Process for preparing triazole substituted azaindoleoxoacetic piperazine derivatives and novel salt forms produced therein 机翻标题: 暂无翻译,请尝试点击翻译按钮。

公开号/公开日
US2006293304 A1 2006-12-28 [US20060293304]US7601715 B2 2009-10-13 [US7601715] / 2006-12-282009-10-13
申请号/申请日
2006US-11455338 / 2006-06-19
发明人
SOUNDARARAJAN NACHIMUTHU;QIU YUPING;HU WENHAO;KRONENTHAL DAVID R;SIRARD PIERRE;LAJEUNESSE JEAN;DROGHINI ROBERT;CHIDAMBARAM RAMAKRISHNAN;QIAN XINHUA;NATALIE KENNETH J;PACK SHAWN K;REISING NATHAN;TANG ERQING;FAKES MICHAEL G;GAO Q;
申请人
VIIV HEALTHCARE;
主分类号
IPC分类号
A01N-043/58A61K-031/497A61K-031/50C07D-239/00C07D-239/02C07D-241/00C07D-241/02C07D-295/00
摘要
(US7601715) A process is provided for preparing triazole substituted azaindoleoxoacetic piperazine derivative.  Novel intermediates produced in the above process, and novel N-1 and amorphous forms of a 1,2,3-triazole substituted azaindoleoxoacetic piperazine derivatives and processes for producing such novel forms are also provided.
机翻摘要
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地址
代理人
代理机构
;
优先权号
2005US-60693004 2005-06-22 2006US-11455338 2006-06-19
主权利要求
(US7601715) What is claimed is: 1.  A process for preparing compound IA having the structure       where A is selected from the group consisting of C1-6alkoxy, aryl and heteroaryl; in which said aryl is phenyl or naphthyl; said heteroaryl is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, furanyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, benzoimidazolyl and benzothiazolyl; and said aryl or heteroaryl is optionally substituted with one or two of the same or different members selected from the group consisting of amino, nitro, cyano, hydroxy, C1-6alkoxy,  -- C(O)NH2, C1-6alkyl,  -- NHC(O)CH3, halogen and trifluoromethyl; and R18 is H or alkyl;   R9, R10, R11, R12, R13, R14, R15 and R16 are each independently H or (C1-6)alkyl which may be optionally substituted with 1 to 3 same or different halogens;    which comprises reacting compound D having the structure       with a compound of the structure       in the presence of an organometallic base to form compound IA, wherein the reaction is carried out at a temperature within the range from about -10 to about 30 deg. C. and   where in compounds D and IA, R2 is CH3O, R1 is H and R3 is H. 2. A process for preparing compound IIA as defined in claim 1 having the structure       which comprises reacting compound L as defined in claim 1 of the structure       with a compound of the structure   where R18 is H or alkyl,    where A is selected from the group consisting of C1-6alkoxy, aryl and heteroaryl; in which said aryl is phenyl or naphthyl; said heteroaryl is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, furanyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, benzoimidazolyl and benzothiazolyl; and said aryl or heteroaryl is optionally substituted with one or two of the same or different members selected from the group consisting of amino, nitro, cyano, hydroxy, C1-6alkoxy,  -- C(O)NH2, C1-6alkyl,  -- NHC(O)CH3, halogen and trifluoromethyl; and R9, R10, R11, R12, R13, R14, R15 and R16 are each independently H or (C1-6)alkyl which may be optionally substituted with 1 to 3 same or different halogens;    in the presence of an organometallic base to form compound IIA, wherein the reaction is carried out at a temperature within the range from about -20 to about 50 deg. C. and   where in the compounds IIA and L, R2 is F, R3 is H and R1 is H. 10. A pharmaceutical formulation in the form of an oral solution comprising a) the crystalline form of the 1,2,3-triazole derivative IIA having the structure;     and   b) a vehicle comprising 1) 75% (w/w) polyethylene glycol 400;   2) 10% (w/w) d-alpha tocopheryl polyethylene glycol 1000-succinate; and   3) 15% (w/w) ethyl alcohol; wherein said crystalline form is the N-1 form of the free base, and is characterized by one or more of the following:    a) unit cell parameters substantially equal to the following:    Cell Dimensions: a=39.2481(14) .ANG.   b=5.5577(2) .ANG.   c=21.8072(10) .ANG.   alpha =90 deg.   beta =122.399(4) deg.   gamma =90 deg.   