Claims for Patent: 9,498,479

Summary for Patent: 9,498,479

Title:	Dihydropyrimidine compounds and their application in pharmaceuticals
Abstract:	Provided herein are dihydropyrimidine compounds and their pharmaceutical applications, especially for use in treating and preventing HBV diseases. Specifically, provided herein are compounds having Formula (I) or (Ia), or an enantiomer, a diastereoisomer, a tautomer, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, wherein the variables of the formulas are as defined in the specification. Also provided herein is the use of the compounds having Formula (I) or (Ia), or an enantiomer, a diastereoisomer, a tautomer, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof for treating and preventing HBV diseases. ##STR00001##
Inventor(s):	Zhang; Yingjun (Dongguan, CN), Liu; Xinchang (Dongguan, CN), Zou; Zhifu (Dongguan, CN), Liang; Jinsheng (Dongguan, CN), Goldmann; Siegfried (Wuppertal, DE), Ren; Qingyun (Dongguan, CN)
Assignee:	SUNSHINE LAKE PHARMA CO., LTD. (Dongguan, Guangdong, CN)
Application Number:	15/022,562
Patent Claims:	1. A compound having Formula (I) or (Ia), or an enantiomer, a diastereoisomer, a tautomer, a hydrate, a solvate, a stereoisomer, an N-oxide, or a pharmaceutically acceptable salt thereof, ##STR00244## wherein R.sup.1 is C.sub.6-10 aryl or C.sub.1-9 heteroaryl; R.sup.3 is a 5-membered heteroaryl group; A is a bond, --O--, --S-- or --NR.sup.5--; R is ##STR00245## wherein, W is CR.sup.4 or N; each of R.sup.2, R.sup.4 and R.sup.5 is independently hydrogen or C.sub.1-4 alkyl; Y is --(CR.sup.8R.sup.8a).sub.k--S(.dbd.O).sub.q-- or --(CR.sup.7R.sup.6).sub.n--; Q is --(CR.sup.8R.sup.8a).sub.k--; each R.sup.7 is independently hydrogen, F or alkyl; each R.sup.6 is independently F or alkyl; or R.sup.6 and R.sup.7, together with the carbon atom to which they are attached, form --C(.dbd.CH.sub.2)-- or --C(.dbd.O)--; each R.sup.8 and R.sup.8a is independently hydrogen, cyano or alkyl; each R.sup.9 is independently --(CR.sup.10R.sup.10a).sub.t--OH, triazolyl, tetrazolyl, --(CR.sup.10R.sup.10a).sub.m--C(.dbd.O)O--R.sup.11, --(CR.sup.10R.sup.10).sub.k--C(.dbd.O)O--(CR.sup.10R.sup.10a).sub.k--OC(.- dbd.O)O--R.sup.11, --S(.dbd.O).sub.qOR.sup.11, --(CR.sup.10R.sup.10a).sub.k--S(.dbd.O).sub.qN(R.sup.11).sub.2, --(CR.sup.10R.sup.10a).sub.k--C(.dbd.O)O--(CR.sup.10R.sup.10a).sub.k--OC(- .dbd.O)--R.sup.11, --(CR.sup.10R.sup.10a).sub.k--C(.dbd.O)O--(CR.sup.10R.sup.10a).sub.k--C(.- dbd.O)O--R.sup.11, --(CR.sup.10R.sup.10a).sub.t--N(R.sup.11).sub.2, --(CR.sup.10R.sup.10a).sub.t--OC(.dbd.O)--R.sup.11, or --(CR.sup.10R.sup.10a).sub.k--C(.dbd.O)N(R.sup.11).sub.2; each R.sup.10 and R.sup.10a is independently hydrogen, halogen, haloalkyl or alkyl, or R.sup.10 and R.sup.10a, together with the carbon atom to which they are attached, form cycloalkyl, heterocyclyl or --C(.dbd.O)--; each R.sup.11 is independently hydrogen, alkyl, alkoxy, hydroxy, alkyl-S(.dbd.O).sub.q--, aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl, heterocyclyl-S(.dbd.O).sub.q--, heteroaryl-S(.dbd.O).sub.q--, cycloalkyl-S(.dbd.O).sub.q-- or aryl-S(.dbd.O).sub.q--; each n is