HK1107343B - Bicyclic heterocycles as hiv integrase inhibitors - Google Patents

Description

Bicyclic heterocycles as HIV integrase inhibitors

Cross reference to related applications

This application claims the benefit of U.S. provisional application serial No. 60/603,371, filed on 8/20/2004 and 60/575,513, filed on 5/28/2004.

Background

Human Immunodeficiency Virus (HIV) has been identified as the causative agent responsible for the Acquired Immune Deficiency Syndrome (AIDS), an incurable disease characterized by destruction of the immune system and failure to combat life-threatening opportunistic infections. Recent statistics (UNAIDS: Report on the Global HIV/AIDS Epidemic, 12 months 1998) show that up to thirty-three million people worldwide are infected with the virus. In addition to a large number of individuals already infected, the virus continues to spread. The 1998 evaluation indicated that nearly 6 million new infections were present in only that year. In the same year, approximately 250 million people die, and these people are associated with HIV and AIDS.

A large number of antiviral drugs are currently available to combat infections. These drugs can be divided into three categories based on the viral proteins they target and their mode of action. In particular, saquinavir, indinavir, ritonavir, nelfinavir and amprenavir (amprenavir) are competitive inhibitors of aspartyl protease expressed by HIV. Zidovudine, didanosine, stavudine, lamivudine, zalcitabine and abacavir (abacavir) are nucleoside reverse transcriptase inhibitors, which correspond to substrate mimetics that interrupt viral cDNA synthesis. Non-nucleoside reverse transcriptase inhibitors, nevirapine (nevaripine), delavirdine and efavir inhibit the synthesis of viral cDNA by a non-competitive (or non-competitive) mechanism. These drugs alone are effective in reducing viral replication. This effect is only temporary, since the virus is easily tolerized to all known agents. However, in a large number of patients, combination therapy has proven to be very effective in both reducing the virus and suppressing the appearance of tolerance. The number of HIV-associated deaths has decreased in the united states where combination therapy is commonly available (Palella, f.j.; Delany, k.m.; Moorman, a.c.; loveliness, m.o.; Furher, j.; Satten, g.a.; Aschman, d.j.; Holmberg, s.d.n.engl.j.med.1998, 338, 853-.

Unfortunately, not all patients are responsive, and this treatment is ineffective in a large number of patients. In fact, approximately 30-50% of patients eventually fail combination therapy. In most cases, the emergence of viral tolerance causes treatment failure. In turn, viral tolerance is caused by the rapid turnover of HIV-1 during infection combined with a high viral mutation rate. In this case, incomplete viral suppression, caused by inadequate drug efficacy, poor compliance with complex drug systems, and inherent pharmacological exposure barriers, provides fertile soil for the emergence of tolerance. More interference was recently found, which indicated that low levels of replication continued even when viral plasma levels had decreased below detectable levels (< 50 copies/ml) (Carpenter, C.C.; Cooper, D.A.; Fischl, M.A.; Gatel, J.M.; Gazzard, B.G.; Hammer, S.M.; Hirsch, M.S.; Jacobsen, D.M.; Katzenstein, D.A.; Montaner, J.S.; Richman, D.D.; Saag, M.S.; Schhtager, M.Schooley, R.T.; Thompson, M.A.; Vella, S.; Yeni, P.G.; Volberding, P.A.JAMA, 2000, 283, 390). Clearly, there is a need for new antiviral agents, preferably targeting other viral enzymes, to further reduce the rate of tolerance and inhibit viral replication.

HIV expresses three enzymes: reverse transcriptase, aspartyl protease and integrase. All three of these are targets for treatment of AIDS and HIV infection. HIV integrase catalyzes the insertion of viral cDNA into the host cell genome, a critical step in the viral life cycle. HIV integrase inhibitors belong to a class of diketonic acid compounds that prevent viral integration in cells and inhibit HIV-1 replication (Hazuda et al Science 2000, 287, 646). Recently, HIV integrase inhibitors have been accepted into clinical trials for the treatment of AIDS and HIV infection (neamuli expert. opin. ther. patents 2002, 12, 709, Pais and Burke drugs fut.2002, 27, 1101).

Description of the invention

The present invention includes compounds of formula I, including pharmaceutically acceptable salts and solvates, their pharmaceutical compositions, and their use in inhibiting HIV integrase and in the treatment of HIV or AIDS infection.

One aspect of the present invention are compounds of formula I

Wherein:

R¹is C_1-6(Ar¹) Alkyl radical, C_1-6(Ar¹)(CON(R⁸)(R⁹) Alkyl radical, C_1-6(Ar¹)(CO₂R¹⁴) Alkyl radical, C_1-6(Ar¹) Hydroxyalkyl, or C_1-6(Ar¹) An oxyalkyl group;

R²is hydrogen, C_1-6Alkyl, OR OR¹⁴；

R³Is hydrogen, halogen, hydroxy, cyano, C_1-6Alkyl radical, C_3-7Cycloalkyl radical, C_5-7Cycloalkenyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C _1-6Alkylthio radical, C_1-6Haloalkoxy, N (R)⁸)(R⁹)，NHAr²，N(R⁶)SO₂R⁷，N(R⁶)COR⁷，N(R⁶)CO₂R⁷，OCOR⁷，OCO₂R⁷，OCON(R⁸)(R⁹)，OCH₂CO₂R⁷，OCH₂CON(R⁸)(R⁹)，COR⁶，CO₂R⁶，CON(R⁸)(R⁹)，SOR⁷，S(＝N)R⁷，SO₂R⁷，SO₂N(R⁶)(R⁶)，PO(OR⁶)₂，C_2-4(R¹²) Alkynyl radical, R¹³，Ar²Or Ar³；