Space group C2/c    wherein said crystalline form is at about 25 deg. C.; b) fractional atomic coordinates substantially as listed in Table 2;   c) a powder X-ray diffraction pattern substantially in accordance with that shown in FIG. 5;   d) a powder X-ray diffraction pattern comprising the following typical and representative 2theta  values (CuKalpha  lambda =1.5418 .ANG.) 5.3+-0.1, 8.1+0.1, 9.6+-0.1, 16.2+-0.1, 17.0+-0.1, 19.6+-0.1, 20.7+-0.1 and 23.0+-0.1 at about room temperature;   e) a differential scanning calorimetry thermogram substantially in accordance with that shown in FIG. 6;   f) a thermal gravimetric analysis curve substantially in accordance with that shown in FIG. 7; and/or   g) a moisture-sorption isotherm substantially as shown in FIG. 8. 3. A process for preparing compound IA having the structure       wherein R18 is H or alkyl, R1, R2 and R3 are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, COOR56, XR57, C(O)R7, C(O)NR55R56, B, D, and E; B is selected from the group consisting of  -- C(.dbd.NR46)(R47), C(O)NR40R41, aryl, heteroaryl, heteroalicyclic, S(O)2R8, C(O)R7, XR8a, (C1-6)alkylNR40R41, (C1-6)alkylCOOR8b; wherein said aryl, heteroaryl, and heteroalicyclic are optionally substituted with one to three same or different halogens or from one to three same or different substituents selected from the group F; wherein aryl is naphthyl or substituted phenyl; wherein heteroaryl is a mono or bicyclic system which contains from 3 to 7 ring atoms for a mono cyclic system and up to 12 atoms in a fused bicyclic system, including from 1 to 4 heteroatoms; wherein heteroalicyclic is a 3 to 7 membered mono cyclic ring which may contain from 1 to 2 heteroatoms in the ring skeleton and which may be fused to a benzene or pyridine ring;   D is selected from the group consisting of (C1-6)alkyl and (C2-6)alkenyl; wherein said (C1-6)alkyl and (C2-6)alkenyl are optionally substituted with one to three same or different halogens or from one to three same or different substituents selected from the group consisting of C(O)NR55R56, hydroxy, cyano and XR57;   X is NH, NCH3 O or S;   E is selected from the group consisting of (C1-6)alkyl and (C2-6)alkenyl; wherein said (C1-6)alkyl and (C2-6)alkenyl are independently optionally substituted with a member selected from the group consisting of phenyl, heteroaryl, SMe, SPh,  -- C(O)NR56R57, C(O)R57, SO2(C1-6)alkyl and SO2Ph; wherein heteroaryl is a monocyclic system which contains from 3 to 7 ring atoms, including from 1 to 4 heteroatoms;   F is selected from the group consisting of (C1-6)alkyl, (C3-7)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C1-6)alkoxy, aryloxy, (C1-6)thioalkoxy, cyano, halogen, nitro,  -- C(O)R57, benzyl,  -- NR42C(O) -- (C1-6)alkyl,  -- NR42C(O) -- (C3-6)cycloalkyl,  -- NR42C(O)-aryl,  -- NR42C(O)-heteroaryl,  -- NR42C(O)-heteroalicyclic, a 4, 5, or 6 membered ring cyclic N-lactam,  -- NR42S(O)2 -- (C1-6)alkyl,  -- NR42S(O)2 -- (C3-6)cycloalkyl,  -- NR42S(O)2-aryl,  -- NR42S(O)2-heteroaryl,  -- NR42S(O)2-heteroalicyclic, S(O)2(C1-6)alkyl, S(O)2aryl,  -- S(O)2NR42R43, NR42R43, (C1-6)alkylC(O)NR42R43, C(O)NR42R43, NHC(O)NR42R43, OC(O)NR42R43, NHC(O)OR54, (C1-6)alkylNR42R43, COOR54, and (C1-6)alkylCOOR54; wherein said (C1-6)alkyl, (C3-7)cycloalkyl, aryl, heteroaryl, heteroalicyclic, (C1-6)alkoxy, and aryloxy, are optionally substituted with one to nine same or different halogens or from one to five same or different substituents selected from the group G; wherein aryl is phenyl; heteroaryl is a monocyclic