Pyrimidinone-containing 17-beta-hydroxysteroid dehydrogenase type 13 inhibitors

Abstract

The present invention relates to a compound represented by formula (I) [Formula 1] JPEG2025516002000118.jpg3949 The present invention provides compounds of the formula (I), pharmaceutical compositions containing these compounds, and methods of using these compounds to treat metabolic diseases or liver conditions. The present invention relates generally to compounds and pharmaceutical compositions useful as 17β-HSD13 inhibitors. Specifically, the present invention relates to compounds useful as inhibitors of 17β-HSD13, and methods of their preparation and use.

Description

[Technical field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 335,840, filed April 28, 2022, the entire teachings of which are incorporated herein by reference.

[0002] The present invention relates generally to compounds and pharmaceutical compositions useful as 17β-HSD13 inhibitors. Specifically, the present invention relates to compounds useful as inhibitors of 17β-HSD13, and methods for their preparation and use. [Background technology]

[0003] 17-beta-hydroxysteroid dehydrogenases (17β-HSDs) are NADP- or NAD+-dependent oxidoreductases that catalyze the oxidation / reduction reactions of 17β-hydroxysteroids or 17-ketosteroids, respectively. For example, 17β-HSDs can catalyze the interconversion of androstenedione and testosterone, estrone and estradiol, or dehydroepiandrosterone (DHEA) and androstenediol. Of the 15 identified 17β-HSDs, all but one (17β-HSD type 5) are short-chain dehydrogenases / reductases (SDRs) (JM Day, et al., Endocrine-Related Cancer 2008,15,665-692).

[0004] More specifically, 17-beta-hydroxysteroid dehydrogenase type 13 (17β-HSD13), encoded by the HSD17B13 gene, is expressed primarily in the liver (S. Liu, et al., Acta Biochim. Pol. 2007, 54, 213-218). Furthermore, 17β-HSD13 has been identified as a lipid droplet-associated protein and is upregulated in mice and nonalcoholic fatty liver disease (NAFLD) patients (Y. Horiguchi, et al., Biochem. Biophys. Res. Commun. 2008, 370, 235-238; W. Su, et al., Mol. Cell. Endocrinol. 2019, 489, 119-125). Further studies have shown that 17β-HSD13 loss-of-function variants are associated with a significantly reduced risk of NAFLD, nonalcoholic steatohepatitis (NASH)-associated cirrhosis, alcoholic liver disease, alcoholic cirrhosis, hepatocellular carcinoma (HCC), NASH disease severity, balloon degeneration, lobular inflammation and fibrosis (NSAbul-Husn, et al., N. Engl. J. Med. 2018, 378, 1096-1106; CJ Pirola, et al., J. Lipid Res. 2019, 60, 176-185). This variant also shows reduced liver damage in obese children (A. Di Sessa, et al., J. Pediatr. Gastroenterol. Nutr. 2020, 70, 371-374).

[0005] Recently, small molecule compounds acting as 17β-HSD13 inhibitors have been published, namely WO 2023 / 023310, WO 2022 / 020714, WO 2022 / 020730, WO 2021 / 211974, and WO 2021 / 003295. Other agents that act as 17β-HSD13 inhibitors are disclosed in the following publications: WO 2021 / 211981, WO 2021 / 211959, WO 2020 / 132564, WO 2020 / 061177, WO 2019 / 075181, WO 2019 / 183164, WO 2019 / 183329, U.S. Patent Application Publication No. 2019 / 0106749 and WO 2018 / 136758.

[0006] There is a need for the development of 17β-HSD13 inhibitors for the treatment and prevention of disease. The present invention has identified compounds that inhibit 17β-HSD13, as well as methods of using these compounds to treat disease. Summary of the Invention

[0007] The present invention relates to compounds and pharmaceutical compositions useful as 17β-HSD13 inhibitors. In particular, the present invention relates to compounds useful as inhibitors of 17β-HSD13, and methods for their preparation and use. Furthermore, the present invention includes methods for preparing said compounds.

[0008] In a primary aspect, the present invention provides a compound represented by formula (I), or a pharma- ceutically acceptable salt or ester thereof: [ka] (In the formula, M is S, SO, SO 2 , O or NR 7 and R 1 and R 2 are each independently 1) Hydrogen, 2) optionally substituted -C 1 ~C 8 Alkyl, 3) optionally substituted -C 2 ~C 8 Alkenyl, 4) optionally substituted -C 2 ~C 8 Alkynyl, 5) optionally substituted -C 3 ~C 8 Cycloalkyl, 6) optionally substituted aryl; 7) optionally substituted arylalkyl; 8) optionally substituted 3- to 8-membered heterocycloalkyl; 9) optionally substituted heteroaryl, and 10) optionally substituted heteroarylalkyl is selected from the group consisting of R 3 , R 4 , R 5 and R 6 are each independently hydrogen, halogen, -CN, -OR 9 , -SR 9 , -C(O)R 7 , -C(O)OR 7 , -NR 7 R 8 , -C(O)NR 7 R 8 , optionally substituted -C 1 ~C 8 selected from the group consisting of alkyl, optionally substituted aryl, and optionally substituted heteroaryl; Or, R 5 and R 6 together with the carbon atom to which they are attached form an optionally substituted carbocyclic or heterocyclic ring; Or, R 4 and R 5 together with the carbon atom to which they are attached form an optionally substituted carbocyclic or heterocyclic ring; Or, R 3 and R 4together with the carbon atom to which they are attached form an optionally substituted carbocyclic or heterocyclic ring; Each R 7 and R 8 is independently 1) Hydrogen, 2) optionally substituted -C 1 ~C 8 Alkyl, 3) optionally substituted -C 2 ~C 8 Alkenyl, 4) optionally substituted -C 2 ~C 8 Alkynyl, 5) optionally substituted -C 3 ~C 8 Cycloalkyl, 6) optionally substituted 3- to 8-membered heterocycloalkyl; 7) optionally substituted aryl; 8) optionally substituted arylalkyl; 9) optionally substituted heteroaryl, and 10) optionally substituted heteroarylalkyl is selected from the group consisting of Or, R 7 and R 8 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring; R 9 teeth, 1) Hydrogen, 2) optionally substituted -C 1 ~C 8 Alkyl, 3) optionally substituted -C 2 ~C 8 Alkenyl, 4) optionally substituted -C 2 ~C 8 Alkynyl, 5) optionally substituted -C 3 ~C 8 Cycloalkyl, 6) optionally substituted 3- to 8-membered heterocycloalkyl; 7) optionally substituted aryl; 8) optionally substituted arylalkyl; 9) optionally substituted heteroaryl; 10) optionally substituted heteroarylalkyl; 11)-C(O)R 11 , 12)-C(O)NR 11 R 12 , 13)-C(O)OR 11 , 14)-P(O)(OR 13 ) 2 , and 15)-P(O)(OR 13 )(NR 11 R 12 ) is selected from the group consisting of R 11 and R 12 are each independently 1) Hydrogen, 2) optionally substituted -C 1 ~C 8 Alkyl, 3) optionally substituted -C 2 ~C 8 Alkenyl, 4) optionally substituted -C 2 ~C 8 Alkynyl, 5) optionally substituted -C 3 ~C 8 Cycloalkyl, 6) optionally substituted 3- to 8-membered heterocycloalkyl; 7) optionally substituted aryl; 8) optionally substituted arylalkyl; 9) optionally substituted heteroaryl, and 10) optionally substituted heteroarylalkyl is selected from the group consisting of R 13 is hydrogen, optionally substituted -C 1 ~C 8 Alkyl, or Na + (It is.)

[0009] In certain embodiments, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of the present invention, or a pharma- ceutically acceptable salt, ester, or combination thereof, in combination with a pharma- ceutically acceptable carrier or excipient.

[0010] In certain embodiments, the present invention provides a method for preventing or treating 17β-HSD13 mediated disease or condition.The method comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for preventing or treating 17β-HSD13 mediated disease or condition, including but not limited to non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver cirrhosis, liver fibrosis, hepatocellular carcinoma (HCC) and other metabolic disorders. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] In one embodiment of the present invention is a compound represented by formula (I) above, or a pharma- ceutically acceptable salt or ester thereof.

[0012] In certain embodiments of the compounds of formula (I), R 3 is hydrogen or a halogen.

[0013] In certain embodiments of the compounds of formula (I), R 4 is hydrogen or a halogen.

[0014] In certain embodiments of the compounds of formula (I), R 5 is hydrogen or a halogen.

[0015] In certain embodiments of the compounds of formula (I), R 3 is hydrogen, and R 4 is hydrogen, and R 5 is hydrogen.

[0016] In certain embodiments of the compounds of formula (I), R 6 -OR9 It is.

[0017] In certain embodiments of the compounds of formula (I), R 6 is -OH.

[0018] In certain embodiments of the compounds of formula (I), R 1 is optionally substituted aryl or optionally substituted heteroaryl.

[0019] In certain embodiments of the compounds of formula (I), R 1 is an optionally substituted heterocycloalkyl-C 1 ~C 6 -alkyl.

[0020] In certain embodiments of the compounds of formula (I), R 1 is an optionally substituted -C 3 ~C 8 It is a cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl.

