. Each plate is prepared in duplicate (one for HBV DNA extraction and one for CellTiter-Glo 2.0 measurement). Cells are incubated at 37°C and 5% CO2 for 3 days.

[0436] On day 4, cell viability is assessed using CellTiter-Glo 2.0 and cell lysates are prepared for HBV DNA extraction and subsequent quantification by qPCR.

[0437] HBV DNA quantification by qPCR The medium was removed from each well and 100 μL of 0.33% NP-40 in H2O was added to each well. The plate was sealed, incubated at 4°C for 5 min, vortexed vigorously and centrifuged briefly. Then, 35 μL of lysate was added to 65 μL of QuickExtract DNA extraction solution (Epicentre) in the PCR plate of each well. The PCR plate was incubated at 65°C for 6 min, 98°C for 2 min and finally cooled to 4°C. HBV DNA was then quantified by qPCR using the HBV-specific primers and probes specified in Table 3 on a CFX96 instrument (Bio-Rad) using Bio-Rad SSOAdvanced Universal Probes Supermix. The PCR cycle program consisted of 95°C for 3 min, followed by 40 cycles of 95°C for 10 s and 60°C for 30 s.

[0438] [Table 4]

[0439] Prepare DNA standards by diluting the IDT gBlock corresponding to the amplicon at concentrations ranging from 10^2 to 10^8 copies / input (i.e. per 4 µL) and use to generate a standard curve by plotting Cq values ​​versus HBV DNA standard concentration. Determine the amount of HBV DNA in each sample by interpolating from the standard curve.

[0440] Cell viability Using other plates, quantify cell viability by CellTiter-Glo 2.0 according to the manufacturer's manual. Briefly, 100 μL of reagent solution is added to the culture plate and shaken for 2 min. The plate is incubated at room temperature for 10 min, after which the luminescence signal is measured with a VarioSkan Lux (ThermoFisher) plate reader.

[0441] Data analysis Cell viability is calculated as follows: % cell viability = (luminescence value of test sample) / (mean luminescence value of 2% DMSO control) x 100%. HBV DNA inhibition was calculated as follows: 100-(HBV DNA copy number of test sample) / (mean HBV DNA copy number of 2% DMSO control) x 100%. Due to the excellent dynamic window of this assay, normalization to entecavir is not necessary. CC 50 , E.C. 50 , and E.C. 90 Values ​​were determined by dose-response curves fitted using nonlinear regression.

[0442] As shown in Table 4, the compounds of formula (I) are active against HBV, and "A" indicates an EC 50 "B" indicates EC ≦50 nM 50 >50nM and ≤500nM, "C" indicates EC 50 >500nM and ≤5000nM, "D" indicates EC 50 >5000 nM. Cell viability assessment showed a large window between effective antiviral and cytotoxic compound concentrations.

[0443] [Table 5]

[0444] Although the foregoing has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be appreciated by those skilled in the art that numerous and varied changes may be made thereto without departing from the spirit of the present disclosure. It is therefore to be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather encompass all modifications and alternative forms consistent with the true scope and spirit of the present disclosure.