system which contains from 3 to 7 ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, and morpholine;   G is selected from the group consisting of (C1-6)alkyl, (C3-7)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C1-6)alkoxy, aryloxy, cyano, halogen, nitro,  -- C(O)R57, benzyl,  -- NR48C(O) -- (C1-6)alkyl,  -- NR48C(O) -- (C3-6)cycloalkyl,  -- NR48C(O)-aryl,  -- NR48C(O)-heteroaryl,  -- NR48C(O)-heteroalicyclic, a 4, 5, or 6 membered ring cyclic N-lactam,  -- NR48S(O)2-(C1-6)alkyl,  -- NR48S(O)2 -- (C3-6)cycloalkyl,  -- NR48S(O)2-aryl,  -- NR48S(O)2-heteroaryl,  -- NR48S(O)2-heteroalicyclic, sulfinyl, sulfonyl, sulfonamide, NR48R49, (C1-6)alkyl C(O)NR48R49, C(O)NR48R49, NHC(O)NR48R49, OC(O)NR48R49, NHC(O)OR54', (C1-6)alkylNR48R49, COOR54, and (C1-6)alkylCOOR54; wherein aryl is phenyl; heteroaryl is a monocyclic system which contains from 3 to 7 ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, and morpholine;   R7 is selected from the group consisting of aryl, heteroaryl, and heteroalicyclic; wherein said aryl, heteroaryl, and heteroalicyclic are optionally substituted with one to three same or different halogens or with from one to three same or different substituents selected from the group F; wherein for R7, R8, R8a, R8b aryl is phenyl; heteroaryl is a mono or bicyclic system which contains from 3 to 7 ring atoms for mono cyclic systems and up to 10 atoms in a bicyclic system, including from 1 to 4 heteroatoms; wherein heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, and morpholine;   R8 is selected from the group consisting of hydrogen, (C1-6)alkyl, (C3-7)cycloalkyl, (C2-6)alkenyl, (C3-7)cycloalkenyl, (C2-6)alkynyl, aryl, heteroaryl, and heteroalicyclic; wherein said (C1-6)alkyl, (C3-7)cycloalkyl, (C2-6)alkenyl, (C3-7)cycloalkenyl, (C2-6)alkynyl, aryl, heteroaryl, and heteroalicyclic are optionally substituted with one to six same or different halogens or from one to five same or different substituents selected from the group F;   R8a is a member selected from the group consisting of aryl, heteroaryl, and heteroalicyclic; wherein each member is independently optionally substituted with one to six same or different halogens or from one to five same or different substituents selected from the group F;   R8b is selected from the group consisting of hydrogen, (C1-6)alkyl and phenyl;   R40 and R41 are independently selected from the group consisting of   (a) hydrogen;   (b) (C1-6)alkyl or (C3-7)cycloalkyl substituted with one to three same or different halogens or from one to two same or different substituents selected from the group F; and   (c) (C1-6)alkoxy, aryl, heteroaryl or heteroalicyclic; or R40 and R41 taken together with the nitrogen to which they are attached form a member selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, 4-NMe piperazine, piperidine, azepine, and morpholine; and wherein said aryl, heteroaryl, and heteroalicyclic are optionally substituted with one to three same or different halogens or from one to two same or different substituents selected from the group F; wherein for R40 and R41 aryl is phenyl; heteroaryl is a monocyclic system which contains from 3 to 6 ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, and morpholine; provided when B is C(O)NR40R41, at least one of R40 and R41 is not selected from groups (a) or (b);   R42 and R43 are independently selected from the group consisting of hydrogen, (C1-6)alkyl, allyl, (C1-6)alkoxy, (C3-7)cycloalkyl, aryl, heteroaryl and heteroalicyclic; or R42 and R43 taken together with the nitrogen to which they are attached form a member selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, 4-NMe piperazine, piperidine, azepine, and morpholine; and wherein said (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl, heteroaryl, and heteroalicyclic are optionally