[0021] In certain embodiments of the compounds of formula (I), R 1 is selected from the following groups, each of which is optionally substituted: [ka]

[0022] In certain embodiments of the compounds of formula (I), R 2 is an optionally substituted -C 1 ~C 8 Alkyl, preferably optionally substituted C 1 ~C 6 -alkyl. Preferred substituents include halogen, C 3 ~C 6 -Cycloalkyl, hydroxy, amino, C 1 ~C 6 -Alkylamino, di(C 1 ~C 6 -alkyl)amino, C 1 ~C 6-AlkylNHC(O)-, di(C 1 ~C 6 -alkyl)NC(O)- and -C(O)OC 1 ~C 6 -alkyl.

[0023] In certain embodiments of the compounds of formula (I), R 2 is an optionally substituted -C 2 ~C 8 Alkenyl, preferably optionally substituted C 2 ~C 6 -alkenyl. Preferred substituents include halogen, C 3 ~C 6 -Cycloalkyl, hydroxy, amino, C 1 ~C 6 -Alkylamino, di(C 1 ~C 6 -alkyl)amino and -C(O)OC 1 ~C 6 -alkyl.

[0024] In certain embodiments of the compounds of formula (I), R 2 is an optionally substituted -C 3 ~C 8 Cycloalkyl, preferably optionally substituted C 3 ~C 6 -cycloalkyl. Preferred substituents include halogen, C 1 ~C 4 -alkyl and hydroxy.

[0025] In certain embodiments of the compounds of formula (I), R 2 is an optionally substituted arylalkyl or an optionally substituted heteroarylalkyl.

[0026] In certain embodiments of the compounds of formula (I), R 2 is an optionally substituted aryl-C 1 ~C 6 -alkyl, optionally substituted heteroaryl-C 1 ~C 6-alkyl, or optionally substituted heterocyclyl-C 1 ~C 6 -alkyl, preferably optionally substituted aryl-C 1 ~C 4 -alkyl, optionally substituted heteroaryl-C 1 ~C 4 -alkyl, or optionally substituted heterocyclyl-C 1 ~C 4 -alkyl. Preferred substituents include halogen, C 1 ~C 4 -alkyl and hydroxy.

[0027] In certain embodiments of the compounds of formula (I), R 2 is an optionally substituted aryl-C 2 ~C 6 -alkenyl, optionally substituted heteroaryl-C 2 ~C 6 -alkenyl, or optionally substituted heterocyclyl-C 2 ~C 6 -alkenyl, preferably optionally substituted aryl-C 2 ~C 4 -alkenyl, optionally substituted heteroaryl-C 2 ~C 4 -alkenyl, or optionally substituted heterocyclyl-C 2 ~C 4 -alkenyl. Preferred substituents include halogen, C 1 ~C 4 -alkyl and hydroxy.

[0028] In certain embodiments of the compounds of formula (I), R 2 is an optionally substituted -C 1 ~C 4 -AlkylN(R)-C 1 ~C 4 -alkylaryl, optionally substituted -C 1 ~C 4 -AlkylN(R)-C 1 ~C 4-alkylheteroaryl, or optionally substituted -C 1 ~C 4 -AlkylN(R)-C 1 ~C 4 -alkylheterocyclyl, where R is H or C 1 ~C 4 -alkyl. Preferred substituents include halogen, C 1 ~C 4 -alkyl and hydroxy.

[0029] In certain embodiments of the compounds of formula (I), R 2 -C 1 ~C 6 -alkyl-L-R', where L is -O-, -S-, -N(R)-, -N(R)C(O)-, -NRC(O)O-, or -N(R)SO 2 -, and R' is optionally substituted C 1 ~C 6 -alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or R, R' and the nitrogen atom to which they are attached form an optionally substituted 3- to 8-membered heterocyclyl.

[0030] In certain embodiments of the compounds of formula (I), R 2 is selected from the group consisting of: [ka] [ka]

[0031] In one embodiment, the present invention provides a compound represented by formula (II) or (III), or a pharma- ceutically acceptable salt or ester thereof: [ka] (In the formula, R 1 , R 2, R 3 , R 4 , R 5 , R 6 and R 7 is as defined above).

[0032] In certain embodiments, the present invention provides a compound represented by formula (IV) or (V), or a pharma- ceutically acceptable salt or ester thereof: [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 and R 9 is as defined above).

[0033] In certain embodiments, the present invention provides a compound represented by formula (IV) or (V), or a pharma- ceutically acceptable salt or ester thereof, wherein R 9 is selected from the groups listed below, where each group is optionally substituted: [ka]

[0034] In one embodiment, the present invention provides a compound represented by formula (VI) or (VII), or a pharma- ceutically acceptable salt or ester thereof: [ka] (In the formula, R 1 , R 2 , R 3 , R 6 and R 7 is as defined above).

[0035] In certain embodiments, the present invention provides a compound represented by formula (VIII) or (IX), or a pharma- ceutically acceptable salt or ester thereof: [ka] (In the formula, R 1 , R 2 , R 3 , R 7 and R 9 is as defined above).

[0036] In certain embodiments, the present invention provides a compound represented by formula (X) or (XI), or a pharma- ceutically acceptable salt or ester thereof: [ka] (In the formula, R 1 , R 2 , R 7 and R 9 is as defined above). Preferably, R 9 is hydrogen.

[0037] In certain embodiments, the present invention provides a compound represented by formula (X) or (XI), or a pharma- ceutically acceptable salt or ester thereof, wherein R 9 is selected from the group consisting of the following, each of which is optionally substituted: [ka]

[0038] Representative compounds of the present invention include, but are not limited to, R 9 is hydrogen and R 1 and R 2 The following compounds according to formula (X) are included (Entry 1 to Entry 80 of Table 1), where: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0039] Representative compounds of the present invention include, but are not limited to, R 1 , R 2 and R 9 The following compounds according to formula (X) are included (Entry 81 to Entry 230 of Table 2), where: [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12] [Table 2-13] [Table 2-14] [Table 2-15] [Table 2-16] [Table 2-17] + [Table 2-18]

[0040] In certain embodiments, the present invention provides a compound represented by formula (XII) or (XIII), or a pharma- ceutically acceptable salt or ester thereof: [ka] (In the formula, each R 21 , R 22 , R 23 , R24 or R 25 are independently hydrogen, halogen, or optionally substituted -C 1 ~C 6 Alkyl, optionally substituted -C 1 ~C 6 Alkoxyl, or optionally substituted -C 3 ~C 8 -cycloalkyl, R 26 is an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heteroarylalkyl, an optionally substituted -C 3 ~C 8 -cycloalkyl, optionally substituted -C 1 ~C 6 Alkyl, -NR 7 R 8 , -CH 2 NR 7 R 8 , -CH 2 NR 7 C(O)R 8 ,or [ka] or [ka] and R 3 , R 7 , R 8 and R 9 is as defined above).

[0041] Or, R 21 and R 22 together with the carbon atom to which they are attached form an optionally substituted carbocyclic or heterocyclic ring fused to the phenyl.

[0042] Or, R 22 and R 23 together with the carbon atom to which they are attached form an optionally substituted carbocyclic or heterocyclic ring fused to the phenyl.

[0043] Or, R 7 and R 8 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring.

[0044] In certain embodiments, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of the present invention, or a pharma- ceutically acceptable salt, ester, or combination thereof, in combination with a pharma- ceutically acceptable carrier or excipient.

[0045] In certain embodiments, the present invention provides a method for preventing or treating 17β-HSD13 mediated disease or condition.The method comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for preventing or treating 17β-HSD13 mediated disease or condition, including but not limited to non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver cirrhosis, liver fibrosis, hepatocellular carcinoma (HCC) and metabolic disorders.

[0046] It is understood that the description of the invention herein should be interpreted in accordance with the rules and principles of chemical bonding. In some cases, it may be necessary to remove a hydrogen atom to accommodate a substituent at any given position.

[0047] It is further understood that the compound of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic form, diastereoisomers and optically active form.It is further understood that certain compounds of the present invention may exist in different tautomeric forms.It is intended that all tautomers are within the scope of the present invention.

[0048] It is to be understood that the compounds encompassed by the present invention are those that are suitably stable for use as pharmaceutical agents.

[0049] definition Listed below are definitions of various terms used to describe this invention. These definitions apply to those terms as they are used throughout the specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0050] The term "aryl" as used herein refers to a monocyclic or polycyclic carbocyclic ring system containing at least one aromatic ring. Preferred aryl groups include, but are not limited to, C aryl, naphthyl, tetrahydronaphthyl, indanyl, and indenyl. 6 ~C 12 -aryl group. A polycyclic aryl is a polycyclic ring system that includes at least one aromatic ring. A polycyclic aryl can include fused rings, covalently linked rings, or combinations thereof.

[0051] The term "heteroaryl" as used herein refers to a monocyclic or polycyclic aromatic radical having one or more ring atoms selected from S, O, and N, with the remaining ring atoms being carbon, and optionally oxidized to N or S contained within the ring. In certain embodiments, the heteroaryl group is a 5-10 membered heteroaryl, such as a 5- or 6-membered monocyclic heteroaryl or an 8-10 membered bicyclic heteroaryl. Heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinoxalinyl. Polycyclic heteroaryls can contain fused rings, covalently bonded rings, or combinations thereof. Heteroaryl groups can be C-linked or N-linked where possible.

[0052] According to the present invention, the aryl and heteroaryl groups can be substituted or unsubstituted.

[0053] The term "bicyclic aryl" or "bicyclic heteroaryl" refers to a ring system consisting of two rings, at least one of which is aromatic, and the two rings may be fused or covalently linked.