R⁴Is hydrogen, halogen, hydroxy, cyano, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, or N (R)⁶)(R⁶)；

R⁵Is hydrogen, halogen, hydroxy, cyano, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, or N (R)⁶)(R⁶)；

R⁶Is hydrogen, C_1-6Alkyl, or C_3-7A cycloalkyl group;

R⁷is C_1-6Alkyl or C_3-7A cycloalkyl group;

R⁸is hydrogen, C_1-6Alkyl radical, C_1-6Hydroxyalkyl radical, C_1-6(C_1-6Alkoxy) alkyl or C_1-6(C_1-6Dialkylamino) alkyl;

R⁹is hydrogen, C_1-6Alkyl radical, C_1-6Hydroxyalkyl radical, C_1-6(C_1-6Alkoxy) alkyl or C_1-6(C_1-6Dialkylamino) alkyl; or

N(R⁸)(R⁹) Taken together are azetidinyl, pyrrolidinyl, (R)¹⁰) -piperidinyl, N- (R)¹¹) -piperazinyl, morpholinyl, thiomorpholinyl, or dioxothiazinyl;

R¹⁰is hydrogen, C_1-6Alkyl, orC_1-6A hydroxyalkyl group;

R¹¹is hydrogen, C_1-6Alkyl radical, C_3-7Cycloalkyl radical, COR⁶Or CO₂R⁶；

R¹²Is hydrogen, hydroxy, N (R)⁶)(R⁶)，SO₂R⁷，OSO₂R⁷Or dioxothiazinyl;

R¹³is azetidinone, pyrrolidinone, valerolactam, caprolactam, maleimidyl, oxazolidone, or dioxothiazinyl and is substituted with 0-1 substituent selected from hydroxymethyl, acetoxymethyl, and aminomethyl;

R¹⁴is hydrogen or C _1-6An alkyl group;

Ar¹is that

Ar²Is tetrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, furyl, thienyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridyl, hydroxypyridinyl, quinolinyl, isoquinolinyl, or indolyl, and is substituted with 0-2 substituents selected from the group consisting of: halogen, cyano, benzyl, C_1-6Alkyl radical, C_1-6Alkoxy radical, N (R)⁸)(R⁹)，CON(R⁸)(R⁹)，CO₂R⁶，CONHSO₂N(R⁶)(R⁶)，CONHSO₂N(R⁶) (phenyl), and CONHSO₂N(R⁶) (halophenyl);

Ar³is phenyl substituted with 0-2 substituents selected from: halogen, cyano, hydroxy，C_1-6Alkyl radical, C_1-6Alkoxy group, (C)_1-6Alkoxy) methyl, C_1-6Haloalkyl, C_1-6Haloalkoxy, N (R)⁸)(R⁹)，CON(R⁶)(R⁶) And CH₂N(R⁸)(R⁹) Or is dioxolanylphenyl; and

X-Y-Z is C (R)¹⁴)₂OC(R¹⁴)₂，C(R¹⁴)₂OC(R¹⁴)₂C(R¹⁴)₂Or C (R)¹⁴)₂OC(R¹⁴)₂C(R¹⁴)₂C(R¹⁴)₂；

Or a pharmaceutically acceptable salt or solvate thereof.

Another aspect of the present invention is wherein R is¹Is C_1-6(Ar¹) Alkyl compounds of formula I.

Another aspect of the invention are compounds of formula I, wherein R¹Is that

Another aspect of the invention are compounds of formula I, wherein R¹Is that

Another aspect of the invention are compounds of formula I, wherein R²Is hydrogen.

Another aspect of the invention are compounds of formula I, wherein R³Is hydrogen, halogen, N (R) ⁸)(R⁹)，N(R⁶)COR⁷，OCON(R⁸)(R⁹)，CON(R⁸)(R⁹)，SOR⁷，SO₂R⁷，SO₂N(R⁶)(R⁶)，PO(OR⁶)₂，R¹³Or Ar²。

Another aspect of the invention are compounds of formula I, wherein X-Y-Z is C (R)¹⁴)₂OCH₂，C(R¹⁴)₂OCH₂CH₂Or C (R)¹⁴)₂OCH₂CH₂CH₂。

Another aspect of the invention are compounds of formula I, wherein X-Y-Z is CH₂OCH₂，C(CH₃)HOCH₂，C(CH₃)₂OCH₂，CH₂OCH₂CH₂，C(CH₃)HOCH₂CH₂，C(CH₃)₂OCH₂CH₂，CH₂OCH₂CH₂CH₂，C(CH₃)HOCH₂CH₂CH₂Or C (CH)₃)₂OCH₂CH₂CH₂。

For compounds of formula I, R¹，R²，R³，R⁴，R⁵，R⁶，R⁷，R⁸，R⁹，R¹⁰，R¹¹，R¹²，R¹³，R¹⁴，Ar¹，Ar²，Ar³And any range of X-Y-Z, may be used independently with any range of any other substituent.