substituted with one to three same or different halogens or from one to two same or different substituents selected from the group G; wherein for R42 and R43 aryl is phenyl; heteroaryl is a monocyclic system which contains from 3 to 6 ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic is a member selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, and morpholine;   R46 is selected from the group consisting of H, OR57, and NR55R56;   R47 is selected from the group consisting of H, amino, halogen, phenyl, and (C1-6)alkyl;   R48 and R49 are independently selected from the group consisting of hydrogen, (C1-6)alkyl and phenyl;   R54 is selected from the group consisting of hydrogen and (C1-6)alkyl;   R56 is independently selected from the group consisting of hydrogen and (C1-6)alkyl; and   R57 is selected from the group consisting of hydrogen, (C1-6)alkyl and phenyl, where A is selected from the group consisting of C1-6alkoxy, aryl and heteroaryl; in which said aryl is phenyl or naphthyl; said heteroaryl is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, furanyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, benzoimidazolyl and benzothiazolyl; and said aryl or heteroaryl is optionally substituted with one or two of the same or different members selected from the group consisting of amino, nitro, cyano, hydroxy, C1-6alkoxy,  -- C(O)NH2, C1-6alkyl,  -- NHC(O)CH3, halogen and trifluoromethyl; and   R9, R10, R11, R12, R13, R14, R15 and R16 are each independently H or (C1-6)alkyl which may be optionally substituted with 1 to 3 same or different halogens;    which comprises subjecting compound C as defined in claim 1 of the structure       to a Grignard acylation reaction wherein acid chloride 1       is reacted with compound C to form compound D       and reacting compound D with a compound of the structure Da       in the presence of an organometallic base to form compound IA. 4. The process as defined in claim 3 wherein the Grignard acylation reaction is carried out in the presence of C2H5MgCl, in an organic solvent, 2-CH3THF and organic base, wherein the Grignard acylation reaction is carried out at a temperature within the range from about -50 to about -40 deg. C.,   where in compounds E, C and D, R2 is CH3O, R1 is H and R3 is H and   wherein the reaction of D and Da is carried out at a temperature within the range from about -5 to about 5 deg. C. 5. A process for preparing compound IIA having the structure       wherein R18 is H or alkyl, R1, R2 and R3 are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, COOR56, XR57, C(O)R7, C(O)NR55R56, B, D, and E; B is selected from the group consisting of  -- C(.dbd.NR46)(R47), C(O)NR40R41, aryl, heteroaryl, heteroalicyclic, S(O)2R8, C(O)R7, XR8a, (C1-6)alkylNR40R41, (C1-6)alkylCOOR8b; wherein said aryl, heteroaryl, and heteroalicyclic are optionally substituted with one to three same or different halogens or from one to three same or different substituents selected from the group F; wherein aryl is naphthyl or substituted phenyl; wherein heteroaryl is a mono or bicyclic system which contains from 3 to 7 ring atoms for a mono cyclic system and up to 12 atoms in a fused bicyclic system, including from 1 to 4 heteroatoms; wherein heteroalicyclic is a 3 to 7 membered mono cyclic ring which may contain from 1 to 2 heteroatoms in the ring skeleton and which may be fused to a benzene or pyridine ring;   D is selected from the group consisting of (C1-6)alkyl and (C2-6)alkenyl; wherein said (C1-6)alkyl and (C2-6)alkenyl are optionally substituted with one to three same or different halogens or from one to three same or different substituents selected from the group consisting of C(O)NR55R56, hydroxy, cyano and XR57;   E is selected from the group consisting of (C1-6)alkyl and (C2-6)alkenyl; wherein said (C1-6)alkyl