[0054] The term "alkyl" as used herein refers to a saturated straight or branched chain hydrocarbon radical. 1 ~C 4 Alkyl, C 1 ~C 6 Alkyl, C 1 ~C 8 Alkyl, C 1 ~C 12 Alkyl, C 2 ~C 4 Alkyl" and "C 3 ~C 6 "Alkyl" refers to alkyl groups containing 1-4, 1-6, 1-8, 1-12, 2-4, and 3-6 carbon atoms, respectively. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl, and n-octyl radicals.

[0055] The term "alkenyl" as used herein refers to a straight or branched chain hydrocarbon radical having at least one carbon-carbon double bond. 2 ~C 8 alkenyl", "C 2 ~C 12 alkenyl", "C 2 ~C 4 alkenyl", "C 3 ~C 4 alkenyl" and "C 3 ~C 6 "Alkenyl" refers to alkenyl groups containing 2 to 8, 2 to 12, 2 to 4, 3 to 4, or 3 to 6 carbon atoms, respectively. Alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 2-methyl-2-buten-2-yl, heptenyl, octenyl, and the like.

[0056] The term "alkynyl" as used herein refers to a straight or branched chain hydrocarbon radical having at least one carbon-carbon triple bond. 2 ~C 8 alkynyl", "C 2 ~C 12 alkynyl", "C 2 ~C 4 alkynyl", "C 3 ~C 4 alkynyl" and "C 3 ~C 6 "Alkynyl" refers to alkynyl groups containing 2 to 8, 2 to 12, 2 to 4, 3 to 4, or 3 to 6 carbon atoms, respectively. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, heptynyl, octynyl, and the like.

[0057] The term "cycloalkyl" as used herein refers to a monocyclic or polycyclic saturated carbocyclic ring, such as a bicyclic or tricyclic fused, bridged or spiro system. The ring carbon atoms are optionally oxo-substituted or optionally substituted with an exocyclic olefinic double bond. Preferred cycloalkyl groups include C 3 ~C 12 Cycloalkyl, C 3 ~C 6 Cycloalkyl, C 3 ~C 8 Cycloalkyl and C 4 ~C 7 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl, 4-methylene-cyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.0]hexyl, spiro[2.5]octyl, 3-methylenebicyclo[3.2.1]octyl, spiro[4.4]nonanyl, and the like.

[0058] The term "cycloalkenyl" as used herein refers to a monocyclic or polycyclic carbocyclic ring, such as a bicyclic or tricyclic fused, bridged or spiro system having at least one carbon-carbon double bond. The ring carbon atoms are optionally oxo-substituted or optionally substituted with an exocyclic olefinic double bond. Preferred cycloalkenyl groups include C 3 ~C 12 Cycloalkenyl, C 4 ~C 12 -Cycloalkenyl, C 3 ~C 8 Cycloalkenyl, C 4 ~C 8 Cycloalkenyl and C 5 ~C 7 Examples of cycloalkenyl include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[2.2.1]hept-2-enyl, bicyclo[3.1.0]hex-2-enyl, spiro[2.5]oct-4-enyl, spiro[4.4]non-2-enyl, bicyclo[4.2.1]non-3-en-12-yl, and the like.

[0059] As used herein, the term "arylalkyl" refers to a functional group in which an alkylene chain is attached to an aryl group, e.g., -(CH 2 ) n -phenyl, where n is 1 to 12, preferably 1 to 6, more preferably 1 or 2. The term "substituted arylalkyl" refers to an arylalkyl functional group in which the aryl group is substituted. Similarly, the term "heteroarylalkyl" refers to a functional group in which an alkylene chain is attached to a heteroaryl group, e.g., -(CH 2 ) n -heteroaryl, where n is 1 to 12, preferably 1 to 6, more preferably 1 or 2. The term "substituted heteroarylalkyl" refers to a heteroarylalkyl functional group in which the heteroaryl group is substituted.

[0060] As used herein, the term "alkoxy" refers to a radical in which an alkyl group having the specified number of carbon atoms is attached to the remainder of the molecule through an oxygen atom. Alkoxy groups include C 1 ~C 12 -Alkoxy, C 1 ~C 8 -Alkoxy, C 1 ~C 6 -Alkoxy, C 1 ~C 4 -Alkoxy and C 1 ~C 3 -alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, 2-propoxy (isopropoxy) and higher homologs and isomers. Preferred alkoxy groups are C 1 ~C 3 It is an alkoxy.

[0061] An "aliphatic" group is a non-aromatic moiety composed of any combination of carbon, hydrogen, halogen, oxygen, nitrogen or other atoms, and optionally containing one or more units of unsaturation, e.g., double and / or triple bonds. Examples of aliphatic groups are alkyl, alkenyl, alkynyl, O, OH, NH, NH 2 , C(O), S(O) 2 , C(O)O, C(O)NH, OC(O)O, OC(O)NH, OC(O)NH 2 , S(O) 2 N.H., S(O) 2 NH 2 , NHC(O)NH 2 , NHC(O)C(O)NH, NHS(O) 2 NH, NHS(O) 2 NH 2 , C(O)NHS(O) 2 , C(O)NHS(O) 2 NH or C(O)NHS(O) 2 NH 2and the like, groups containing one or more functional groups, non-aromatic hydrocarbons (optionally substituted), and groups in which one or more carbons of a non-aromatic hydrocarbon (optionally substituted) are replaced by a functional group. The carbon atoms of the aliphatic group may be optionally oxo-substituted. The aliphatic group may be linear, branched, cyclic, or a combination thereof, and preferably contains from about 1 to about 24 carbon atoms, more typically from about 1 to about 12 carbon atoms. In addition to aliphatic hydrocarbon groups, as used herein, aliphatic groups explicitly include, for example, alkoxyalkyl, polyalkoxyalkyl, such as, for example, polyalkylene glycols, polyamines, and polyimines. The aliphatic group may be optionally substituted.

[0062] The terms "heterocyclic" and "heterocycloalkyl" may be used interchangeably and refer to non-aromatic or polycyclic ring systems, such as bicyclic or tricyclic fused, bridged, or spiro systems, where (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur, and nitrogen, (ii) each ring system may be saturated or unsaturated, (iii) the nitrogen and sulfur heteroatoms may be optionally oxidized, (iv) the nitrogen heteroatom may be optionally quaternized, (v) any of the above rings may be fused to an aromatic ring, and (vi) the remaining ring atoms are carbon atoms that may be optionally oxo-substituted or optionally substituted with an exocyclic olefinic double bond. Representative heterocycloalkyl groups include, but are not limited to, 1,3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, 2-azabicyclo[2.2.1]-heptyl, 8-azabicyclo[3.2.1]octyl, 5-azaspiro[2.5]octyl, 2-oxa-7-azaspiro[4.4]nonanyl, 7-oxoxoxepan-4-yl, and tetrahydrofuryl. Such heterocyclic or heterocycloalkyl groups may be further substituted. Heterocycloalkyl or heterocyclic groups may be C- or N-linked where possible.

[0063] It is understood that any alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphatic moiety, etc. described herein, when used as a link to connect two or more groups or substituents, may also be a divalent or polyvalent group, which may be on the same or different atoms. One of ordinary skill in the art can readily determine the valency of any such group from the context in which it occurs.