"alkyl", "alkoxy", "hydroxyalkyl" and related terms with an alkyl moiety include both straight and branched chain configurations. Terms such as "C_1-6(R) alkyl "means a straight or branched chain alkyl of one to six carbons substituted by substituent R. "haloalkyl" and "halophenyl" include all substitutions from monohalo to perhaloalkyl or phenyl. "aryl" refers to aromatic ring systems, including carbocyclic and heterocyclic systems. Some substituents are divalent, such as X-Y-Z. The asymmetric divalent substituents may be attached in either configuration.

“C_1-6(Ar¹) The "oxyalkyl" is Ar¹Attached at the oxygen site.

"Dioxolanyl" means

"dioxothiazinyl" means

The invention includes all pharmaceutically acceptable salt forms of the compounds. Pharmaceutically acceptable salts are those in which the counter ion does not significantly affect the physiological activity or toxicity of the compound and thus serves a pharmacologically equivalent effect. These salts can be prepared according to conventional organic techniques using commercially available reagents. Some anionic salt forms include acetate, acetate stearate, benzenesulfonate, bromide, chloride, citrate, fumarate, glucuronate (glucuronate), hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, methanesulfonate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Some cationic salt forms include ammonium, aluminum, benzathine (benzathine), bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc salts.

The invention also includes all solvated forms, especially hydrates, of the compounds. Solvates do not significantly affect the physiological activity or toxicity of the compounds and therefore play a pharmacologically equivalent role. Solvates may be formed in stoichiometric amounts, or may be formed from extraneous solvents or a combination of both. One type of solvate is a hydrate, some hydrated forms include monohydrate, hemihydrate and dihydrate.

Some of the compounds of the present invention exist in stereoisomeric forms. The present invention includes all stereoisomeric forms of the compounds, including enantiomers and diastereomers. Examples of enantiomers are shown below. Methods for preparing and separating stereoisomers are known in the art.

The present invention includes all tautomeric forms of the compounds. Examples of tautomeric pairs are shown below.

Synthesis method

The compounds of the present invention can be prepared by various methods known in the art, including those in the following reaction schemes and in the detailed description. The variables shown in the synthetic reaction schemes are different from and should not be confused with the variables in the claims or the rest of the specification. The variables in the reaction schemes are meant only to illustrate how to prepare some of the compounds of the invention.

Some compounds can be synthesized according to scheme I from the appropriately substituted heterocycle I-1, where R is_aAnd P can act as a protecting group (see Greene, T.W. and Wutz, P.G.M.protective Groups in Organic Synthesis, second edition, 1991, John Wiley and sons, New York). When P is benzyl or substituted benzyl, it may be prepared by hydrogenolysis (H)₂-Pd/C) or acid hydrolysis (trifluoroacetic acid) to give intermediate I-2. By reaction with amine I-3, I-2 can be transaminated to I-4. In a large number of cases, the reaction can be carried out by heating I-3 and I-2 together in the presence of a base. Alternatively, standard amide coupling reagents can be used to effect amide bond formation. When R is_aWhen it is lower alkyl, R_aCan be removed under ester hydrolysis conditions, e.g., by treatment with NaOH, LiOH or KOH, to provide the corresponding carboxylic acid I-5. Or, R_aCan be removed by nucleophilic displacement using NaI. When R is_aWhen it is benzyl or substituted benzyl, R_aCan be removed by hydrogenolysis. Intermediate I-5 can be coupled using an amide bond forming reagent such as BOP, DCC, EDCI, PyBrop, PyBop or other reagents (see March, J.advanced organic chemistry, 4 th edition, 1992, John Wiley&Sons, New York). The resulting intermediate I-6 can be deprotected as described for intermediate I-1.

Reaction scheme I

In scheme II, intermediate II-3 can be used and described in Sunderland, J.S.; botta, m.; aime, S.; raymond, K.N.Inorg.chem. (2001), 40, 6756-6756. A. 6756 wherein II-1 and II-2 are condensed provides intermediate II-3. The reaction is typically carried out in the presence of a base such as sodium hydride (NaH), sodium ethoxide (EtONa) or lithium hexamethyldisilazide (LiHMDS). II-3 can be condensed with an appropriately substituted amidine II-4 to form II-5 using the methods described in the reference. Substituent B may be a leaving group, for example-halogen (Cl, Br or I), or may be converted to a leaving group under suitable conditions, for example by formation of the corresponding mesylate. When substituent B is a methylsulfide group, it can be treated with methyl iodide to form a dimethylsulfonium intermediate that is active for nucleophilic attack, effecting ring closure.

Reaction scheme II

In scheme III, intermediate II-3 can be condensed with a cyclic amidine to provide intermediate I-1. Intermediate III-1 can be prepared using known methods (see Patai, S. and Rappoport, Z. the Chemistry of amides and imides, Volume 2, 1991, John Wiley & Sons, New York).

Reaction scheme III

In scheme IV, a nitrile IV-1 having a latent leaving group B can be reacted with hydroxylamine to form intermediate IV-2. This intermediate can be reacted with an appropriately protected alkyne to form IV-3, and IV-3 can be rearranged according to literature procedures to form intermediate IV-4(Culbertson, T.P. journal of Heterocyclic Chemistry, 1979, 16, 1423-1424).