and (C2-6)alkenyl are independently optionally substituted with a member selected from the group consisting of phenyl, heteroaryl, SMe, SPh,  -- C(O)NR56R57, C(O)R57, SO2(C1-6)alkyl and SO2Ph; wherein heteroaryl is a monocyclic system which contains from 3 to 7 ring atoms, including from 1 to 4 heteroatoms;   X is NH, NCH3, O or S;   F is selected from the group consisting of (C1-6)alkyl, (C3-7)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C1-6)alkoxy, aryloxy, (C1-6)thioalkoxy, cyano, halogen, nitro,  -- C(O)R57, benzyl,  -- NR42C(O) -- (C6)alkyl,  -- NR42C(O) -- (C3-6)cycloalkyl,  -- NR42C(O)-aryl,  -- NR42C(O)-heteroaryl,  -- NR42C(O)-heteroalicyclic, a 4,5, or 6 membered ring cyclic N-lactam,  -- NR42S(O)2 -- (C1-6)alkyl,  -- NR42S(O)2 -- (C3-6)cycloalkyl,  -- NR42S(O)2-aryl,  -- NR42S(O)2-heteroaryl,  -- NR42S(O)2-heteroalicyclic, S(O)2(C1-6)alkyl, S(O)2aryl,  -- S(O)2NR42R43, NR42R43, (C1-6)alkylC(O)NR42R43, C(O)N42R43, NHC(O)NR42R43, OC(O)NR42R43, NHC(O)OR54, (C1-6)alkylNR42R43, COOR54, and (C1-6)alkylCOOR54; wherein said (C1-6)alkyl, (C3-7)cycloalkyl, aryl, heteroaryl, heteroalicyclic, (C1-6)alkoxy, and aryloxy, are optionally substituted with one to nine same or different halogens or from one to five same or different substituents selected from the group G; wherein aryl is phenyl; heteroaryl is a monocyclic system which contains from 3 to 7 ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, and morpholine;   G is selected from the group consisting of (C1-6)alkyl, (C3-7)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C1-6)alkoxy, aryloxy, cyano, halogen, nitro,  -- C(O)R57, benzyl,  -- NR48C(O) -- (C1-6)alkyl,  -- NR48C(O) -- (C3-6)cycloalkyl,  -- NR48C(O)-aryl,  -- NR48C(O)-heteroaryl,  -- NR48C(O)-heteroalicyclic, a 4,5, or 6 membered ring cyclic N-lactam,  -- NR48S(O)2 -- (C1-6)alkyl,  -- NR48S(O)2 -- (C3-6)cycloalkyl,  -- NR48S(O)2-aryl,  -- NR48S(O)2-heteroaryl,  -- NR48S(O)2-heteroalicyclic, sulfinyl, sulfonyl, sulfonamide, NR48R49, (C1-6)alkyl C(O)NR48R49, C(O)NR48R49, NHC(O)NR48R49, OC(O)NR48R49, NHC(O)OR54', (C1-6)alkylNR48R49, COOR54, and (C1-6)alkylCOOR54; wherein aryl is phenyl; heteroaryl is a monocyclic system which contains from 3 to 7 ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, and morpholine;   R7 is selected from the group consisting of aryl, heteroaryl, and heteroalicyclic; wherein said aryl, heteroaryl, and heteroalicyclic are optionally substituted with one to three same or different halogens or with from one to three same or different substituents selected from the group F; wherein for R7, R8, R8a, R8b aryl is phenyl; heteroaryl is a mono or bicyclic system which contains from 3 to 7 ring atoms for mono cyclic systems and up to 10 atoms in a bicyclic system, including from 1 to 4 heteroatoms; wherein heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, and morpholine;   R8 is selected from the group consisting of hydrogen, (C1-6)alkyl, (C3-7)cycloalkyl, (C2-6)alkenyl, (C3-7)cycloalkenyl, (C2-6)alkynyl, aryl, heteroaryl, and heteroalicyclic; wherein said (C1-6)alkyl, (C3-7)cycloalkyl, (C2-6)alkenyl, (C3-7)cycloalkenyl, (C2-6)alkynyl, aryl, heteroaryl, and heteroalicyclic are optionally substituted with one to six same or different halogens or from one to five same or different substituents selected from the group F;   R8a is a member selected from the group consisting of aryl, heteroaryl, and heteroalicyclic; wherein each member is independently optionally substituted with one to six same or different halogens or from one to five same or different substituents selected from the group F;   R8b is selected from the group consisting of hydrogen, (C1-6)alkyl and phenyl;   R40 and R41 are independently selected from the group consisting of   (a) hydrogen;   (b) (C1-6)alkyl or (C3-7)cycloalkyl substituted with one to