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Last Updated: March 28, 2024

Claims for Patent: 9,475,812


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Summary for Patent: 9,475,812
Title:Pyridonaphthyridine type dual PI3K and mTOR inhibitor and its preparation and use
Abstract: The present invention relates to a pyridonaphthyridine compound as represented by general formula (I), which has a dual PI3K and mTOR inhibition effect, and its pharmaceutically acceptable salt, stereoisomer and deuteride thereof, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and X are as defined in the specification; the present invention also relates to a method for preparing said compound, a pharmaceutical composition and a pharmaceutical formulation containing said compound, and uses of said compound in treating and/or preventing a proliferative disease and in the manufacture of a medicament for treating and/or preventing a proliferative disease. ##STR00001##
Inventor(s): Wu; Frank (Jinan, CN), Zhang; Yan (Jinan, CN)
Assignee: Xuanzhu Pharma Co., Ltd. (Jinan, CN)
Application Number:14/123,934
Patent Claims:1. A compound represented by general formula (I), or a pharmaceutically acceptable salt, stereoisomer or deuteride thereof: ##STR00143## wherein: X is O; R.sup.1 is 6-10-membered aryl, 3-8-membered saturated monocyclic heterocyclyl or 5-6-membered aromatic monocyclic heterocyclyl, all of which are unsubstituted or substituted by 1-3 R.sup.8; R.sup.2 is 6-10-membered aryl or 5-10-membered heterocyclyl, which is unsubstituted or substituted by 1-3 R.sup.8'; each of R.sup.3, R.sup.4 and R.sup.5 is hydrogen; each of R.sup.6 and R.sup.7 is independently hydrogen or C.sub.1-4alkyl; R.sup.8 is (1) hydroxy, halogen, cyano, amino or --C(O)R.sup.c, (2) C.sub.1-4alkyl or C.sub.1-4alkoxyl, both of which are unsubstituted or substituted by 1-3 substitutents selected from cyano, halogen and/or hydroxy, or (3) 5-6-membered saturated monocyclic heterocyclyl, which is unsubstituted or substituted by 1-3 substitutents selected from cyano, trifluoromethyl, halogen, --C(O)R.sup.c', --C(O)(CH).sub.2).sub.nNR.sup.aR.sup.b and/or --S(O).sub.2R.sup.c'; R.sup.8' is (1) hydroxy, halogen, cyano, amino, --(CH.sub.2).sub.nNR.sup.aC(O)R.sup.c or --(CH.sub.2).sub.nS(O).sub.mR.sup.c, (2) C.sub.1-4alkyl or C.sub.1-4alkoxyl, both of which are unsubstituted or substituted by 1-3 substitutents selected from cyano, halogen and/or hydroxy, or each of R.sup.a and R.sup.b is independently hydrogen, or C.sub.1-4alkyl that is unsubstituted or substituted by 1-3 substitutents selected from hydroxy and/or halogen; R.sup.c is C.sub.1-4alkyl or C.sub.1-4alkoxyl, both of which are unsubstituted or substituted by 1-3 substitutents selected from hydroxy, halogen and/or cyano; R.sup.c' is C.sub.1-4alkyl or C.sub.1-4alkoxyl, both of which are unsubstituted or substituted by 1-3 substitutents selected from hydroxy and/or halogen; m is 0, 1 or 2; and n is 0, 1, 2 or 3.

2. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer or deuteride thereof, wherein R.sup.1 is phenyl, naphthyl or 5-6-membered saturated monocyclic heterocyclyl, all of which are unsubstituted or substituted by 1-3 R.sup.8; R.sup.2 is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, indazolyl, quinolinyl, isoquinolinyl, indolyl, pyrrolopyridine, dihydropyrrolopyridine or pyrazolopyridinyl, all of which are unsubstituted or substituted by 1-3 R.sup.8'; each of R.sup.6 and R.sup.7 is independently hydrogen or methyl; R.sup.8 is (1) amino or --C(O)R.sup.c, R.sup.c is C.sub.1-4alkyl that is unsubstituted or substituted by hydroxy or halogen, (2) C.sub.1-4alkyl or C.sub.1-4alkoxyl, both of which are unsubstituted or substituted by cyano or 1-3 fluoro, or (3) piperazinyl or piperidinyl, both of which are unsubstituted or substituted by cyano or trifluoromethyl; R.sup.8' is (1) hydroxy, halogen, amino, cyano, --NHC(O)R.sup.c or --S(O).sub.mR.sup.c, wherein m is 0 or 2, R.sup.c is C.sub.1-4alkyl, (2) C.sub.1-4alkyl or C.sub.1-4alkoxyl, both of which are unsubstituted or substituted by hydroxy or 1-3 fluoro.

3. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer or deuteride thereof, wherein R.sup.1 is 6-10-membered aryl or 5-6-membered saturated monocyclic heterocyclyl, both of which are unsubstituted or substituted by 1-3 R.sup.8, wherein R.sup.8 is (1) amino or --C(O)R.sup.c, R.sup.c is C.sub.1-4alkyl that is unsubstituted or substituted by hydroxy or halogen, (2) C.sub.1-4alkyl or C.sub.1-4alkoxyl, both of which are unsubstituted or substituted by cyano or 1-3 halogens, or (3) 5-6-membered saturated monocyclic heterocyclyl that is unsubstituted or substituted by cyano or trifluoromethyl; and/or R.sup.2 is 6-10-membered aryl, 5-6-membered partially saturated monocyclic heterocyclyl, 5-6-membered aromatic monocyclic heterocyclyl or 9-10-membered fused heterocyclyl, all of which are unsubstituted or substituted by 1-3 R.sup.8', wherein R.sup.8' is (1) hydroxy, halogen, amino, cyano, --NHC(O)R.sup.c or --S(O).sub.mR.sup.c, wherein m is 0, 1 or 2, R.sup.c is C.sub.1-4alkyl, (2) C.sub.1-4alkyl or C.sub.1-4alkoxyl, both of which are unsubstituted or substituted by hydroxy or 1-3 halogens.

4. The compound of claim 2, or a pharmaceutically acceptable salt, stereoisomer or deuteride thereof, wherein R.sup.1 is phenyl, piperidinyl or piperazinyl, all of which are unsubstituted or substituted by 1-2 R.sup.8; R.sup.2 is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, isoquinolinyl, pyrrolopyridine, dihydropyrrolopyridine or indolyl, all of which are unsubstituted or substituted by 1-2 R.sup.8'; R.sup.8 is (1) amino or --C(O)R.sup.c, R.sup.c is C.sub.1-4alkyl that is unsubstituted or substituted by hydroxy, (2) C.sub.1-4alkyl that is unsubstituted or substituted by cyano or three fluoro, or (3) piperazinyl or piperidinyl, both of which are unsubstituted or substituted by cyano or trifluoromethyl; R.sup.8' is (1) halogen, amino, cyano, --NHC(O)R.sup.c or --S(O).sub.mR.sup.c, wherein m is 0 or 2, R.sup.c is C.sub.1-4alkyl, (2) C.sub.1-4alkyl or C.sub.1-4alkoxyl, both of which are unsubstituted or substituted by hydroxy or three fluoro.

5. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer or deuteride thereof, wherein said compound is selected from: 2-(6-aminopyridin-3-yl)-10-(3-(trifluoromethyl)phenyl)pyrido[3,2-c]- [1,5]naphthyridin-9(10H)-one, 2-(6-methoxypyridin-3-yl)-10-(4-(piperazin-1-yl)-3-(trifluoromethyl)pheny- l)pyrido[3,2-c][1,5]naphthyridin-9(10H)-one, (R)-2-(6-aminopyridin-3-yl)-10-(1-(2-hydroxypropanoyl)piperidin-4-yl)pyri- do[3,2-c][1,5]naphthyridin-9(10H)-one, (R)-10-(1-(2-hydroxypropanoyl)piperidin-4-yl)-2-(6-methoxypyridin-3-yl)py- rido[3,2-c][1,5]naphthyridin-9(10H)-one, 2-methyl-2-(4-(9-oxo-2-(quinolin-3-yl)pyrido[3,2-c][1,5]naphthyridin-10(9- H)-yl)phenyl)propanenitrile, 2-(6-aminopyridin-3-yl)-10-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)- pyrido[3,2-c][1,5]naphthyridin-9(10H)-one, 2-(4-(2-(6-aminopyridin-3-yl)-9-oxopyrido[3,2-c][1,5]naphthyridin-10(9H)-- yl)phenyl)-2-methylpropanenitrile, 2-(6-methoxypyridin-3-yl)-10-(3-(trifluoromethyl)phenyl)pyrido[3,2-c][1,5- ]naphthyridin-9(10H)-one, 2-(quinolin-3-yl)-10-(3-(trifluoromethyl)phenyl)pyrido[3,2-c][1,5]naphthy- ridin-9(10H)-one, 10-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-2-(quinolin-3-yl)pyrido- [3,2-c][1,5]naphthyridin-9(10H)-one, (R)-10-(1-(2-hydroxypropanoyl)piperidin-4-yl)-2-(quinolin-3-yl)pyrido[3,2- -c][1,5]naphthyridin-9(10H)-one, 2-(4-(2-(6-methoxypyridin-3-yl)-9-oxopyrido[3,2-c][1,5]naphthyridin-10(9H- )-yl)phenyl)-2-methylpropanenitrile, 2-(2-aminopyrimidin-5-yl)-10-(3-(trifluoromethyl)phenyl)pyrido[3,2-c][1,5- ]naphthyridin-9(10H)-one, 2-(2-methoxypyrimidin-5-yl)-10-(3-(trifluoromethyl)phenyl)pyrido[3,2-c][1- ,5]naphthyridin-9(10H)-one, N-(5-(9-oxo-10-(3-(trifluoromethyl)phenyl)-9, 10-dihydropyrido[3,2-c][1,5]naphthyridin-2-yl)pyridin-2-yl)acetamide, 5-(9-oxo-10-(3-(trifluoromethyl)phenyl)-9,10-dihydropyrido[3,2-c][1,5]nap- hthyridin-2-yl)-2-cyanopyridine, 2-(1H-pyrrolo[2,3-b]pyridin-3-yl)-10-(3-(trifluoromethyl)phenyl)pyrido[3,- 2-c][1,5]naphthyridin-9(10H)-one, 2-(6-(hydroxymethyl)pyridin-3-yl)-10-(3-(trifluoromethyl)phenyl)pyrido[3,- 2-c][1,5]naphthyridin-9(10H)-one, 2-(4-(2-(2-methoxypyrimidin-5-yl)-9-oxopyrido[3,2-c][1,5]naphthyridin-10(- 9H)-yl)phenyl)-2-methylpropanenitrile, 2-(6-(methylsulfonyl)pyridin-3-yl)-10-(3-(trifluoromethyl)phenyl)pyrido[3- ,2-c][1,5]naphthyridin-9(10H)-one, 2-(6-methoxypyridin-3-yl)-10-(3-(trifluoromethyl)phenyl)pyrido[3,2-c][1,5- ]naphthyridin-9(10H)-one, 2-(5-methoxypyridin-3-yl)-10-(3-(trifluoromethyl)phenyl)pyrido[3,2-c][1,5- ]naphthyridin-9(10H)-one, 2-(2-methoxypyridin-3-yl)-10-(3-(trifluoromethyl)phenyl)pyrido[3,2-c][1,5- ]naphthyridin-9(10H)-one, 10-(3-(trifluoromethyl)phenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)pyrido[- 