Reaction scheme IV

As shown in scheme V, 2- (methylthio) ethanol can be alkylated with a suitable α -haloacetic acid (V-1) to provide intermediate V-2, wherein X is a leaving group such as Cl, Br, OTs, OMs or OTf. After this, the carboxylic acids can be converted into the corresponding amidine derivatives using known synthetic methods (Geilen et al Tetrahedron Letters 2002, 43, 419-421). As described above, the amidine may be further reacted with intermediate V-5 in the presence of a base (e.g., sodium ethoxide) to give intermediate V-6. Methylation of the sulfide ether can be achieved by treating V-6 with methyl iodide and treating the resulting sulfonium derivative (V-7) with a base to form bicyclic template V-8. This intermediate can be used in the synthesis of the final compound using the procedures described in scheme I.

Reaction scheme V

In scheme VI, 3-methylthiopropanal is converted to dioxolane VI-1 using well-known chemistry. In the presence of zinc iodide (ZnI)₂) With trimethylsilyl cyanide (TMSCN) in the presence of a base to give intermediate VI-2. Reaction with ammonia affords the amidine VI-3, which VI-3 is used in the synthesis of pyrimidinone VI-4 according to the procedures described in the previous scheme. By CH₃SO₂Cl and triethylamine (Et)₃N) to yield the corresponding bicyclic intermediate VI-5. The synthesis can be concluded as illustrated in scheme I.

Reaction scheme VI

Another process is illustrated in scheme VII. This synthetic route starts from an appropriately substituted ketone, which can be converted to the corresponding nitrile intermediate VII-1. Which can then be reacted with 2-chloroethanol to produce compound VII-2, VII-2 can be reacted with hydroxylamine and acetylene dicarboxylate to provide intermediate VII-4. This intermediate was heated to give intermediate VII-5. The synthesis of the corresponding amide derivatives can be accomplished according to scheme I.

Reaction scheme VII

As a method for protecting the functional group in scheme VIII, basic conditions (e.g., K) can be used₂CO₃Or NaH), benzylbromide is used to benzylate the hydroxy group of VII-5. Saponification of the ester group of VIII-1 to provide VIII-2, can be used Known amide bond-forming reagents such as benzotriazol-1-yloxy-tri-pyrrolidinyl-phosphonium hexafluorophosphate (PyBOP) or O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), VIII-2 can be reacted with an appropriately substituted amine (R-R)¹R²NH) coupling. Alternatively, the corresponding acid chloride may be formed by treatment with oxalyl chloride and reacted with a suitable amine to form an amide bond. Under a variety of conditions, including with CF₃CO₂H or H₂The benzyl group can be removed by (Pd-C) treatment.

Reaction scheme VIII

In yet another method, some compounds of the present invention can be synthesized according to scheme IX. In scheme IX, pyrimidinone IX-3 can be prepared using methods similar to those described in the previous scheme. This intermediate can be continued to the final product by various routes. In one route, hydroxy can be benzoylated to provide intermediate IX-4, which can be prepared using K₂CO₃IX-4 was further processed to effect a closed loop to form a bicyclic template IX-5. Or, with K₂CO₃Direct treatment of IX-3 may provide intermediate IX-6. Using the procedure described in scheme I, intermediates IX-5, IX-6 can be used for the synthesis of the final products.

Scheme IX

In scheme X, IX-3 can be used for the synthesis of benzylated intermediate X-1. This intermediate can be continued to the final product using methods similar to those described in scheme VIII.

Reaction scheme X

The synthesis of (2- (aminomethyl) -5-fluorophenyl) (morpholino) methanone hydrochloride is illustrated in scheme XI.

Reaction scheme XI

In scheme XII, the bicyclic intermediate XII-1, prepared as described above, can be saponified using well-known methods. The resulting carboxylic acid XII-3 is then coupled with an amine XII-2 using standard amide bond forming reagents and methods. The benzyl groups are removed by hydrogenolysis or acid mediated hydrolysis to provide the final product.

Scheme XII

In scheme XIII, alternative routes to compounds similar to those present in scheme XII are given. In this scheme, the ester group of XIII-1 can be hydrolyzed and the resulting carboxylic acid coupled with methyl 2- (aminomethyl) -5-fluorobenzoate. A second hydrolysis reaction can produce XIII-4, which can be coupled with a second amine. The benzyl group is then removed to provide the final product.

Reaction scheme XIII

In yet another approach, scheme XIV illustrates the synthesis of sulfonamide-containing examples starting from 5-fluoro-2-methylbenzene-1-sulfonylamide.

Scheme XIV

Further illustration of the methods for synthesizing certain compounds of the present invention is shown in scheme XV. Methylation of 5- (2-bromo-5-fluorophenyl) -1H-tetrazole can give a mixture of XV-1 and XV-2, which can be isolated and continued to the corresponding end product.

Reaction scheme XV

Some diazirine (diazarine) and diaziridine (diaziradine) analogs can be synthesized according to scheme XVI.

Reaction scheme XVI

Some embodiments of the invention may be synthesized according to the methods illustrated in schemes XVII-XX.

Reaction scheme XVII

Reaction scheme XVIII

Reaction scheme XIX

Reaction scheme XX

In scheme XXI, 2-bromo-benzonitrile or 2-bromo-4-fluoro-benzonitrile can be coupled with a suitable amide to provide XXI-1. Reduction of the cyano group can provide XXI-2, which can be used for synthesis of the final product according to the methods described in the previous schemes. In most cases, it is not necessary to isolate compound XXI-1, which can be carried directly into the coupling reaction to form XXI-3.

Reaction scheme XXI

The examples and methods shown in scheme XXII are similar to those described in scheme XXI.

Reaction scheme XXII

Schemes XXIV and XXV further illustrate methods for synthesizing some of the compounds of the present invention.