independently 1, 2 or 3; each t and m is independently 1, 2, 3 or 4; each q is independently 1 or 2; and each k is independently 0, 1, 2, 3 or 4; wherein each alkoxy, alkyl-S(.dbd.O).sub.q--, aryl, heteroaryl, arylalkyl, heterocyclyl-S(.dbd.O).sub.q--, heteroaryl-S(.dbd.O).sub.q--, cycloalkyl-S(.dbd.O).sub.q-- and aryl-S(.dbd.O).sub.q-- described in R.sup.11, alkyl described in R.sup.6, R.sup.7, R.sup.8, R.sup.8a, R.sup.10, R.sup.10a, and R.sup.11, haloalkyl described in R.sup.10 and R.sup.10a, heterocyclyl and cycloalkyl described in R.sup.10, R.sup.10a, and R.sup.11, triazolyl and tetrazolyl described in R.sup.9, a 5-membered heteroaryl group described in R.sup.3, C.sub.1-4 alkyl described in R.sup.1, R.sup.4 and R.sup.5, and C.sub.6-10 aryl and C.sub.1-9 heteroaryl described in R.sup.1, is optionally and independently substituted with one or more substituents independently selected from hydrogen, fluoro, chloro, bromo, iodo, oxo (.dbd.O), methylene (.dbd.CH.sub.2), alkyl, alkoxy, cyano, hydroxy, nitro, alkylamino, amino, aryl, heteroaryl, heterocyclyl, cycloalkyl, trifluoromethyl, trifluoromethoxy, haloalkyl-substituted aryl, halogen-substituted aryl or trifluoromethylsulfonyl. 2. The compound according to claim 1, wherein R is ##STR00246## wherein, Y is --(CR.sup.8R.sup.8a).sub.k--S(.dbd.O).sub.q-- or --(CR.sup.7R.sup.6).sub.n--; Q is --(CR.sup.8R.sup.8a).sub.k--; each R.sup.7 is independently hydrogen, C.sub.1-4 alkyl or F; each R.sup.6 is independently F or C.sub.1-4 alkyl; or R.sup.6 and R.sup.7, together with the carbon atom to which they are attached, form --C(.dbd.CH.sub.2)-- or --C(.dbd.O)--; each R.sup.8 and R.sup.8a is independently hydrogen or C.sub.1-4 alkyl; each R.sup.9 is independently --(CR.sup.10R.sup.10a).sub.t--OH, triazolyl, tetrazolyl, --(CR.sup.10R.sup.10a).sub.m--C(.dbd.O)O--R.sup.11, --(CR.sup.10R.sup.10a).sub.k--C(.dbd.O)O--(CR.sup.10R.sup.10a).sub.k--OC(- .dbd.O)O--R.sup.11, --S(.dbd.O).sub.qOR.sup.11, --(CR.sup.10R.sup.10a).sub.k--S(.dbd.O).sub.qN(R.sup.11).sub.2, --(CR.sup.10R.sup.10a).sub.k--C(.dbd.O)O--(CR.sup.10R.sup.10a).sub.k--OC(- .dbd.O)--R.sup.11, --(CR.sup.10R.sup.10a).sub.k--C(.dbd.O)O--(CR.sup.10R.sup.10a).sub.k--C(.- dbd.O)O--R.sup.11, --(CR.sup.10R.sup.10a).sub.t--N(R.sup.11).sub.2, --(CR.sup.10R.sup.10a).sub.t--OC(.dbd.O)--R.sup.11, or --(CR.sup.10R.sup.10a).sub.k--C(.dbd.O)N(R.sup.11).sub.2; each R.sup.10 and R.sup.10a is independently hydrogen, halogen, C.sub.1-4 haloalkyl or C.sub.1-4 alkyl, or R.sup.10 and R.sup.10a, together with the carbon atom to which they are attached, form C.sub.3-6 cycloalkyl, C.sub.2-9 heterocyclyl or --C(.dbd.O)--; and each R.sup.11 is independently hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkyl-S(.dbd.O).sub.q--, C.sub.6-10 aryl, C.sub.1-9 heteroaryl, C.sub.3-6 cycloalkyl, C.sub.2-9 heterocyclyl, C.sub.6-10 aryl-C.sub.1-6-alkyl, C.sub.2-9 heterocyclyl-S(.dbd.O).sub.q--, C.sub.1-9 heteroaryl-S(.dbd.O).sub.q--, C.sub.3-6 cycloalkyl-S(.dbd.O).sub.q-- or C.sub.6-10 aryl-S(.dbd.O).sub.q. 3. The compound according to claim 2, wherein R is ##STR00247## wherein, each R.sup.7 is independently hydrogen, methyl, ethyl