3,2-c][1,5]naphthyridin-9(10H)-one, 2-(6-methylpyridin-3-yl)-10-(3-(trifluoromethyl)phenyl)pyrido[3,2-c][1,5]- naphthyridin-9(10H)-one, 2-(3,5-dimethylisoxazol-4-yl)-10-(3-(trifluoromethyl)phenyl)pyrido[3,2-c]- [1,5]naphthyridin-9(10H)-one, 2-(5-fluoropyridin-3-yl)-10-(3-(trifluoromethyl)phenyl)pyrido[3,2-c][1,5]- naphthyridin-9(10H)-one, 10-(3-(trifluoromethyl)phenyl-2-(5-(trifluoromethyl)pyridin-3-yl)pyrido[3- ,2-c][1,5]naphthyridin-9(10H)-one, 2-(1-methyl-1H-pyrazol-5-yl)-10-(3-(trifluoromethyl)phenyl)pyrido[3,2-c][- 1,5]naphthyridin-9(10H)-one, 2-(thiazol-5-yl)-10-(3-(trifluoromethyl)phenyl)pyrido[3,2-c][1,5]naphthyr- idin-9(10H)-one, 3-methyl-5-(9-oxo-10-(3-(trifluoromethyl)phenyl)-9, 10-dihydropyrido[3,2-c][1,5]naphthyridin-2-yl)-2-cyanopyridine, 5-(9-oxo-10-(3-(trifluoromethyl)phenyl)-9,10-dihydropyrido[3,2-c][1,5]nap- hthyridin-2-yl)-3-cyanopyridine, 2-(1-methyl-1H-pyrazol-4-yl)-10-(3-(trifluoromethyl)phenyl)pyrido[3,2-c][- 1,5]naphthyridin-9(10H)-one, 2-(6-(methylthio)pyridin-3-yl)-10-(3-(trifluoromethyl)phenyl)pyrido[3,2-c- ][1,5]naphthyridin-9(10H)-one, 2-(1H-pyrrolo[2,3-b]pyridin-5-yl)-10-(3-(trifluoromethyl)phenyl)pyrido[3,- 2-c][1,5]naphthyridin-9(10H)-one, 2-(6-(methylsulfonyl)pyridin-3-yl)-10-(4-(piperazin-1-yl)-3-(trifluoromet- hyl)phenyl)pyrido[3,2-c][1,5]naphthyridin-9(10H)-one, (R)-10-(1-(2-hydroxypropanoyl)piperidin-4-yl)-2-(6-(methylsulfonyl)pyridi- n-3-yl)pyrido[3,2-c][1,5]naphthyridin-9(10H)-one, 2-methyl-2-(4-(2-(6-(methylsulfonyl)pyridin-3-yl)-9-oxopyrido[3,2-c][1,5]- naphthyridin-10(9H)-yl)phenyl)propanenitrile, N-(5-(9-oxo-10-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-9,10-dihydr- opyrido[3,2-c][1,5]naphthyridin-2-yl)pyridin-2-yl)acetamide, (R)--N-(5-(10-(1-(2-hydroxypropanoyl)piperidin-4-yl)-9-oxo-9,10-dihydropy- rido[3,2-c][1,5]naphthyridin-2-yl)pyridin-2-yl)acetamide, N-(5-(10-(4-(2-cyanopropan-2-yl)phenyl)-9-oxo-9,10-dihydropyrido[3,2-c][1- ,5]naphthyridin-2-yl)pyridin-2-yl)acetamide, 5-(9-oxo-10-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-9,10-dihydropy- rido[3,2-c][1,5]naphthyridin-2-yl)-2-cyanopyridine, (R)-5-(10-(1-(2-hydroxypropanoyl)piperidin-4-yl)-9-oxo-9,10-dihydropyrido- [3,2-c][1,5]naphthyridin-2-yl)-2-cyanopyridine, 5-(10-(4-(2-cyanopropan-2-yl)phenyl)-9-oxo-9,10-dihydropyrido[3,2-c][1,5]- naphthyridin-2-yl)-2-cyanopyridine, 2-(6-(methylthio)pyridin-3-yl)-10-(4-(piperazin-1-yl)-3-(trifluoromethyl)- phenyl)pyrido[3,2-c][1,5]naphthyridin-9(10H)-one, (R)-1-(1-(2-hydroxypropanoyl)piperidin-4-yl)-2-(6-(methylthio)pyridin-3-y- l)pyrido[3,2-c][1,5]naphthyridin-9(10H)-one, and 2-methyl-2-(4-(2-(6-(methylthio)pyridin-3-yl)-9-oxopyrido[3,2-c][1,5]naph- thyridin-10(9H)-yl)phenyl)propanenitrile.