[0064] The term "substituted" refers to a group in which one, two, or more of the hydrogen atoms have been replaced with -F, -Cl, -Br, -I, -OH, C 1 ~C 12 -Alkyl, C 2 ~C 12 -Alkenyl, C 2 ~C 12 -Alkynyl, -C 3 ~C 12 -Cycloalkyl, protected hydroxy, -NO 2 , -N 3 , -CN, -NH 2 , protected amino, oxo, thioxo, -NH-C 1 ~C 12 -Alkyl, -NH-C 2 ~C 8 -Alkenyl, -NH-C 2 ~C 8 -Alkynyl, -NH-C 3 ~C 12 -Cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -OC 1 ~C 12 -Alkyl, -OC 2 ~C 8 -Alkenyl, -OC 2 ~C 8 -Alkynyl, -OC 3 ~C 12 -Cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocycloalkyl, -C(O)-C 1 ~C12 -Alkyl, -C(O)-C 2 ~C 8 -Alkenyl, -C(O)-C 2 ~C 8 -Alkynyl, -C(O)-C 3 ~C 12 -Cycloalkyl, -C(O)-aryl, -C(O)-heteroaryl, -C(O)-heterocycloalkyl, -CONH 2 , -CONH-C 1 ~C 12 -Alkyl, -CONH-C 2 ~C 8 -Alkenyl, -CONH-C 2 ~C 8 -Alkynyl, -CONH-C 3 ~C 12 -Cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, -OCO 2 -C 1 ~C 12 -Alkyl, -OCO 2 -C 2 ~C 8 -Alkenyl, -OCO 2 -C 2 ~C 8 -Alkynyl, -OCO 2 -C 3 ~C 12 -Cycloalkyl, -OCO 2 -Aryl, -OCO 2 -heteroaryl, -OCO 2 -heterocycloalkyl, -CO 2 -C 1 ~C 12 Alkyl, -CO 2 -C 2 ~C 8 Alkenyl, -CO 2 -C 2 ~C 8 Alkynyl, -CO 2 -C 3 ~C 12 -Cycloalkyl, -CO 2 -aryl, -CO 2 -heteroaryl, -CO 2-heterocycloalkyl, -OCONH 2 , -OCONH-C 1 ~C 12 -Alkyl, -OCONH-C 2 ~C 8 -Alkenyl, -OCONH-C 2 ~C 8 -Alkynyl, -OCONH-C 3 ~C 12 -cycloalkyl, -OCONH-aryl, -OCONH-heteroaryl, -OCONH-heterocycloalkyl, -NHC(O)H, -NHC(O)-C 1 ~C 12 -Alkyl, -NHC(O)-C 2 ~C 8 -Alkenyl, -NHC(O)-C 2 ~C 8 -Alkynyl, -NHC(O)-C 3 ~C 12 -Cycloalkyl, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)-heterocycloalkyl, -NHCO 2 -C 1 ~C 12 -Alkyl, -NHCO 2 -C 2 ~C 8 -Alkenyl, -NHCO 2 -C 2 ~C 8 -Alkynyl, -NHCO 2 -C 3 ~C 12 -Cycloalkyl, -NHCO 2 -Aryl, -NHCO 2 -Heteroaryl, -NHCO 2 -heterocycloalkyl, -NHC(O)NH 2 , -NHC(O)NH-C 1 ~C 12 -Alkyl, -NHC(O)NH-C 2 ~C 8 -Alkenyl, -NHC(O)NH-C 2 ~C 8 -Alkynyl, -NHC(O)NH-C 3 ~C 12-cycloalkyl, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, -NHC(O)NH-heterocycloalkyl, -NHC(S)NH 2 , -NHC(S)NH-C 1 ~C 12 -Alkyl, -NHC(S)NH-C 2 ~C 8 -Alkenyl, -NHC(S)NH-C 2 ~C 8 -Alkynyl, -NHC(S)NH-C 3 ~C 12 -Cycloalkyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, -NHC(S)NH-heterocycloalkyl, -NHC(NH)NH 2 , -NHC(NH)NH-C 1 ~C 12 -Alkyl, -NHC(NH)NH-C 2 ~C 8 -Alkenyl, -NHC(NH)NH-C 2 ~C 8 -Alkynyl, -NHC(NH)NH-C 3 ~C 12 -cycloalkyl, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NH-heterocycloalkyl, -NHC(NH)-C 1 ~C 12 -Alkyl, -NHC(NH)-C 2 ~C 8 -Alkenyl, -NHC(NH)-C 2 ~C 8 -Alkynyl, -NHC(NH)-C 3 ~C 12 -cycloalkyl, -NHC(NH)-aryl, -NHC(NH)-heteroaryl, -NHC(NH)-heterocycloalkyl, -C(NH)NH 2 , -C(NH)NH-C 1 ~C 12 -Alkyl, -C(NH)NH-C 2 ~C 8 -Alkenyl, -C(NH)NH-C 2 ~C 8 -Alkynyl, -C(NH)NH-C3 ~C 12 -Cycloalkyl, -C(NH)NH-aryl, -C(NH)NH-heteroaryl, -C(NH)NH-heterocycloalkyl, -S(O)-C 1 ~C 12 -Alkyl, -S(O)-C 2 ~C 8 -Alkenyl, -S(O)-C 2 ~C 8 -Alkynyl, -S(O)-C 3 ~C 12 -Cycloalkyl, -S(O)-aryl, -S(O)-heteroaryl, -S(O)-heterocycloalkyl, -SO 2 NH 2 , -SO 2 NH-C 1 ~C 12 -Alkyl, -SO 2 NH-C 2 ~C 8 -Alkenyl, -SO 2 NH-C 2 ~C 8 -Alkynyl, -SO 2 -C 1 ~C 12 -Alkyl, -SO 2 -C 2 ~C 8 -Alkenyl, -SO 2 -C 2 ~C 8 -Alkynyl, -SO 2 -C 3 ~C 12 -Cycloalkyl, -SO 2 -Aryl, -SO 2 -heteroaryl, -SO 2 -heterocycloalkyl, -SO 2 NH-C 3 ~C 12 -Cycloalkyl, -SO 2 NH-aryl, -SO 2 NH-heteroaryl, -SO 2 NH-heterocycloalkyl, -NHSO 2 -C 1 ~C 12 -Alkyl, -NHSO 2 -C2 ~C 8 -alkenyl, -NHSO 2 -C 2 ~C 8 -alkynyl, -NHSO 2 -C 3 ~C 12 -cycloalkyl, -NHSO 2 -aryl, -NHSO 2 -heteroaryl, -NHSO 2 -heterocycloalkyl, -CH 2 NH 2 、-CH 2 SO 2 CH 3 、-aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -C 3 ~C 12 -cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-C 1 ~C 12 -alkyl, -S-C 2 ~C 8 -alkenyl, -S-C 2 ~C 8 -alkynyl, -S-C 3 ~C 12 -cycloalkyl, -S-aryl, -S-heteroaryl, -S-heterocycloalkyl, or substitution by being independently replaced with substituents including but not limited to methylthio-methyl. In certain embodiments, the substituents are halo, preferably Cl and F, C 1 ~C 4 -alkyl, preferably methyl and ethyl, halo-C 1 ~C 4 -alkyl, such as fluoromethyl, difluoromethyl and trifluoromethyl, C 2 ~C 4 -alkenyl, halo-C 2 ~C 4 -alkenyl, C 3 ~C 6 -cycloalkyl, such as cyclopropyl, C 1 ~C 4-alkoxy, such as methoxy and ethoxy, halo-C 1 ~C 4 -Alkoxy, such as fluoromethoxy, difluoromethoxy and trifluoromethoxy, -CN, -OH, NH 2、 C 1 ~C 4 -Alkylamino, di(C 1 ~C 4 -alkyl)amino and NO 2 It is understood that the aryl, heteroaryl, alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl in the substituents may be further substituted. In certain embodiments, the substituents of the substituted moiety are optionally further substituted with one or more groups, each of which is selected from C 1 ~C 4 -Alkyl, -CF 3 , -OCH 3 , -OCF 3 , -F, -Cl, -Br, -I, -OH, -NO 2 , -CN and -NH 2 Preferably, the substituted alkyl groups are substituted with one or more halogen atoms, more preferably one or more fluorine or chlorine atoms.

[0065] The terms "halo" or "halogen," as used herein, alone or as part of another substituent, refer to a fluorine, chlorine, bromine, or iodine atom.

[0066] The term "optionally substituted" as used herein means that the referenced group can be substituted or unsubstituted. In one embodiment, the referenced group is optionally substituted with 0 substituents, i.e., the referenced group is unsubstituted. In certain embodiments, the referenced group is optionally substituted with one or more additional groups individually and independently selected from the groups described herein.

[0067] The term "hydrogen" includes hydrogen and deuterium. Furthermore, the recitation of an element includes all isotopes of that element, so long as the resulting compound is pharma- ceutically acceptable. In certain embodiments, the isotopes of an element are present at a particular position according to their natural abundance. In other embodiments, one or more isotopes of an element at a particular position are enriched above their natural abundance.

[0068] The term "hydroxy activating group" as used herein refers to a labile chemical moiety known in the art to activate a hydroxyl group for release during a synthetic procedure such as a substitution or elimination reaction. Examples of hydroxyl activating groups include, but are not limited to, mesylates, tosylates, triflates, p-nitrobenzoates, phosphonates, and the like.

[0069] As used herein, the term "activated hydroxyl" refers to a hydroxy group that has been activated with a hydroxyl activating group as defined above, including, but not limited to, a mesylate, tosylate, triflate, p-nitrobenzoate, or phosphonate group.

[0070] The term "hydroxy protecting group" as used herein refers to a labile chemical moiety known in the art to protect hydroxyl groups from undesired reactions during synthetic procedures. After said synthetic procedures, the hydroxy protecting groups described herein can be selectively removed. Hydroxy protecting groups known in the art are generally described in PGM Wuts, Greene's Protective Groups in Organic Synthesis, 5th edition, John Wiley & Sons, Hoboken, NJ (2014). Examples of hydroxyl protecting groups include, but are not limited to, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, tert-butoxy-carbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, allyl, benzyl, triphenyl-methyl(trityl), methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-(trimethylsilyl)-ethoxymethyl, methanesulfonyl, trimethylsilyl, triisopropylsilyl, and the like.

[0071] The term "protected hydroxy" as used herein refers to a hydroxy group protected with a hydroxy protecting group as defined above, including, for example, but not limited to, a benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl group.

[0072] The term "hydroxy prodrug group" as used herein refers to a promoiety group known in the art to temporarily change the physicochemical and therefore biological properties of parent drug by covering or masking hydroxy group.After the synthesis procedure, the hydroxy prodrug group described herein must be able to revert to hydroxy group in vivo.Hydroxy prodrug groups known in the art are generally described in Kenneth B. Sloan, Prodrugs, Topical and Ocular Drug Delivery, (Drugs and the Pharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York (1992).

[0073] The term "amino protecting group" as used herein refers to a labile chemical moiety known in the art to protect amino groups from undesired reactions during synthetic procedures. After said synthetic procedures, the amino protecting groups described herein can be selectively removed. Amino protecting groups known in the art are generally described in PGM Wets, Greene's Protective Groups in Organic Synthesis, 5th edition, John Wiley & Sons, Hoboken, NJ (2014). Examples of amino protecting groups include, but are not limited to, methoxycarbonyl, t-butoxycarbonyl, 12-fluorenyl-methoxycarbonyl, benzyloxycarbonyl, and the like.