or F; each R.sup.6 is independently F, methyl or ethyl; or R.sup.6 and R.sup.7, together with the carbon atom to which they are attached, form --C(.dbd.CH.sub.2)-- or --C(.dbd.O)--; each R.sup.8 and R.sup.8a is independently hydrogen, methyl, ethyl or propyl; each R.sup.9 is independently --(CR.sup.10R.sup.10a).sub.t--OH, triazolyl, tetrazolyl, --(CR.sup.10R.sup.10a).sub.m--C(.dbd.O)O--R.sup.11, --(CR.sup.10R.sup.10a).sub.k--C(.dbd.O)O--(CR.sup.10R.sup.10a).sub.k--OC(- .dbd.O)O--R.sup.11, --S(.dbd.O).sub.qOR.sup.11, --(CR.sup.10R.sup.10a).sub.k--S(.dbd.O).sub.qN(R.sup.11).sub.2, --(CR.sup.10R.sup.10a).sub.k--C(.dbd.O)O--(CR.sup.10R.sup.10a).sub.k--OC(- .dbd.O)--R.sup.11, --(CR.sup.10R.sup.10a).sub.k--C(.dbd.O)O--(CR.sup.10R.sup.10a).sub.k--C(.- dbd.O)O--R.sup.11, --(CR.sup.10R.sup.10a).sub.t--N(R.sup.11).sub.2, --(CR.sup.10R.sup.10a).sub.t--OC(.dbd.O)--R.sup.11, or --(CR.sup.10R.sup.10a).sub.k--C(.dbd.O)N(R.sup.11).sub.2; each R.sup.10 and R.sup.10a is independently hydrogen, fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, ethyl, propyl, or R.sup.10 and R.sup.10a, together with the carbon atom to which they are attached, form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or --C(.dbd.O)--; and each R.sup.11 is independently hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxyl, C.sub.1-4 alkyl-S(.dbd.O).sub.2--, phenyl, pyridyl, thiazolyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl, triazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-S(.dbd.O).sub.2--, cyclobutyl-S(.dbd.O).sub.2--, cyclopentyl-S(.dbd.O).sub.2--, cyclohexyl-S(.dbd.O).sub.2--, naphthyl-S(.dbd.O).sub.2-- or phenyl-S(.dbd.O).sub.2--. 4. The compound according to claim 1, wherein R.sup.1 is phenyl; R.sup.3 is thiazolyl or 1-methyl-1H-imidazolyl; and each of R.sup.2, R.sup.4 and R.sup.5 is independently hydrogen, methyl or ethyl; wherein each thiazolyl and 1-methyl-1H-imidazolyl described in R.sup.3, phenyl described in R.sup.1, and methyl and ethyl described in R.sup.2, R.sup.4 and R.sup.5, is optionally and independently substituted with one or more substituents independently selected from hydrogen, C.sub.1-4 alkyl, fluoro, chloro or bromo. 5. The compound according to claim 1 having Formula (II) or (IIa), or an enantiomer, a diastereoisomer, a tautomer, a hydrate, a solvate, a stereoisomer, an N-oxide or a pharmaceutically acceptable salt thereof, ##STR00248## wherein R.sup.2 is hydrogen or C.sub.1-4 alkyl; R.sup.3 is thiazolyl or 1-methyl-1H-imidazolyl; R is ##STR00249## wherein each R.sup.7 is independently hydrogen, C.sub.1-4 alkyl or F; each R.sup.6 is independently F or C.sub.1-4 alkyl; or R.sup.6 and R.sup.7, together with the carbon atom to which they are attached, form --C(.dbd.CH.sub.2)-- or --C(.dbd.O)--; Q is --(CR.sup.8R.sup.8a).sub.k--; each R.sup.8 and R.sup.8a is independently hydrogen or C.sub.1-4 alkyl; each R.sup.9 is independently --(CR.sup.10R.sup.10a).sub.t--OH, triazolyl, tetrazolyl, --(CR.sup.10R.sup.10a).sub.m--C(.dbd.O)O--R.sup.11, --(CR.sup.10R.sup.10a).sub.k--C(.dbd.O)O--(CR.sup.10R.sup.10a).sub.k--OC(- .dbd.O)O--R, --S(.dbd.O).sub.qOR.sup.11, --(CR.sup.10R.sup.10a).sub.k--S(.dbd.O).sub.qN(R.sup.11).sub.2, --(CR.sup.10R.sup.10a).sub.k--C(.dbd.O)O--(CR.sup.10R.sup.10a).sub.k--OC(- .dbd.O)--R.sup.11, --(CR.sup.10R.sup.10a).sub.k--C(.dbd.O)O--(CR.sup.10R.sup.10a).sub.k--C(.