6. A pharmaceutical composition, comprising the compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer or deuteride thereof.

7. The pharmaceutical composition of claim 6, which further comprises one or more antineoplastic agent(s) and/or immunosuppressive agent(s), said antineoplastic agent and said immunosuppressive agent are antimetabolite selected from capecitabine, gemcitabine, pemetrexed disodium; growth factor inhibitor selected from pazopanib, imatinib, erlotinib, lapatinib, gefitinib, vandetanib; antibody selected from herceptin, bevacizumab; mitotic inhibitor selected from paclitaxel, vinorelbine, docetaxel, doxorubicin; antineoplastic hormone selected from letrozole, tamoxifen, fulvestrant, flutamide, triptorelin; alkylating agent selected from cyclophosphamide, chlormethine, mnelphalan, chlorambucil, carmustine; metallic platinum selected from carboplatin, cisplatin, oxaliplatin; topoismerase inhibitor selected from topotecan camptothecin, topotecan, irinotecanpto; immunosuppressive agent selected from everolimus, sirolimus, torisel; purine analogues selected from 6-mercaptopurine, 6-thioguanine, azathioprine; antibiotics selected from actinomycin D, daunorubicin, adriamycin, mitoxantrone, bleomycin, plicamycin; platinum complex selected from cisplatin, carboplatin; adrenal cortex inhibitors selected from aminoglutethimide.

8. A pharmaceutical formulation comprising the compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer or deuteride thereof, and one or more pharmaceutically acceptable carriers, which is in any dosage form that is clinically or pharmaceutically acceptable.

9. A method for treating a proliferative disease, selected from lung cancer, non-small cell lung cancer, small cell lung cancer, glioma, glioma sarcomatosum, mammary cancer, prostrate tumor, renal cancer, ovarian cancer and colon cancer which comprises a step of administering an effective amount of the compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer or deuteride thereof to a subject in need thereof.

10. A method for preparing the compound of general formula (I) of claim 1, i.e., the following formula ##STR00144## which method comprises the following steps: ##STR00145## ##STR00146## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are defined as hereinbefore, Hal.sup.1, Hal.sup.2 and Hal.sup.3 represent halogen, which is each independently selected from the group consisting of F, Cl, Br and I, and Hal, Hal.sup.2 and Hal.sup.3 can be identical or different; Alk represents a lower alkyl; "anhydride" is an organic acid anhydride; (1) preparation of intermediate 1 starting material 1 and starting material 2 are reacted under heating to reflux in an alcohol organic solvent in presence of a base until the starting material disappears to produce intermediate 1; (2) preparation of intermediate 2' intermediate 1 is reacted with an reductant in an alcohol organic solvent; the solvent is removed under a reduced pressure; water is added to the reaction mixture; the resulting mixture is extracted with a halogenated hydrocarbon organic solvent; the organic phase is concentrated, to which is added an oxidant; the resulting mixture is reacted under stirring to produce intermediate 2'; (3) preparation of intermediate 2 in the nitrogen protection, intermediate 2' and a Grignard reagent R.sup.6--Mg-Hal.sup.3 are reacted and then oxidized to produce Intermediate 2; (4) preparation of intermediate 3 method 1: in a sealed vessel, intermediate 2 and starting material 3 are reacted in an alcohol organic solvent in the presence of an inorganic base at 110-180.degree. C. to produce intermediate 3; or method 2: intermediate 2 is dissolved in a non-protonic polar organic solvent and starting material 3'; the reaction is conducted in a microwave reactor until the starting material disappears to produce intermediate 3; and (5) preparation of compound of formula (I) intermediate 3 and starting material 4 are dissolved in an organic solvent; the resulting mixture was reacted in the presence of a catalyst and a base under reflux in a nitrogen-protecting atmosphere to produce the compound of formula (I); if necessary, a functional group that needs to be protected can be protected; and afterwards can be deprotected according to the conventional method.

11. The pharmaceutical formulation of claim 8, comprising a dosage of the compound of claim 1, or the pharmaceutically acceptable salt, stereoisomer or deuteride thereof, that inhibits both PI3K.alpha. and mTOR.

Details for Patent 9,475,812

Applicant Tradename Biologic Ingredient Dosage Form BLA Approval Date Patent No. Expiredate
Genentech, Inc. HERCEPTIN trastuzumab For Injection 103792 09/25/1998 ⤷  Try a Trial 2031-06-04
Genentech, Inc. HERCEPTIN trastuzumab For Injection 103792 02/10/2017 ⤷  Try a Trial 2031-06-04
Genentech, Inc. AVASTIN bevacizumab Injection 125085 02/26/2004 ⤷  Try a Trial 2031-06-04
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

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