[0074] The term "protected amino" as used herein refers to an amino group protected with an amino-protecting group as defined above.

[0075] The term "leaving group" means a functional group or atom that can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction. By way of example, representative leaving groups include chloro, bromo, and iodo groups, sulfonate ester groups, such as mesylate, tosylate, brosylate, nosylate, and the like, and acyloxy groups, such as acetoxy, trifluoroacetoxy, and the like.

[0076] The term "aprotic solvent" as used herein refers to a solvent that is relatively inert to proton activity, i.e., does not act as a proton donor. Examples include, but are not limited to, hydrocarbons such as hexane and toluene, halogenated hydrocarbons such as methylene chloride, ethylene chloride, chloroform, heterocyclic compounds such as tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether. Such compounds are well known to those skilled in the art, and it will be clear to those skilled in the art that individual solvents or mixtures thereof may be preferred for certain compounds and reaction conditions, depending on factors such as, for example, the solubility of the reagents, the reactivity of the reagents, and the preferred temperature range. Further discussion of aprotic solvents can be found in organic chemistry textbooks or specialized monographs, such as Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et al., Vol. II in Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.

[0077] The term "protic solvent" as used herein refers to a solvent that tends to provide a proton, such as alcohols, e.g., methanol, ethanol, propanol, isopropanol, butanol, t-butanol, etc. Such solvents are well known to those skilled in the art, and it will be apparent to those skilled in the art that individual solvents or mixtures thereof may be preferred for certain compounds and reaction conditions, depending on factors such as, for example, the solubility of the reagents, the reactivity of the reagents, and the preferred temperature range. Further discussion of proton-donating solvents can be found in organic chemistry textbooks or specialized monographs, such as Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et al., Vol. II in Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.

[0078] Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. As used herein, the term "stable" refers to compounds that have sufficient stability to permit their manufacture and maintain their integrity for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

[0079] The synthesized compounds can be separated from the reaction mixture and further purified by methods such as column chromatography, high pressure liquid chromatography, or recrystallization. As can be understood by those skilled in the art, further methods of synthesizing the compounds of the formulas herein will be apparent to those skilled in the art. Furthermore, various synthetic steps can be performed in an alternative order or sequence to obtain the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful for synthesizing the compounds described herein are known in the art and are described, for example, in R. Larock, Comprehensive Organic Transformations, 2001, Vol. 1, No. 1, pp. 111-115, 2001. ndEd. Wiley-VCH (1999); PGM Wets, Greene's Protective Groups in Organic Synthesis, 5th edition, John Wiley & Sons, Hoboken, NJ (2014); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and successive editions thereof.

[0080] The term "subject" as used herein refers to an animal. Preferably, the animal is a mammal. More preferably, the mammal is a human. Subject also refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, fish, birds, etc.

[0081] The compounds of the present invention may be modified by appending appropriate functional groups to enhance selective biological properties. Such modifications are known in the art and may include those that increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), those that increase oral availability, those that increase solubility to allow administration by injection, those that alter metabolism, and those that alter excretion rate.

[0082] The compounds described herein contain one or more asymmetric centers, thus giving rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined in terms of absolute stereochemistry as (R)- or (S)- for amino acids, or as (D)- or (L)-. The present invention is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optical isomers can be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixture. Resolution can be carried out in the presence of a resolving agent, by chromatography, or by repeated crystallization, or by some combination of these techniques known to those skilled in the art. Further details regarding resolution can be found in Jacques, et al., Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). When the compounds described herein contain olefinic double bonds, other unsaturation, or other geometrically asymmetric centers, it is intended that the compounds include both E and Z geometric isomers or cis and trans isomers, unless otherwise specified. Likewise, all tautomeric forms are intended to be included. Tautomers may be cyclic or acyclic. Any carbon-carbon double bond configurations appearing herein are merely selected for convenience and are not intended to indicate a specific configuration unless otherwise stated in the text. Thus, any carbon-carbon double bond or carbon-heteroatom double bond shown herein as trans may be cis, trans, or a mixture of the two in any ratio.

[0083] Certain compounds of the present invention may also exist in different stable conformational forms that may be separable. Torsional asymmetry due to restricted rotation around an asymmetric single bond, for example due to steric hindrance or ring strain, may allow the separation of different conformers. The present invention includes each conformational isomer of these compounds and mixtures thereof.

[0084] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,66:2-19(1977). Salts can be prepared in situ during the final isolation and purification of the compounds of the present invention, or separately by reacting the free base function with a suitable organic acid. Examples of pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts of amino groups formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids, such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane-propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobiotin, and the like. Representative salts include, but are not limited to, phosphate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.Further pharma-ceutically acceptable salts include non-toxic ammonium, quaternary ammonium and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyls having 1 to 6 carbon atoms, sulfonates and arylsulfonates.

[0085] As used herein, the term "pharmaceutical acceptable ester" refers to esters including those that hydrolyze in vivo and decompose easily in the human body to leave the parent compound or its salt. Suitable ester groups include, for example, those derived from pharmaceutical acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, each alkyl or alkenyl moiety advantageously having 6 or less carbon atoms. Examples of specific esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.

[0086] Pharmaceutical Compositions Pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharma- ceutically acceptable carriers or excipients.

[0087] As used herein, the term "pharmaceutically acceptable carrier or excipient" means any kind of non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation aid. Some examples of materials that can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate, tragacanth powder, malt, gelatin, talc, excipients such as cocoa butter and suppository waxes, oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil, glycols such as propylene glycol, esters such as ethyl oleate and ethyl laurate, agar, buffering agents such as magnesium hydroxide and aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solution, and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, and coloring agents, release agents, coating agents, sweetening agents, flavoring agents and fragrances, preservatives and antioxidants may also be present in the composition according to the discretion of the formulator.

[0088] The pharmaceutical compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir, preferably by oral administration or administration by injection. The pharmaceutical compositions of the present invention can contain any conventional non-toxic pharmaceutically acceptable carrier, adjuvant or vehicle. In some cases, the pH of the formulation can be adjusted with a pharmaceutically acceptable acid, base or buffer to enhance the stability of the formulated compound or its delivery form. As used herein, the term parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intra-synovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

[0089] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents, and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 - butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan, and mixtures thereof. In addition to the inert diluent, oral compositions may also contain adjuvants such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, and perfuming agents.

[0090] Injectable preparations, for example, sterile aqueous or oleaginous suspensions, may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile solutions, suspensions, or emulsions in sterile injectable solutions, suspensions, or emulsions in a non - toxic parenterally acceptable diluent or solvent, such as, for example, a solution in 1,3 - butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil containing synthetic monoglycerides or diglycerides may be used. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0091] Injectable formulations may be sterilized, for example, by filtration through a bacteria - retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0092] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug depends upon its rate of dissolution, which in turn may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0093] Compositions for rectal or vaginal administration are preferably suppositories, which may be prepared by mixing a compound of the invention with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which is solid at ambient temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active compound.

[0094] The solid dosage form for oral administration includes capsules, tablets, pills, powders and granules.In such solid dosage forms, the active compound is mixed with at least one inert pharma- ceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose and acacia, c) humectants, such as glycerol, d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retarders. In the case of capsules, tablets and pills, the dosage form may also include buffering agents.

[0095] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols.

[0096] The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation field.They can optionally contain opacifying agents, and can be of a composition that releases the active ingredient alone, or preferentially in a certain part of the intestinal tract, optionally in a delayed manner.Examples of embedding compositions that can be used include polymeric substances and waxes.

[0097] The dosage form for topical or transdermal administration of the compound of the present invention includes ointment, paste, cream, lotion, gel, powder, solution, spray, inhalant or patch.The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservative or buffer as necessary.Ophthalmic preparations, ear drops, eye ointments, powders and solutions are also considered to be within the scope of the present invention.

[0098] The ointments, pastes, creams and gels may contain, in addition to the active compounds of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0099] Powders and sprays may contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain conventional propellants such as chlorofluorohydrocarbons.

[0100] Transdermal patch has the additional advantage of providing controlled delivery of compound to body.Such dosage forms can be made by dissolving or dispensing compound in appropriate medium.Absorption enhancers can also be used to increase the flux of compound across the skin.The rate can be controlled by providing a rate-controlling membrane or dispersing compound in a polymer matrix or gel.

[0101] For pulmonary delivery, the therapeutic composition of the present invention is formulated and administered to patient in solid or liquid particulate form by direct administration, for example, inhalation into respiratory system.The solid or liquid particulate form of active compound prepared for carrying out the present invention includes particles of respirable size, i.e., particles of a size small enough to pass through mouth and larynx and enter the bronchi and alveoli of lungs when inhaled.Delivery of aerosolized therapeutic agents, especially aerosolized antibiotics, is known in the art (see, for example, U.S. Patent No. 5,767,068 to Van Devanter et al., U.S. Patent No. 5,508,269 to Smith et al., and WO 98 / 43650 by Montgomery, all of which are incorporated herein by reference).