Claims

1. A compound of formula (I) having the following structure, or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 During the ceremony, R １ but, 【Chemistry 2】 Selected from the group consisting of, R ２ but, 【Transformation 3】 Selected from the group consisting of, X １Ａ , X １Ｂ , and X １Ｃ However, independently, hydrogen, halogen, and unsubstituted C １～５ Alkyl and unsubstituted C １～５ Selected from the group consisting of haloalkyls, Y １Ａ is CH, C-CHF ２ , C-F, C-Cl, C-(NH ２ ), C(NH(unsubstituted C １～５ alkyl)), C(N(unsubstituted C １～５ alkyl) ２ ), or N, and Y ２Ａ However, CH, C-halogen, C-OCH ３ , C-(NH ２ ), C(NH(unsubstituted C １～５ Alkyl)), C(N(unsubstituted C １～５ Alkyl) ２ ), or N, Y ３Ａ However, it is CH or N, Y ４Ａ However, it is CH or N, Y １Ｂ However, CH, C-CHF ２ , C-F, C-Cl, C-(NH ２ ), C(NH(unsubstituted C １～５ Alkyl)), C(N(unsubstituted C １～５ Alkyl) ２ ), or N, Y ２Ｂ However, CH, C-halogen, C-OCH ３ , C-(NH ２ ), C(NH(unsubstituted C １～５ Alkyl)), C(N(unsubstituted C １～５ Alkyl) ２ ), or N, Y ３Ｂ However, it is CH or N, Y ４Ｂ However, it is CH or N, Y １Ｃ , Y ２Ｃ , Y ３Ｃ , and Y ４Ｃ However, each is independently CH, C- (halogen), or N. Y １Ｄ However, CH, C-CH ３ C-OCH ３ , C-(halogen), C-CHF ２ , C-CF ３ , or N, Y ２Ｄ However, CH, C-CH ３ C-OCH ３ , C-(halogen), C-CHF ２ , C-CF ３ , or N, Y ３Ｄ However, it is CH, C- (halogen), or N. Y １Ｅ , Y １Ｆ , and Y １Ｇ However, each is independently CH, C- (halogen), or N. Y １Ｈ , Y ２Ｈ , Y ３Ｈ , Y ４Ｈ , Y ５Ｈ , and Y ６Ｈ However, each is independently CH, C- (halogen), or N. R Ａ１ However, hydrogen, unsubstituted or substituted carbon １～５ Alkyl, or unsubstituted or substituted monocyclic C ３～６ It is a cycloalkyl, and the C １～５ Alkyl and the monocyclic C ３～６ When a cycloalkyl group is substituted, the C １～５ Alkyl and the C ３～６ Cycloalkyl, hydroxy, -NH ２ , unsubstituted C １～５ alkoxy, unsubstituted-NH(unsubstituted C) １～５ Alkyl), -N (unsubstituted C) １～５ Alkyl) ２ , -C(=O)NH ２ , -OP(=O)(OH) ２ , unsubstituted 5 or 6-membered monocyclic heterocyclyl, and one or more unsubstituted C １～４ Substituted with one or more groups selected from the group consisting of 5- or 6-membered monocyclic heterocyclines substituted with alkyl groups, R Ａ２ However, -CH ３ or -CD ３ And, R Ａ３ However, -NH ２ ,-NH(unsubstituted or substituted C) １～５ Alkyl), -N (unsubstituted or substituted C) １～５ Alkyl) ２ ,-NH(unsubstituted or substituted C) ３～６ Monocyclic cycloalkyls), unsubstituted or substituted 5-membered monocyclic heteroaryls, unsubstituted or substituted 6-membered monocyclic heteroaryls, or unsubstituted or substituted 4- to 6-membered monocyclic heterocyclines, R Ａ４ is unsubstituted or substituted C １～５ alkyl, unsubstituted C １～５ haloalkyl, or unsubstituted or substituted monocyclic C ３～６ cycloalkyl, wherein the C １～５ alkyl and the monocyclic C ３～６ cycloalkyl, when substituted, the C １～５ alkyl and the C ３～６ cycloalkyl are substituted with one or more groups selected from the group consisting of hydroxy, -C(=O)OH, and -C(=O)NH ２ and R Ａ５ is selected from the group consisting of hydrogen, halogen, -CN, -OH, -NH ２ , -C(=O)OH, -CH=CH ２ , unsubstituted C １～５ alkyl, and unsubstituted or substituted monocyclic C ３～６ cycloalkyl, and when the monocyclic C ３～６ cycloalkyl is substituted, the C ３～６ cycloalkyl is substituted with one or more hydroxy groups The compound of formula (I) or a pharmaceutically acceptable salt thereof, 【Chemistry 4】 or a compound of formula (I) or a pharmaceutically acceptable salt thereof, other than a pharmaceutically acceptable salt thereof.

2. R １ but, 【Transformation 5】 The compound according to claim 1.

3. R ２ but, 【Transformation 6】 The compound according to claim 1 or 2.

4. R2 is 【Transformation 7】 And; Y １Ａ , Y ２Ａ , Y ３Ａ , and Y ４Ａ The compound according to claim 3, wherein each of them is CH, or one of Y1A, Y2A, Y3A, and Y4A is N.

5. R Ａ１ However, hydroxy, -NH ２ , unsubstituted C １～５ alkoxy, unsubstituted-NH(unsubstituted C) １～５ Alkyl), -N (unsubstituted C) １～５ Alkyl) ２ , -C(=O)NH ２ , -OP(=O)(OH) ２ , unsubstituted 5 or 6-membered monocyclic heterocyclyl, and one or more unsubstituted C １～４ A C substituted with one or more groups selected from the group consisting of 5- or 6-membered monocyclic heterocyclines substituted with alkyl groups. １～５ It is alkyl, or The compound according to claim 4, wherein R A1 is a monocyclic C3-6 cycloalkyl group substituted with one or more groups selected from the group consisting of hydroxyl, -NH2, unsubstituted C1-5 alkoxy, unsubstituted -NH(unsubstituted C1-5 alkyl), -N(unsubstituted C1-5 alkyl)2, -C(=O)NH2, -O-P(=O)(OH)2, unsubstituted 5 or 6-membered monocyclic heterocyclil, and 5 or 6-membered monocyclic heterocyclil substituted with one or more unsubstituted C1-4 alkyl groups.