- dbd.O)O--R.sup.11, --(CR.sup.10R.sup.10a).sub.t--N(R.sup.11).sub.2, --(CR.sup.10R.sup.10a).sub.t--OC(.dbd.O)--R.sup.11, or --(CR.sup.10R.sup.10a).sub.k--C(.dbd.O)N(R.sup.11).sub.2; each R.sup.10 and R.sup.10a is independently hydrogen, fluoro, chloro, bromo, iodo, C.sub.1-4 haloalkyl or C.sub.1-4 alkyl, or R.sup.10 and R.sup.10a, together with the carbon atom to which they are attached, form C.sub.3-6 cycloalkyl or --C(.dbd.O)--; each R.sup.11 is independently hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, C.sub.1-4 alkyl-S(.dbd.O).sub.q--, C.sub.6-10 aryl, C.sub.1-9 heteroaryl, C.sub.3-6 cycloalkyl, C.sub.2-9 heterocyclyl, C.sub.6-10 aryl-C.sub.1-4-alkyl, C.sub.2-9 heterocyclyl-S(.dbd.O).sub.q--, C.sub.1-9 heteroaryl-S(.dbd.O).sub.q--, C.sub.3-6 cycloalkyl-S(.dbd.O).sub.q-- or C.sub.6-10 aryl-S(.dbd.O).sub.q--; each R.sup.12 is independently hydrogen, fluoro, chloro or bromo; each n is independently 1, 2 or 3; each t and m is independently 1, 2, 3 or 4; each q is independently 1 or 2; and each k is independently 0, 1, 2, 3 or 4. 6. The compound according to claim 1 or 5, wherein R is ##STR00250## each R.sup.9 is independently --(CR.sup.10R.sup.10a).sub.t--OH, triazolyl, tetrazolyl, --(CR.sup.10R.sup.10a).sub.m--C(.dbd.O)O--R.sup.11, --(CR.sup.10R.sup.10a).sub.k--C(.dbd.O)O--(CR.sup.10R.sup.10a).sub.k--OC(- .dbd.O)O--R.sup.11, --S(.dbd.O).sub.qOR.sup.11, --(CR.sup.10R.sup.10a).sub.k--S(.dbd.O).sub.qN(R.sup.11).sub.2, --(CR.sup.10R.sup.10a).sub.k--C(.dbd.O)O--(CR.sup.10R.sup.10a).sub.k--OC(- .dbd.O)--R.sup.11, --(CR.sup.10R.sup.10a).sub.k--C(.dbd.O)O--(CR.sup.10R.sup.10a).sub.k--C(.- dbd.O)O--R.sup.11, --(CR.sup.10R.sup.10a).sub.t--N(R.sup.11).sub.2, --(CR.sup.10R.sup.10a).sub.t--OC(.dbd.O)--R.sup.11, or --(CR.sup.10R.sup.10a).sub.k--C(.dbd.O)N(R.sup.11).sub.2; each R.sup.10 and R.sup.10a is independently hydrogen, fluoro, chloro, trifluoromethyl, methyl, ethyl, propyl, isopropyl, tert-butyl or n-butyl, or R.sup.10 and R.sup.10a together with the carbon atom to which they are attached, form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or --C(.dbd.O)--; and each R.sup.11 is independently hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, n-butyl; methoxyl, ethoxy, propoxy, isopropoxy, tert-butoxy, n-butoxy, methyl-S(.dbd.O).sub.2--, ethyl-S(.dbd.O).sub.2--, propyl-S(.dbd.O).sub.2--, isopropyl-S(.dbd.O).sub.2--, pyridyl, thiazolyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl, triazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-S(.dbd.O).sub.2--, cyclobutyl-S(.dbd.O).sub.2--, cyclopentyl-S(.dbd.O).sub.2--, cyclohexyl-S(.dbd.O).sub.2--, naphthyl-S(.dbd.O).sub.2-- or phenyl-S(.dbd.O).sub.2--. 