[0102] Adjunctive and alternative therapies The compounds of the present invention may be used in combination with one or more antiviral or anti-inflammatory therapeutic agents useful in the prevention or treatment of viral diseases or associated pathophysiology. Thus, the compounds of the present invention and their salts, solvates or other pharma- ceutically acceptable derivatives may be used alone or in combination with other antiviral or anti-inflammatory therapeutic agents.The compounds herein and pharma- ceutically acceptable salts thereof may be administered in combination with one or more other agents that may be useful in the prophylaxis or treatment of respiratory diseases, inflammatory diseases, autoimmune diseases, such as, for example, antihistamines, corticosteroids, (e.g., fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, budesonide, ciclesonide, mometasone furoate, triamcinolone, flunisolide), NSAIDs, leukotriene modulators (e.g., montelukast, zafirlukast, pranlukast), tryptase inhibitors, IKK2 inhibitors, and the like. anti-inflammatory agents, p38 inhibitors, Syk inhibitors, protease inhibitors such as elastase inhibitors, integrin antagonists (e.g. beta-2 integrin antagonists), adenosine A2a agonists, mediator release inhibitors such as sodium cromoglycate, 5-lipoxygenase inhibitors (zyflo), DP1 antagonists, DP2 antagonists, PI3K delta inhibitors, ITK inhibitors, LP (lysophosphatidic acid) inhibitors or FLAP (5-lipoxygenase activating protein) inhibitors (e.g. sodium 3-(3-(tert-butylthio) )-1-(4-(6-ethoxypyridin-3-yl)benzyl)-5-((5-ethylpyridin-2-yl)methoxy)-1H-indol-2-yl)-2,2-dimethylpropanoate), bronchodilators (e.g., muscarinic antagonists, beta-2 agonists), methotrexate, and similar agents, monoclonal antibody therapy, e.g., anti-lgE, anti-TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1, and similar agents, cytokine receptor therapy, e.g., etanercept, and similar agents, antigen non-specific immunotherapy (e.g., For example, interferons or other cytokines / chemokines, chemokine receptor modulators, such as CCR3, CCR4 or CXCR2 antagonists, other cytokine / chemokine agonists or antagonists, TLR agonists and similar agents), antibiotics, antifungals, antiparasitics, antimalarials, antiprotozoal, antituberculous, and antiviral agents, including those listed at https: / / www.drugs.com / drug-class / anti-infectives.html.

[0103] The compound of the present invention and any other pharmacoactive agent may be administered together or separately, and when administered separately, administration may be performed simultaneously or sequentially in any order.The amount and relative timing of administration of the compound of the present invention and other pharmacoactive agent are selected to achieve the desired combined therapeutic effect.The administration of the compound of the present invention and its salt, solvate or other pharmacologic acceptable derivative in combination with other therapeutic agents can be achieved by (1) co-administration in a combined pharmaceutical composition containing both compounds, or (2) in separate pharmaceutical compositions, each of which contains one of the compounds.

[0104] In certain embodiments of the combination therapy, the additional therapeutic agent is administered at a lower dose and / or dosing frequency compared to the dose and / or dosing frequency of the additional therapeutic agent required to achieve a similar result in the treatment or prevention of a 17β-HSD13 mediated disease or condition.

[0105] While the invention has been described in terms of various preferred embodiments, it is not intended to be limited thereto, but rather, those skilled in the art will recognize that variations and modifications can be made which are within the spirit of the invention and the scope of the appended claims.

[0106] therapeutic activity The therapeutically effective amount or dose of the compound of the present invention may range from about 0.01 mg / Kg to about 500 mg / Kg, or alternatively from about 1 to about 50 mg / Kg. The therapeutically effective amount or dose will also vary depending on the route of administration, as well as the possibility of co-administration with other drugs.

[0107] In accordance with the therapeutic methods of the invention, viral infections are treated or prevented in a patient, such as a human or another animal, by administering to the patient a therapeutically effective amount of a compound of the invention in an amount and for a time necessary to achieve the desired result.

[0108] A "therapeutically effective amount" of a compound of the present invention means an amount of the compound that confers a therapeutic effect on the treated subject at a reasonable benefit / risk ratio applicable to any medical treatment. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject shows an indication of or feels an effect). An effective amount of the compound described above may range from about 0.1 mg / Kg to about 500 mg / Kg, preferably from about 1 to about 50 mg / Kg. The effective dose will also vary depending on the route of administration, as well as the possibility of co-administration with other drugs. However, it will be understood that the total daily usage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend on a variety of factors, including the disorder and severity of the disorder being treated, the activity of the particular compound employed, the particular composition employed, the age, weight, general health, sex and diet of the patient, the time of administration, route of administration, and excretion rate of the particular compound employed, the duration of treatment, drugs used in combination or simultaneously with the particular compound employed, and similar factors well known in the medical arts.

[0109] The total daily dose of the compounds of this invention administered to a human or other animal in single or divided doses may be, for example, from 0.01 to 50 mg / kg body weight or more, usually from 0.1 to 25 mg / kg body weight. Single dose compositions may contain such amounts, or fractions thereof that make up the daily dose. In general, treatment regimens according to the present invention comprise administration to a patient in need of such treatment of from about 10 mg to about 1000 mg of the compounds of this invention per day, in single or multiple doses.

[0110] The compounds of the invention described herein may be administered, for example, by intravenous, intraarterial, subdermal, intraperitoneal, intramuscular, or subcutaneous injection, or orally, bucally, nasally, transmucosally, topically, in ophthalmic preparations, or by inhalation, at dosages ranging from about 0.1 to about 500 mg / kg body weight, or at dosages of 1 mg to 1000 mg / dose, every 4 to 120 hours, or according to the requirements of the particular drug. The methods herein contemplate administering an effective amount of the compound or compound composition to achieve the desired or described effect. Typically, the pharmaceutical compositions of the invention are administered about 1 to about 6 times per day, or alternatively as a continuous infusion. Such administration can be used as a chronic or acute treatment. The amount of active ingredient that can be combined with pharmaceutical excipients or carriers to produce a single dosage form will vary depending on the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w / w). Alternatively, such preparations may contain from about 20% to about 80% active compound.

[0111] Doses lower or higher than those listed above may be required. The specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, severity and course of the disease, condition or symptom, the disposition of the patient to the disease, condition or symptom, and the judgment of the treating physician.

[0112] When the patient's condition improves, a maintenance dose of the compound, composition or combination of the present invention can be administered as necessary.Then, the dosage or frequency of administration, or both, can be reduced as a function of symptoms to a level at which the improved condition is maintained when symptoms are alleviated to a desired level.However, patients may require intermittent treatment on a long-term basis based on the recurrence of disease symptoms.

[0113] When the compositions of the present invention include a combination of a compound of formula (I) described herein with one or more additional therapeutic or prophylactic agents, both the compound and the additional agents should be present at dosage levels of about 1-100%, more preferably about 5-95%, of the dosage normally administered in a monotherapy regimen. The additional agents may be administered separately from the compounds of the present invention as part of a multiple dose regimen. Alternatively, these agents may be part of a single dosage form, mixed with the compounds of the present invention in a single composition.

[0114] "Additional therapeutic or prophylactic agents" include, but are not limited to, immunotherapy (e.g., interferon), therapeutic vaccines, antifibrotic agents, anti-inflammatory agents such as corticosteroids or NSAIDs, bronchodilators such as beta-2 adrenergic agonists and xanthines (e.g., theophylline), mucolytic agents, antimuscarinics, anti-leukotrienes, cell adhesion inhibitors (e.g., ICAM antagonists), antioxidants (e.g., N-acetylcysteine), cytokine agonists, cytokine antagonists, pulmonary surfactants, and / or antibacterial and antiviral agents (e.g., ribavirin and amantidine). The compositions according to the invention may also be used in combination with gene replacement therapy.

[0115] Abbreviation Abbreviations used in the description of the following schemes and examples are as follows: Alloc for allyloxycarbonyl, Alloc-Cl for allyl chloroformate, ASK1 for apoptosis signal-regulating kinase 1; Adenosine triphosphate (ATP) Boc to tert-butyloxycarbonyl, Bis(2-oxo-3-oxazolidinyl)phosphinic chloride to BOP-Cl, Cbz for benzyloxycarbonyl, Cbz-Cl for benzyl chloroformate, CDI for carbonyldiimidazole, For oxalyl chloride (COCl) 2 , DBU for 1,8-diazabicycloundec-7-ene, DCC for N,N'-dicyclohexylcarbodiimide, 1,2-DCE for 1,2-dichloroethane, DCM for dichloromethane, DIPEA, Hunig's base, or i-Pr for N,N-diisopropylethylamine 2 NEt, DMAc for N,N-dimethylacetamide, DMAP for N,N-dimethylaminopyridine, DMF for N,N-dimethylformamide, EDC for 1-(3-diethylaminopropyl)-3-ethylcarbodiimide hydrochloride, Ethylene glycol-bis(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid to EGTA, ESI for electrospray ionization; Et for triethylamine 3 N or TEA, Et for diethyl ether 2 O. EtOAc for ethyl acetate, Ghosez reagent for 1-chloro-N,N,2-trimethyl-1-propenylamine, HATU for 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid, N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) for HEPES, IC for 50% inhibitory concentration 50 , KOt-Bu for potassium tert-butoxide, LCMS for liquid chromatography-mass spectrometry; MeCN for acetonitrile, MTBE for methyl tert-butyl ether; m / z for mass-to-charge ratio, NaOt-Bu for sodium tert-butoxide, NMP for 1-methyl-2-pyrrolidinone, NMR for Nuclear Magnetic Resonance Spectroscopy; -OMs or mesylates for methanesulfonates, -OTf or triflate for trifluoromethanesulfonate, para-Toluenesulfonate vs. -OTs or tosylates, Pd vs tris(dibenzylideneacetone)dipalladium(0) 2 (dba) 3 , P(o-tolyl) for tri(o-tolyl)phosphine 3 , 7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate to PyAOP, Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate for PyBOP, STK3 for serine / threonine-protein kinase 3 TEA for triethylamine, THF for tetrahydrofuran.