Reaction scheme XXIV

Reaction scheme XXV

In scheme XXVI, intermediate XXVI-1 can be used to synthesize intermediate XXVI-2 by palladium catalyzed coupling. These intermediates may be further modified to provide certain compounds of the invention.

Reaction scheme XXVI

Another process is illustrated in scheme XXVII.

Reaction scheme XXVII

In scheme XXVIII, compound XXVIII-1 can be converted to the corresponding mesylate derivative XXVIII-2, which can then be treated with sodium azide to afford XXVIII-3. This compound can then serve as an intermediate for further transformations as illustrated in the reaction scheme.

Reaction scheme XXVIII

Certain embodiments of the invention can be synthesized according to the methods illustrated in schemes XXIX-XXXVIII.

Reaction scheme XXIX

Reaction scheme XXX

Reaction scheme XXXI

Reaction scheme XXXII

Reaction scheme XXXIII

Reaction scheme XXXIV

Reaction scheme XXXV

Reaction scheme XXXVI

Reaction scheme XXXVII

Reaction scheme XXXVIII

Biological method

To evaluate the in vitro activity against HIV-integrase, 5pmole of biotinylated substrate DNA was bound to 100. mu.g streptavidin-coated PVT SPA beads (Amersham Pharmacia Biotech). Recombinant integrase (0.26ng) was incubated with the pellet for 90 minutes at 37 ℃. The complex was washed to remove free enzyme and then inhibitor and 0.1fmol of P33-labeled targeting DNA were added. The reaction was stopped by adding EDTA to a final concentration of 10 mM. Samples were taken in TopCount NX T (packard) count, CPM was used as a measure of integration. The reaction conditions were as described in A.Engelman and R.Craigie, J.Virol.69, 5908-5911 (1995). The sequences of the substrate and the targeting DNA are described in nucleic acid Research 22, 1121-1122 (1994). The results are shown in Table 1. Activity equal to A means having IC₅₀0.002 to 0.10 μ M, and B and C each represent a compound having IC₅₀0.1 to 1.0 μ M and IC₅₀More than or equal to 1.0 mu M.

TABLE 1

Examples	Activity of
		1	A
2	A
		3	A
4	A
		5	A

Examples	Activity of
		6	A
7	A
		8	A
9	A
		10	A
11	A
		12	A
13	A
		14	A
15	A
		16	A
17	A
		18	A
19	A
		20	A
21	A
		22	B
23	A
		24	B
25	B
		26	A
27	A

Examples	Activity of
		28	A
Examples	Activity of
		29	A
30	A
		31	A
32	A
		33	A
34	A
		35	A
36	A
		37	A
38	A
		39	A
40	A
		41	A
42	A
		43	A
44	A
		45	A
46	A
		47	A
48	A

Examples	Activity of
		49	A
50	A
		51	A
52	A
		53	A
54	A
		55	A
56	A
		57	A
58	A
		Examples	Activity of
59	A
		60	A
61	A
		62	A
63	A
		64	A
65	A
		66	A
67	A
		68	A
69	A

Examples	Activity of
		70	A
71	A
		72	A
73	A
		74	A
75	A
		76	A
77	A
		78	A
79	A
		80	A
81	A
		82	A
83	C
		84	A
85	A
		86	A
87	A
		88	A
Examples	Activity of
		89	A
90	A

Examples	Activity of
		91	A
92	A
		93	A
94	A
		95	A
96	A
		97	A
98	A
		99	A
100	A
		101	A
102	A
		103	A
104	B
		105	A
106	A
		107	A
108	A
		109	A
110	A
		111	A
112	A

Examples	Activity of
		113	A
114	A
		115	A
116	A
		117	A
118	A
		Examples	Activity of
119	A
		120	A
121	A
		122	A
123	A
		124	A
125	A
		126	A
127	A
		128	A
129	A
		130	A
131	B
		132	A
133	B

Examples	Activity of
		134	A
135	A
		136	A
137	A
		138	A
139	A
		140	A
141	A
		142	A
143	A
		144	B
145	C
		146	A
147	A
		148	B
Examples	Activity of
		149	A
150	A
		151	A
152	A
		153	A
154	A

Examples	Activity of
		155	A
156	A
		157	A
158	A
		159	B
160	A
		161	A
162	A
		163	A
164	A
		165	A
166	B
		167	A
168	A
		169	A
170	A
		171	A
172	A
		173	A
174	A
		175	A
176	A

Examples	Activity of
		177	A
178	A
		Examples	Activity of
179	A
		180	A
181	A
		187	A
188	A
		189	A
190	A
		191	A
192	A
		193	A
194	A
		195	A
196	A
		197	A
198	A
		199	A
200	A
		201	A
202	A

Examples	Activity of
		203	A
204	A
		205	A
206	A
		207	A
208	A
		209	A
210	A
		211	A
212	A
		213	A
Examples	Activity of
		214	C
215	A
		216	A
217	A
		218	A
219	A
		220	A
221	A
		222	A
223	A

Examples	Activity of
		224	A
225	A
		226	A
227	A
		228	A
229	A
		230	A
231	A
		232	A
233	A
		234	A
235	A
		236	A
237	A
		238	A
239	A
		240	A
241	A
		242	A
243	A
		Examples	Activity of
244	A

Examples	Activity of
		245	A
246	A
		247	A
248	A
		249	A
250	A
		251	A
252	B
		253	C
254	A
		255	A
256	B
		257	A
258	A
		259	A
260	A
		261	A
262	A
		263	A
264	A
		265	A
266	A