7. The compound according to claim 1 having one of the following structures, or an enantiomer, a diastereoisomer, a tautomer, a hydrate, a solvate, a stereoisomer, an N-oxide, or a pharmaceutically acceptable salt thereof, ##STR00251## ##STR00252## ##STR00253## ##STR00254## ##STR00255## ##STR00256## ##STR00257## ##STR00258## ##STR00259## ##STR00260## ##STR00261## ##STR00262## ##STR00263## ##STR00264## ##STR00265## ##STR00266## ##STR00267## ##STR00268## ##STR00269## ##STR00270## ##STR00271## ##STR00272## ##STR00273## ##STR00274## ##STR00275## ##STR00276## ##STR00277## ##STR00278## ##STR00279## ##STR00280## ##STR00281## ##STR00282## ##STR00283## ##STR00284## ##STR00285## ##STR00286## ##STR00287## ##STR00288## ##STR00289## ##STR00290## ##STR00291## ##STR00292## ##STR00293## ##STR00294## ##STR00295## ##STR00296## ##STR00297## ##STR00298## ##STR00299## ##STR00300## ##STR00301## ##STR00302## ##STR00303## ##STR00304## ##STR00305## ##STR00306## ##STR00307## ##STR00308## ##STR00309## 8. A compound having one of the following structures, or an enantiomer, a diastereoisomer, a tautomer, a hydrate, a solvate, a stereoisomer, an N-oxide, or a pharmaceutically acceptable salt thereof, ##STR00310## ##STR00311## ##STR00312## ##STR00313## ##STR00314## ##STR00315## ##STR00316## ##STR00317## ##STR00318## ##STR00319## ##STR00320## ##STR00321## ##STR00322## 9. A pharmaceutical composition comprising the compound according to claim 1; and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof. 10. The pharmaceutical composition according to claim 9 further comprising an anti-HBV agent. 11. The pharmaceutical composition according to claim 10, wherein the anti-HBV agent is a HBV polymerase inhibitor, immunomodulator or interferon. 12. The pharmaceutical composition according to claim 10, wherein the anti-HBV agent comprises at least one selected from the group consisting of lamivudine, telbivudine, tenofovir, entecavir, adefovir dipivoxil, alfaferone, alloferon, celmoleukin, clevudine, emtricitabine, famciclovir, interferon, hepatect CP, intefen, interferon .alpha.-1b, interferon .alpha., interferon .alpha.-2a, interferon .beta.-1a, interferon .alpha.-2, interleukin-2, mivotilate, nitazoxanide, peginterferon alfa-2a, ribavirin, roferon-A, sizofiran, euforavac, ampligen, phosphazid, heplisav, interferon .alpha.-2b, levamisole and propagermanium. 13. A method for treating a HBV disease comprising administering to a patient a therapeutically effective amount of the compound according to claim 1. 14. The method according to claim 13, wherein the viral disease or HBV disease is hepatitis B infection or a disease caused by hepatitis B infection. 15. The method according to claim 14, wherein the disease caused by hepatitis B infection is cirrhosis or hepatocellular carcinoma. 16. A method for treating a HBV disease comprising administering to a patient a therapeutically effective amount of the pharmaceutical composition according to claim 9. 17. The method according to claim 16, wherein the viral disease or HBV disease is hepatitis B infection or a disease caused by hepatitis B infection. 18. The method according to claim 17, wherein the disease caused by hepatitis B infection is cirrhosis or hepatocellular carcinoma.

Details for Patent 9,498,479

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
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