[0116] Synthesis method All references cited herein, whether in print, electronic, computer readable storage media, or other form, are expressly incorporated by reference in their entirety, including, but not limited to, abstracts, articles, journals, publications, texts, papers, internet websites, databases, patents, and patent publications.

[0117] Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art, and such changes and modifications, including but not limited to those with respect to the chemical structures, substituents, derivatives, formulations and / or methods of the invention, may be made without departing from the spirit of the invention and the scope of the appended claims.

[0118] While the invention has been described in terms of various preferred embodiments, it is not intended to be limited thereto, but rather, those skilled in the art will recognize that variations and modifications can be made which are within the spirit of the invention and the scope of the appended claims.

[0119] The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes which illustrate how the compounds of the present invention may be prepared, and are intended as illustrative only and not limiting the scope of the invention.

[0120] As shown in Scheme 1, in a one-pot manner, the compound of formula (I) was prepared by the reaction of amino ester compound (1) with amide compound (2) prepared according to the literature (New inhibitors of 17β-hydroxysteroid dehydrogenase type 1, Molecular and Cellular Endocrinology 2006, 248, 192-198, Josef Messinger, Leena Hirvela, Pasi Koskimies, Bettina Husen, Lauri Kangas, Olli Pentikainen, Pauli Saarenketo and Hubert Thole) with POCl. 3 , SOCl 2 or PCl 5 can be prepared from a condensation reaction in the presence of 1 , R 2 , R 3 , R 4 , R 5 , R 6 and M are as defined above. Thus, a mixture of amino ester compound (1) and amide compound (2) in an aprotic solvent is reacted with POCl3 , SOCl 2 or PCl 5 to form a compound of formula (I). The aprotic solvent can be, for example, but not limited to, THF, DCE and DMF. The reaction temperature is 0°C to 140°C. Scheme 1 [ka]

[0121] Alternatively, compounds of formula (I) can be prepared in a stepwise manner as shown in Scheme 2, where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and M is as defined above. Amide compound (2) can be prepared by reacting POCl with an aprotic solvent such as DCM, DCE, THF or DMF at 0° C. to 80° C. 3 , SOCl 2 or PCl 5 The reaction can be carried out at a temperature of 0°C to 140°C to form imine chloride (3), which can then be reacted with amino ester compound (1) to give cyclized compound (I). Scheme 2 [ka]

[0122] Alternatively, as shown in Scheme 3, compounds of formula (I) can be prepared by a transition metal / phosphine ligand complex catalyzed coupling reaction between a chloropyrimidone compound (7) and an organometallic reagent, such as a boronic acid or related boron reagent partner (8), where R 1 , R 2 , R 3 , R 4 , R 5 , R 6and M are as defined above. The catalyst used in this reaction can be, but is not limited to, bis(triphenylphosphine)palladium(II) chloride. The base used in this reaction can be, but is not limited to, cesium carbonate. Compound (1) in an aprotic solvent is first treated with amine compound (4) in the presence of a suitable coupling reagent and an organic base to obtain urea compound (5). The suitable coupling reagent can be, for example, but is not limited to, CDI, triphosgene or ethyl chloroformate, and the organic base can be, for example, but is not limited to, DBU, DIPEA or TEA. The aprotic solvent can be, for example, but is not limited to, MeCN, THF, DCE or DMF. The reaction temperature is 0°C to 80°C. The urea compound (5) is then treated with a suitable inorganic base in an alcohol solvent at elevated temperature to obtain pyrimidinedione compound (6). The inorganic base can be, for example, but is not limited to, NaOMe, NaOEt or NaOtBu. The alcohol solvent can be, for example, but not limited to, MeOH, EtOH or tBuOH. The temperature is 40°C to 80°C. The chloropyrimidone compound (7) is prepared from the pyrimidinedione compound (6) in the presence of a suitable chlorinating reagent at elevated temperature in an aprotic solvent. The suitable chlorinating reagent can be, for example, but not limited to, POCl. 3 The aprotic solvent can be, for example, but not limited to, DCE. The reaction temperature is 80°C to 140°C. The chloropyrimidone compound (7) reacts with a boronic acid partner or related boron reagent (8) catalyzed by a transition metal / phosphine ligand complex in a mixed solvent mixture. The solvent in this coupling reaction can be, for example, but not limited to, DME / H 2 O, dioxane / H 2 O, toluene / H 2 The reaction temperature is 0°C to 140°C. Scheme 3 [ka]

[0123] As shown in Scheme 4, the compound of formula (IV) can be prepared by the reaction of compound (9) with R in an aprotic solvent and in the presence of a base. 9 -LG, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and M is as defined above. The base may be an organic or inorganic base, but is preferably pyridine, DIPEA, DMAP, Cs 2 CO 3 , NaH, etc. The aprotic solvent may be, for example, but not limited to, pyridine, MeCN, THF, DCE, or DMF. The reaction temperature is 0°C to 80°C. Scheme 4 [ka]

[0124] example The compounds and processes of the present invention will be better understood in connection with the following examples, which are intended as illustrative only and not limiting the scope of the invention. Starting materials are available from commercial suppliers or prepared by methods well known to those skilled in the art.

[0125] Synthesis of 2-(2-cyclopropyl-4-methoxyphenyl)-3-(oxazol-5-ylmethyl)-4-oxo-3,4-dihydrobenzo[4,5]thieno[2,3-d]pyrimidin-8-yl acetate (Example 1) Example 1 [ka] In a 250 mL round-bottom flask, compound 1-2 (5.0 g, 20.4 mmol), cyclopropylboronic acid (5.3 g, 61.2 mmol), tetrakis(triphenylphosphine)palladium (2.4 g, 2.0 mmol), and potassium carbonate (8.5 g, 61.2 mmol) were added. 2The mixture was added under atmospheric pressure, followed by the addition of dioxane (82 mL) and water (20 mL). The suspension was heated at 100° C. for 48 h. It was cooled to room temperature, diluted with EtOAc, and washed with water and brine, respectively. It was dried (Na 2 SO 4 ), filtered, concentrated, and purified by CombiFlash (SiO 2 The mixture was purified using EA / c-Hex (0-20%) to give compound 1-3 as a colorless liquid (2.4 g, yield 57.0%).

number

[0126] [ka] To a 250 mL round bottom flask containing compound 1-3 (2.4 g, 11.6 mmol), MeOH (87 mL), water (29 mL) and sodium hydroxide (2.3 g, 58.2 mmol) were added respectively and the mixture was stirred at 60° C. overnight. The reaction was complete by TLC (70% EA / Hex). It was cooled to room temperature and concentrated to remove half of the solvent. Water (10 mL) was added and the white suspension was cooled to 0° C. It was acidified to pH ∼1 by dropwise addition of 3N HCl (23.3 mL, 69.8 mmol). The precipitate was filtered through a Buchi funnel and dried in vacuum to give compound 1-4 as a white powder, 2.17 g, 97% yield. LC-MS observed

number

[0127] [ka] In a 25 mL round-bottom flask, add 1-4 (0.45 g, 2.34 mmol), 1-5 (0.32 g, 2.34 mmol), HATU (1.42 g, 3.75 mmol), and CH 2 Cl 2(7.5 mL) and DIPEA (1.31 mL, 7.49 mmol) were added, respectively, and the resulting mixture was stirred at room temperature for 25 h. It was diluted with DCM and saturated NaHCO 3 and brine. It was dried (Na 2 SO 4 ), filtered, concentrated, and purified by CombiFlash (SiO 2 The mixture was purified by 24 g, EtOAc / c-Hex: 0-100%) to give compound 1-6 as a white solid, 0.41 g, 63.8% yield.

number

[0128] [ka] Compound 1-7 (0.52 g, 2.203 mmol), compound 1-6 (0.30 mg, 1.102 mmol), DCE (6.12 mL), and phosphoryl trichloride (154 μL, 1.65 mmol) were added to a 25 mL round-bottom flask, which was prepared according to literature methods (Molecular and Cellular Endocrinology 2006, 248, 192-198), respectively, and the suspension was stirred at 80 °C for 18 h. The mixture was diluted with DCM, and the insoluble brown solid was collected by Büchi funnel. The filtrate was diluted with saturated NaHCO 3 The organic layer was dried (Na 2 SO 4 ), filtered, concentrated, and purified by CombiFlash (SiO 2 Purification with 40 g, EtOAc / cyclohexane: 0-100%) afforded compound 1-8 as a pale yellow solid, 0.14 g, 28.5% yield. LC-MS observed

number

[0129] [ka] To a 2-dram vial was added compound 1-8 (0.1 g, 0.22 mmol) and acetic anhydride (106 μl, 1.12 mmol), respectively, and the reaction was stirred at room temperature for 16 h. Diluted with DCM and saturated NaHCO 3 The mixture was dried and washed with (Na 2 SO 4 ), filtered, concentrated, and purified by CombiFlash (SiO 2 The product was purified by EA / Hex: 0-100%) to give compound 1 as a white foam in 0.1 g and 91% yield.