Examples	Activity of
		267	A
268	A
		269	A
270	A
		271	A
272	A
		273	A
Examples	Activity of
		274	A
275	A
		276	A
277	A
		278	A
279	A
		280	A
281	A
		282	A

Recombinant NL-Rluc virus was established in which the nef gene part derived from NL4-3 was replaced with Renilla luciferase gene. NL-RLuc virus was prepared by co-transfection of two plasmids pNLRLuc and pVSvenv. pnlruc comprises NL-Rluc DNA cloned as pUC18 at the PvuII site, while pvvenv comprises the gene for the VSV G protein linked to the LTR promoter. Transfection was performed on 293T cells at a 1: 3 ratio of pNLRLuc to pVSV using the LipofectAMINE PLUS kit from Invitrogen (Carlsbad, CA) according to the manufacturer's instructions and the pseudotyped virus produced was titrated on MT-2 cells.

The sensitivity of the virus to the compound is determined by culturing in the presence of serial dilutions of the compound. The 50% Effective Concentration (EC) is calculated by using the exponential form of the median result equation₅₀) Wherein (Fa) ═ 1/[1+ (ED)₅₀Drug concentration^m](Johnson VA，Byington In technologies in HIV research Aldovini A, WalkerBD, edit 71-76.New York: stockton press.1990). Under three serum conditions, 10% FBS, 15mg/ml human serum albumin/10% FBS or 40% human serum/5% FBS, compounds were evaluated for antiviral activity, and the results of at least 2 experiments were used to calculate EC₅₀The value is obtained. The results are shown in Table 2. An activity equal to A means having EC₅₀0.003 to 0.10. mu.M, and B and C each represent a compound having EC₅₀0.1 to 1.0. mu.M and EC₅₀More than or equal to 1.0 mu M.

TABLE 2

Examples	Activity of
		1	B
2	A
		3	C
4	A
		5	A
6	A
		7	A
8	A
		9	A
10	A
		11	A
12	A
		13	A
14	A
		15	A
16	A
		17	A
18	A

Examples	Activity of
		19	A
20	A
		21	A
22	B
		23	A
24	C
		25	C
26	A
		27	A
28	B
		Examples	Activity of
29	A
		30	A
31	A
		32	A
33	A
		34	A
35	A
		36	A
37	B
		38	A
39	A

Examples	Activity of
		40	A
41	A
		42	A
43	A
		44	A
45	A
		46	A
47	A
		48	B
49	A
		50	A
51	A
		52	A
53	B
		54	A
55	A
		56	A
57	A
		58	A
Examples	Activity of
		59	B
60	A

Examples	Activity of
		61	B
62	A
		63	A
64	C
		65	A
66	B
		67	A
68	C
		69	A
70	B
		71	B
72	B
		73	A
74	A
		75	A
76	B
		77	A
78	A
		79	B
80	B
		81	A
82	A

Examples	Activity of
		83	C
84	A
		85	A
86	A
		87	A
88	A
		Examples	Activity of
89	A
		90	A
91	A
		92	A
93	A
		94	A
95	A
		96	A
97	A
		98	A
99	A
		100	A
101	A
		102	A
103	B

Examples	Activity of
		104	B
105	A
		106	A
107	A
		108	A
109	A
		110	A
111	A
		113	A
114	A
		115	A
116	A
		117	A
118	A
		119	A
Examples	Activity of
		120	A
121	A
		122	A
123	A
		124	A
125	A

Examples	Activity of
		126	A
127	A
		128	A
129	A
		130	A
132	A
		133	B
134	A
		135	A
136	A
		137	B
138	A
		139	A
140	A
		141	C
142	B
		144	C
146	A
		147	B
148	B
		149	B
150	B

Examples	Activity of
		151	B
152	B
		Examples	Activity of
153	B
		154	B
155	B
		156	B
157	A
		158	A
159	A
		160	B
161	B
		162	A
163	B
		164	B
165	A
		166	C
167	B
		168	A
169	A
		170	A
171	B

Examples	Activity of
		172	B
173	A
		174	A
175	B
		176	A
177	A
		178	A
179	B
		180	C
181	A
		187	B
Examples	Activity of
		188	B
189	A
		190	A
191	B
		192	B
193	C
		194	B
195	B
		196	A
197	C

Examples	Activity of
		198	B
199	B
		200	A
201	B
		202	A
203	A
		204	A
205	A
		206	A
207	A
		208	A
209	B
		210	A
211	A
		212	A
213	A
		214	B
215	A
		216	A
217	A
		Examples	Activity of
218	A

Examples	Activity of
		219	A
220	A
		221	A
222	A
		223	A
224	B
		225	A
226	A
		227	B
228	B
		229	A
230	A
		231	A
232	A
		233	A
234	A
		235	A
236	B
		237	A
238	A
		239	A
240	A

Examples	Activity of
		241	A
242	A
		243	A
244	A
		245	A
246	A
		247	A
Examples	Activity of
		248	A
249	A
		250	A
251	A
		252	C
253	C
		254	A
255	A
		256	B
257	A
		258	A
259	A
		260	A
262	A

Examples	Activity of
		263	B
265	B
		266	A
267	A
		268	A
270	A
		273	B
279	A
		281	A
282	A

Combination study

Example 19 demonstrates synergistic or additive synergistic HIV antiviral activity when used in combination with various other antiviral agents, as described below.