three same or different halogens or from one to two same or different substituents selected from the group F; and   (c) (C1-6)alkoxy, aryl, heteroaryl or heteroalicyclic; or R40 and R41 taken together with the nitrogen to which they are attached form a member selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, 4-NMe piperazine, piperidine, azepine, and morpholine; and wherein said aryl, heteroaryl, and heteroalicyclic are optionally substituted with one to three same or different halogens or from one to two same or different substituents selected from the group F; wherein for R40 and R41 aryl is phenyl; heteroaryl is a monocyclic system which contains from 3 to 6 ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, and morpholine; provided when B is C(O)NR40R41, at least one of R40 and R41 is not selected from groups (a) or (b);   R42 and R43 are independently selected from the group consisting of hydrogen, (C1-6)alkyl, allyl, (C1-6)alkoxy, (C3-7)cycloalkyl, aryl, heteroaryl and heteroalicyclic; or R42 and R43 taken together with the nitrogen to which they are attached form a member selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, 4-NMe piperazine, piperidine, azepine, and morpholine; and wherein said (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl, aryl, heteroaryl, and heteroalicyclic are optionally substituted with one to three same or different halogens or from one to two same or different substituents selected from the group G; wherein for R42 and R43 aryl is phenyl; heteroaryl is a monocyclic system which contains from 3 to 6 ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic is a member selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, and morpholine;   R46 is selected from the group consisting of H, OR57, and NR55R56;   R47 is selected from the group consisting of H, amino, halogen, phenyl, and (C1-6)alkyl;   R48 and R49 are independently selected from the group consisting of hydrogen, (C1-6)alkyl and phenyl;   R54 is selected from the group consisting of hydrogen and (C1-6)alkyl;   R56 is independently selected from the group consisting of hydrogen and (C1-6)alkyl; and   R57 is selected from the group consisting of hydrogen, (C1-6)alkyl and phenyl, where A is selected from the group consisting of C1-6alkoxy, aryl and heteroaryl; in which said aryl is phenyl or naphthyl; said heteroaryl is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, ftzranyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, benzoimidazolyl and benzothiazolyl; and said aryl or heteroaryl is optionally substituted with one or two of the same or different members selected from the group consisting of amino, nitro, cyano, hydroxy, C1-6alkoxy,  -- C(O)NH2, C1-6alkyl,  -- NHC(O)CH3, halogen and trifluoromethyl; and   R9, R10, R11, R12, R13, R14, R15 and R16 are each independently H or (C1-6)alkyl which may be optionally substituted with 1 to 3 same or different halogens; which comprises subjecting compound H as defined in claim 1 of the structure        to a Grignard acylation reaction wherein acid chloride 1       is reacted with compound H to form compound L       and reacting compound L with a compound Da of the structure       in the presence of an organometallic base to form compound IIA. 6. The process as defined in claim 5 wherein the Grignard acylation reaction is carried out in the presence of C2H5MgCl in an organic solvent, 2-CH3THF and organic base, wherein the Grignard acylation reaction is carried out at a temperature within the range from about -40 to about -50 deg. C.,   where in compounds IIA, L and H, R2 is F, and R3 is H and   wherein the reaction of compound L and compound Da is carried out at a temperature within the range from about -5 to about 5 deg. C. 7. A pharmaceutical formulation in the form of an aqueous oral suspension comprising: a) the crystalline form of the 1,2,3-triazine derivative IIA having the structure    b) 6.25% w/v Microcrystalline Cellulose;   c) 0.0001% w/v Denatonium Benzoate; and   d) Purified Water, or Water for Injection; wherein said crystalline form is the N-1 form of the free base, and is characterized by one or more of the following:   a) unit cell parameters substantially equal to the following:    Cell Dimensions: a=39.2481(14) .ANG.   b=5.5577(2) .ANG.   c=21.8072(10) .ANG.   alpha =90 deg.   beta =122.399(4)  deg.   gamma =90 deg.   