number

[0130] Synthesis of 2-(2-cyclopropyl-4-methoxyphenyl)-3-(oxazol-5-ylmethyl)-4-oxo-3,4-dihydrobenzo[4,5]thieno[2,3-d]pyrimidin-8-ylpropionate (Example 2) Example 2 [ka] Example 2 was prepared by using a similar procedure as described for compound 1. LC-MS measurements

number

[0131] Synthesis of 2-(2-cyclopropyl-4-methoxyphenyl)-3-(oxazol-5-ylmethyl)-4-oxo-3,4-dihydrobenzo[4,5]thieno[2,3-d]pyrimidin-8-ylbenzoate (Example 3) Example 3 [ka] Example 3 was prepared by using a similar procedure as described for compound 1. LC-MS measurement

number

[0132] The following examples were prepared using similar procedures as above: Compounds 17-24 were isolated as trifluoroacetate salts. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11] [Table 3-12] [Table 3-13] [Table 3-14] [Table 3-15] [Table 3-16] [Table 3-17] [Table 3-18] [Table 3-19] [Table 3-20]

[0133] Assay 17β-HSD13 rapid-fire mass spectrometry assay (RF / MS assay). Recombinant human 17β-HSD13 was expressed and purified from sf9 cells at Charles River Labs (Saffron Walden, UK). Leukotriene B4 (catalog no. 71160-24-2) and 12-oxoleukotriene B4 (catalog no. 20140) were purchased from Cayman Chemicals (Ann Arbor, MI). NAD+ (catalog no. N8285), BSA (catalog no. A7030), DMSO (catalog no. D2650) and Tween-20 (catalog no. 11332465001) were purchased from Sigma (St. Louis, MO). Formic acid (catalog no. 28905) was from ThermoFisher Scientific and 384 deep-well PP microplates (catalog no. 784261) were from Greiner Bio-One. Typical IC performed in 384w PP microplates 50 In the assay, test compounds (0-100 μM) were incubated with HSD17B13 (80 nM), LTB4 (10 μM) and NAD +It was incubated at room temperature for 3 hours in 10 μL of assay buffer (20 mM Tris (pH 7.5), BSA (0.005%) and Tween-20 (0.01%)) together with [[ID=]],

[0134] Data analysis. The 17β-HSD13 enzyme activity was measured as the percent conversion of the extracted ion counts and normalized against high and low controls to determine the percent residual activity in various concentrations of the test compounds. The data was fit to a normalized activity (variable slope) vs. concentration fit in GraphPad Prism 7 to determine the IC 50 . All experiments were performed in duplicate.

[0135] By using the above method, the inhibition of 17β-HSD13 was evaluated for the compounds of formula (I). The IC 50The ranges are as follows: A is <0.1 μM, B is 0.1 μM-1.0 μM, C is 1.0 μM-10 μM, and D is >10 μM. [Table 4]

[0136] While the present invention has been particularly shown and described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention as encompassed by the appended claims.

Claims

1. A compound represented by formula I, or a pharma- ceutically acceptable salt or ester thereof. 【Chemistry 1】 (In the formula, M is S, SO, SO ２ , O or NR ７ and R １ and R ２ are each independently 1) Hydrogen, 2) optionally substituted -C １ ~C ８ Alkyl, 3) optionally substituted -C ２ ~C ８ Alkenyl, 4) Optionally substituted -C ２ ~C ８ alkynyl, 5) optionally substituted -C ３ ~C ８ Cycloalkyl, 6) optionally substituted aryl; 7) optionally substituted arylalkyl; 8) optionally substituted 3- to 8-membered heterocycloalkyl; 9) optionally substituted heteroaryl, and 10) optionally substituted heteroarylalkyl is selected from the group consisting of R ３ , R ４ , R ５ and R ６ are each independently hydrogen, halogen, -CN, or -OR ９ , -SR ９ , -C(O)R ７ , -C(O)OR ７ , -NR ７ R ８ , -C(O)NR ７ R ８ , optionally substituted -C １ ~C ８ selected from the group consisting of alkyl, optionally substituted aryl, and optionally substituted heteroaryl; Or, R ５ and R ６ together with the carbon atom to which they are attached form an optionally substituted carbocyclic or heterocyclic ring; Or, R ４ and R ５ together with the carbon atom to which they are attached form an optionally substituted carbocyclic or heterocyclic ring; Or, R ３ and R ４ together with the carbon atom to which they are attached form an optionally substituted carbocyclic or heterocyclic ring; Each R ７ and R ８ is independently 1) Hydrogen, 2) optionally substituted -C １ ~C ８ Alkyl, 3) optionally substituted -C ２ ~C ８ Alkenyl, 4) optionally substituted -C ２ ~C ８ Alkynyl, 5) optionally substituted -C ３ ~C ８ Cycloalkyl, 6) optionally substituted 3- to 8-membered heterocycloalkyl; 7) optionally substituted aryl; 8) optionally substituted arylalkyl; 9) optionally substituted heteroaryl, and 10) optionally substituted heteroarylalkyl is selected from the group consisting of Or, R ７ and R ８ together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring; R ９ teeth, 1) Hydrogen, 2) optionally substituted -C １ ~C ８ Alkyl, 3) optionally substituted -C ２ ~C ８ Alkenyl, 4) optionally substituted -C ２ ~C ８ Alkynyl, 5) optionally substituted -C ３ ~C ８ Cycloalkyl, 6) optionally substituted 3- to 8-membered heterocycloalkyl; 7) optionally substituted aryl; 8) optionally substituted arylalkyl; 9) optionally substituted heteroaryl; 10) optionally substituted heteroarylalkyl; 11)-C(O)R １１ 、 12)-C(O)NR １１ R １２ 、 13)-C(O)OR １１ 、 14)-P(O)(OR １３ ) ２ , and 15)-P(O)(OR １３ )(NR １１ R １２ ) is selected from the group consisting of Each R １１ and R １２ is independently 1) Hydrogen, 2) optionally substituted -C １ ~C ８ Alkyl, 3) Optionally substituted -C ２ ~C ８ alkenyl, 4) optionally substituted -C ２ ~C ８ Alkynyl, 5) optionally substituted -C ３ ~C ８ Cycloalkyl, 6) optionally substituted 3- to 8-membered heterocycloalkyl; 7) optionally substituted aryl; 8) optionally substituted arylalkyl; 9) optionally substituted heteroaryl, and 10) optionally substituted heteroarylalkyl is selected from the group consisting of R １３ is hydrogen, optionally substituted -C １ ~C ８ Alkyl, or Na ＋ (It is.)

2. M is S or NR ７ and R ７ The compound according to claim 1, wherein:

3. R １ is selected from the following groups: 【Chemistry 2】 wherein each group is optionally substituted; R ２ is selected from the following groups: 【Chemistry 3】 2. The compound of claim 1 , wherein each group is optionally substituted.

4. The compound according to claim 1, represented by formula (IV) or formula (V), or a pharma- ceutically acceptable salt thereof. 【Chemistry 4】 (In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ９ and R ７ is as defined in claim 1).

5. R ９ The following group: 【Chemistry 5】 5. The compound of claim 4, wherein each group is optionally substituted.

6. The compound according to claim 1, represented by formula (X) or formula (XI), or a pharma- ceutically acceptable salt thereof. 【Chemistry 6】 (In the formula, R １ , R ２ , R ７ and R ９ is as defined in claim 1).

7. The compound according to claim 1, selected from the compounds represented by formula (X) or a pharma- ceutically acceptable salt thereof. 【Chemistry 7】 (In the formula, R ９ is hydrogen, R １ and R ２ is shown for each compound in the table below). 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】

8. The compound according to claim 1, selected from the compounds represented by formula (X) or a pharma- ceutically acceptable salt thereof. 【Chemistry 8】 (In the formula, R １ , R ２ and R ９ is shown for each compound in the table below). 【Table 2-1】 【Table 2-2】 【Table 2-3】 【Table 2-4】 【Table 2-5】 【Table 2-6】 【Table 2-7】 【Table 2-8】 【Table 2-9】 【Table 2-10】 【Table 2-11】 【Table 2-12】 【Table 2-13】 【Table 2-14】 【Table 2-15】 【Table 2-16】 【Table 2-17】 【Table 2-18】

9. 2. The compound of claim 1, selected from the compounds shown below, or a pharma- ceutically acceptable salt thereof. 【Table 3-1】 【Table 3-2】 【Table 3-3】 【Table 3-4】 【Table 3-5】 【Table 3-6】 【Table 3-7】 【Table 3-8】 【Table 3-9】

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and a pharma- ceutically acceptable carrier or excipient.

11. A method for preventing or treating a 17β-HSD13 mediated disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 9.

12. 12. The method of claim 11, wherein the 17β-HSD13 mediated disease or condition is selected from the group consisting of nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver cirrhosis, liver fibrosis, and hepatocellular carcinoma (HCC).

13. 10. Use of a compound according to any one of claims 1 to 9 in the manufacture of a medicament for treating or preventing a 17β-HSD13 mediated disease or condition.

14. 14. The use according to claim 13, wherein the 17β-HSD13 mediated disease or condition is selected from the group consisting of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver cirrhosis, liver fibrosis, and hepatocellular carcinoma (HCC).

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