T cell line MT-2 was obtained by AIDS Research and Reference ReagenProgram. MT-2 cells were re-cultured twice weekly in RPMI 1640 medium supplemented with 10% fetal bovine serum, 2mM L-glutamine and 10mM HEPES buffer (pH 7.5). The HIV-1303B virus is a molecular clone of NL4-3 line derived from HIV-1, HIV-1 being obtained from NIH AIDS Research and Reference reagent PCR. For combination with enfuvirtide, NL36G virus was used. In gp41(36D), which is converted to the sensitive phenotype (D36G), NL4-3 derivatives have naturally occurring enrividual tolerance mutations. Viral stocks were prepared by transfecting 293T cells with proviral DNA using LipofectAMINE PLUS (Invitrogen) according to the manufacturer's instructions. Three days after transfection, virus was collected and passed once in MT-2 cells before titration in MT-2 cells.

Example 19, atazanavir (atazanavir), didanosine, stavudine, efavirenz, and enfuvirdine (T-20) were synthesized by Bristol-Myers Squibb using published or known reactions. Amprenavir, indinavir, nelfinavir, nevirapine, lopinavir, lamivudine, ritonavir, tenofovir, saquinavir, delavirdine, and abacavir are extracted from commercial formulations of the prescribed drug and purified using published or conventional techniques. Tenofovir was tested as tenofovir disoproxil fumarate. Zidovudine and zalcitabine were purchased from Sigma and emtricitabine (emtricitabine) was derived from Moravek Biochemicals.

Drug sensitivity and cytotoxicity assays for drug sensitivityTest, MT-2 cells were infected with HIV-1303B (or NL36G), at an MOI of 0.001, and seeded into 96-well microtiter plates (2.5X 10) containing serial dilutions of test compounds⁵Individual cells/ml). Drug combinations were set using two drugs in 1: 1, 1: 2.5 and 2.5: 1 fold ratios, and the EC for each drug was determined prior to the experiment₅₀The value is obtained. Each drug ratio consisted of a series of 3-fold serial dilutions and was performed in eight or more fold replicates in separate multiwell plates. HIV-infected cells were incubated at 37 ℃ in 5% CO ₂And five days after infection, the extent of virus replication was determined by measuring cell viability using the CellTiter 96 aqueous nonradioactive cell proliferation assay (Promega). Maximum cytoprotection can typically be seen in samples treated with the highest drug concentration. In a cell viability assay, the tetrazolium compound MTS (3- (4, 5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2-4-sulfophenyl-2H-tetrazolium) was added to cells, whereby the enzyme in metabolically active cells converted it to a chromogenic formazanThe product was determined by reading the absorbance at 490 nm. Cytotoxicity assays were performed in parallel experiments with combinatorial experiments. Here, uninfected cells were contacted with the same drug combination, and five days later, the MTS assay was used to determine cell viability.

To determine Combination Index (CI) values, drugs are diluted at fixed ratios and analyzed in multiple ratios. Drug sequence dilutions were made at approximately the EC for each compound₅₀The concentration of the values was within the range to compare equivalent antiviral activity. The normalized response of each therapy was fitted with a four-parameter logistic model with common minimum and maximum values across all therapies. Conceptually, this equation can be written as

Wherein

1, 2, 3, 4, or 5 for j.

In this equation, Fa represents the "fraction of infection" and represents the fraction of viral load that has been inactivated. For example, a Fa of 0.75 indicates that viral replication has been inhibited by 75% relative to the drug-free control. From C in the above equation_iRepresentative of EC₅₀Value, drug concentration to reduce 50% of viral load, B_iIs a parameter that reflects the slope of the concentration-response curve. For this trial, a is the bottom plateau common to all curves, D is the common top plateau, Bj is the "slope" parameter of jth therapy, and Cj is the concentration that yields a result equal to the average of a and D of jth therapy. Therapies 1 and 2 correspond to monotherapies 1 and 2, respectively. Therapies 3, 4 and 5 correspond to three combination therapies. Using the above equation, the EC for each drug was determined from a single drug experiment₅₀The value is obtained. The equations were fitted on a PC SAS version8.2(SAS Institute Inc) using a non-linear regression program (Proc Nlin).

To evaluate the antiviral outcome of the different drug combination treatments, Combination Indices (CIs) were calculated according to Chou and Rideout. The combination index is calculated as follows

In this equation, [ Dm]₁And [ Dm]₂Is the concentration of the drug that produces a particular level of outcome, respectively, [ D ] ]₁And [ D ]]₂Is the concentration of the drug in the combination that produces the same level of result.

Theoretically, if CI is equal to 1, additive effects are implied, if CI is less than 1, synergistic effects are implied, and if CI is greater than 1, antagonistic effects are implied. However, rich experience with joint studies shows that inherent laboratory variables must be considered in the interpretation of CIs. At best, only a range containing the appropriate CI value can be established to obtain interference data. In this report, these ranges are recorded in brackets next to the point estimates for each CI. For example, when recording a CI of "0.52 (0.36, 0.69), this means that the best estimate of CI is 0.52, but values from 0.36 to 0.69 are also reasonable values for CI due to data interference. This range of 0.36 to 0.69 is well below the 1.0 value, whereby all suitable values of CI are less than 1.0. It can therefore be concluded that this combination has a synergistic effect. If the range falls well above 1.0, we would conclude that antagonism is present. If the range includes 1.0, we will infer additivity.