Space group C2/c    wherein said crystalline form is at about 25 deg. C.; b) fractional atomic coordinates substantially as listed in Table 2;   c) a powder X-ray diffraction pattern substantially in accordance with that shown in FIG. 5;   d) a powder X-ray diffraction pattern comprising the following typical and representative 2theta  values (CuKalpha  lambda =1.5418 .ANG.) 5.3+-0.1, 8.1+0.1, 9.6+-0.1, 16.2+-0.1, 17.0+-0.1, 19.6+-0.1, 20.7+-0.1 and 23.0+-0.1 at about room temperature;   e) a differential scanning calorimetry thermogram substantially in accordance with that shown in FIG. 6;   f) a thermal gravimetric analysis curve substantially in accordance with that shown in FIG. 7; and/or   g) a moisture-sorption isotherm substantially as shown in FIG. 8. 8. A process for preparing a stabilized amorphous form of a 1,2,3-triazole derivative IIA having the structure   which comprises flash evaporating or spray drying a solution of the crystalline Form N-1 of the 1,2,3-triazole derivative and a stabilizer in an organic solvent and recovering the stabilized amorphous form of the 1,2,3-triazole derivative II; wherein said crystalline Form N-1 is characterized by one or more of the following:   a) unit cell parameters substantially equal to the following:    Cell Dimensions: a=39.2481(14) .ANG.   b=5.5577(2) .ANG.   c=21.8072(10) .ANG.   alpha =90 deg.   beta =122.399(4) deg.   gamma =90 deg.   Space group C2/c    wherein said crystalline form is at about 25 deg. C.; b) fractional atomic coordinates substantially as listed in Table 2;   c) a powder X-ray diffraction pattern substantially in accordance with that shown in FIG. 5;   d) a powder X-ray diffraction pattern comprising the following typical and representative 2theta  values (CuKalpha  lambda =1.5418 .ANG.) 5.3+-0.1, 8.1+0.1, 9.6+-0.1, 16.2+-0.1, 17.0+-0.1, 19.6+-0.1, 20.7+-0.1 and 23.0+-0.1 at about room temperature;   e) a differential scanning calorimetry thermogram substantially in accordance with that shown in FIG. 6;   f) a thermal gravimetric analysis curve substantially in accordance with that shown in FIG. 7; and/or   g) a moisture-sorption isotherm substantially as shown in FIG. 8. 9. The process as defined in claim 8 wherein the stabilizer is polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer, or polyvinylpyrrolidone-vinyl acetate copolymer and d-alpha -tocopheryl polyethylene glycol 1000 succinate. 11. A pharmaceutical formulation comprising the 1,2,3-triazole derivative II prepared as defined in claim 8 in the form of a spray-dried intermediate, a filler, a disintegrant, a dissolution enhancer and a lubricant. 12. A process for preparing the N-1 crystalline form of the 1,2,3-triazole derivative IIA of the structure II       as defined in claim 7, which comprises dissolving or slurrying or suspending the 1,2,3-triazole derivative IIA in an aqueous organic solvent or organic solvent to form a solution, slurry or suspension of the 1,2,3-triazole derivative II, removing the solvent and recovering the 1,2,3-triazole derivative II in the form of Form N-1 crystals, wherein the solvent employed is water/ethanol, acetonitrile, acetonitrile/methanol, dichloromethane, methanol, ethanol, and/or isopropyl alcohol.
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