6. R2 is 【Transformation 8】 And; Y １Ｂ , Y ２Ｂ , Y ３Ｂ , and Y ４Ｂ The compound according to claim 3, wherein each of them is CH, or one of Y1B, Y2B, Y3B, and Y4B is N.

7. R2 is 【Chemistry 9】 And; Y １Ｃ , Y ２Ｃ , Y ３Ｃ , and Y ４Ｃ The compound according to claim 3, wherein each is CH, or one of Y1C, Y2C, Y3C, and Y4C is N; and R A3 is -NH2, -NH (unsubstituted or substituted C1-5 alkyl), -NH (unsubstituted or substituted C3-6 monocyclic cycloalkyl), unsubstituted or substituted 5-membered monocyclic heteroaryl, unsubstituted or substituted 4-membered monocyclic heterocyclil, unsubstituted or substituted 5-membered monocyclic heterocyclil, or unsubstituted or substituted 6-membered monocyclic heterocyclil.

8. R ２ but, 【Chemistry 10】 The compound according to claim 1 or 2.

9. R2 is 【Chemistry 11】 And; R Ａ５ The compound according to claim 8, wherein the compound is hydrogen.

10. Y1D is CH or C- (halogen); Y 2D is CH, C-CH3, C-OCH3, C-(halogen), C-CHF2, or C-CF3; The compound according to claim 9, wherein Y 3D is CH, C-CH3, C-OCH3, C-(halogen), C-CHF2, or C-CF3.

11. Y1D is CH or C- (halogen); Y 2D is N; The compound according to claim 9, wherein Y 3D is CH, C-CH3, C-OCH3, C-(halogen), C-CHF2, or C-CF3.

12. R ２ but, 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 A compound according to claim 1 or 2, selected from the group consisting of the following. 【Request Item 13】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 The compound according to claim 1, or selected from the group consisting of any of the pharmaceutically acceptable salts described above. 【Request Item 14】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 The compound according to claim 1, or selected from the group consisting of any of the pharmaceutically acceptable salts described above. 【Request Item 15】 【Chemistry 28】 【Chemistry 29】 Alternatively, the compound according to claim 13, selected from the group consisting of any of the pharmaceutically acceptable salts described above.

16. The compound is 【Transformation 30】 The compound according to claim 14, which is either or a pharmaceutically acceptable salt thereof.

17. The compound is 【Chemistry 31】 The compound according to claim 14, which is either or a pharmaceutically acceptable salt thereof. 【Request Item 18】 【Chemistry 32】 The aforementioned compound, The compound according to claim 14, which is either or a pharmaceutically acceptable salt thereof.

19. The compound is 【Transformation 33】 The compound according to claim 14, which is either or a pharmaceutically acceptable salt thereof.

20. The compound is 【Transformation 34】 The compound according to claim 14, which is either or a pharmaceutically acceptable salt thereof.

21. The compound is 【Chemistry 35】 The compound according to claim 14, which is either or a pharmaceutically acceptable salt thereof.

22. The compound is 【Transformation 36】 The compound according to claim 15, which is either or a pharmaceutically acceptable salt thereof.

23. The compound is 【Chemistry 37】 The compound according to claim 15, which is either or a pharmaceutically acceptable salt thereof.

24. The compound is 【Transformation 38】 The compound according to claim 15, which is either or a pharmaceutically acceptable salt thereof.

25. A pharmaceutical composition for treating hepatitis B or hepatitis D, comprising an effective amount of the compound described in any one of claims 1 or 16 to 24 or a pharmaceutically acceptable salt thereof.

26. The pharmaceutical composition according to claim 25, further comprising an additional agent selected from the group consisting of interferon, nucleoside analog, nucleotide analog, sequence-specific oligonucleotide, nucleic acid polymer, entry inhibitor, and small molecule immunomodulator.

27. The pharmaceutical composition according to claim 26, wherein the additional agent is selected from the group consisting of recombinant interferon alpha-2b, IFN-α, PEG-IFN-α-2a, lamivudine, terbivudine, adefovir dipivoxil, klevudine, entecavir, tenofovir alafenamide, tenofovir disoproxil, and modified oligonucleotides selected from numbers 1 to 392 of U.S. Patent Application Publication No. 2020 / 0147124 (A1).

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