In carrying out the combination drug experiments, the EC of example 19 was determined during each study period₅₀Values and each comparative (comparator) compound were used for subsequent data analysis. Measurement value: consistent with the data published in advance and shown in table 3.

TABLE 3 anti-HIV Activity of Compounds in two-drug combination Studies

Compound (I)	EC(μM)	Maximum drug concentration (μ M)
			Example 19	0.022	2.5
Zidovudine	0.012	2.5
			Didanosine	10.7	100
Stavudine	0.241	15
			Lamivudine	0.203	15
Abacavir	1.04	30
			Tenofovir	0.018	2.5
Emtricitabine	0.053	20
			Zalcitabine	0.124	10
Efavirenz	0.0016	0.2
			Nevirapine	0.095	5
Delavirdine	0.043	5
			Ritonavir	0.048	2.5
Indinavir	0.026	2.5
			Nelfinavir	0.022	2.5
Saquinavir	0.011	2.5

Compound (I)	EC(μM)	Maximum drug concentration (μ M)
			Amipronivir	0.062	2.5
Atazanavir	0.010	1
			Lopinavir	0.017	2.5
Enfuvirdi	0.061	2.2

Example 19 combination with two drugs of nucleoside reverse transcriptase inhibitors eight nucleoside RT inhibitors (didanosine, stavudine, zidovudine, lamivudine, abacavir, zalcitabine, emtricitabine and nucleoside phosphonates, tenofovir) were used to approximate the EC of each compound₅₀The concentration range of values was combined with example 19 in order to compare equivalent antiviral activity. All estimates were calculated using the sassproc NLIN and two parameter logarithms. The data are presented in table 4 in the form of combined indices and asymptotic confidence intervals for RT inhibitors at different molar ratios.

Four nucleoside RT inhibitors: didanosine, stavudine, abacavir and emtricitabine showed synergistic antiviral effects in combination with all effective levels and all molar ratios of example 19. Four other RT inhibitors: zidovudine, lamivudine, tenofovir and zalcitabine all have a combination index that is synergistic with the proposed performance of example 19. However, the upper bound of confidence intervals for some effective levels is greater than 1, thus classifying the overall effect of these compounds with example 19 as synergistic-to-additive. No significant antagonism of anti-HIV activity was observed. No enhanced cytotoxicity was encountered as determined by the XTT reduction assay at the highest concentration tested in combination with any drug.

TABLE 4 two pharmaceutical compositions using example 19 and nucleoside reverse transcriptase inhibitors

^aExample 19 ratio to comparative Compound

^bThe lower limit of the asymptotic confidence interval greater than 1 indicates antagonism, the upper limit less than 1 indicates synergy, and the value 1 included in the interval indicates additivity. The 95% confidence intervals are shown in parentheses and represent variability in the data.

EXAMPLE 19 two drugs in combination with a non-nucleoside reverse transcriptase inhibitor three non-nucleoside RT inhibitors were used to approximate the EC of each compound₅₀The value concentration ranges were combined with example 19, as described above for nucleoside RT inhibitors. The data are presented in table 5 in the form of combined indices and asymptotic confidence intervals for different molar ratios. Of the three, nevaripine showed a strong synergistic effect in combination with example 19. Synergy can be seen at all effective concentrations and all molar ratios. Sustiva and nevirapine also show a combination index in the most effective concentrations and molar ratios that is predictive of a synergistic effect. However, in some cases, the upper bound of the asymptotic confidence interval is greater than 1, so the additive effect cannot be excluded. No enhanced cytotoxicity was observed in the highest concentrations tested in combination with any drug, indicating that the combination of example 19 with a non-nucleoside RT inhibitor has potential therapeutic efficacy.

TABLE 5 two drug combinations using example 19 and non-nucleoside reverse transcriptase inhibitors

^aExample 19 ratio to comparative compound.

^bThe lower limit of the asymptotic confidence interval greater than 1 indicates antagonism, the upper limit less than 1 indicates synergy, and the value 1 included in the interval indicates additivity. The 95% confidence intervals are shown in parentheses and represent variability in the data.

Evaluation of the drug combination therapy of example 19 with a protease inhibitor was performed using indinavir, amprenavir, nelfinavir, lopinavir, saquinavir, ritonavir, and atazanavir. The results of these two drug combination studies are summarized in table 6. Likewise, the combination index observed for example 19 and all protease inhibitors at almost all effective levels and molar ratios suggests a synergistic relationship. This is particularly true for saquinavir and atazanavir, where the confidence interval for all concentrations and effective levels is below 1. Meanwhile, the upper bound of the confidence intervals for ritonavir, indinavir and lopinavir is greater than 1 under only one condition, and thus the addition relationship with example 19 cannot be excluded. Furthermore, the upper bound of the confidence intervals for nelfinavir and amprenavir is slightly greater than 1 under a few conditions, suggesting that these compounds have a synergistic-additive effect with example 19. No cytotoxicity was observed for the highest concentration used in any combination antiviral assay.

TABLE 6 two drug combinations using example 19 and protease inhibitors

^aExample 19 ratio to comparative compound.

^bThe lower limit of the asymptotic confidence interval greater than 1 indicates antagonism, the upper limit less than 1 indicates synergy, and the value 1 included in the interval indicates additivity. The 95% confidence intervals are shown in parentheses and represent variability in the data.

Example 19 combination of two drugs with Enfuvirdine (T-20) is HIV

gp41 fusion inhibitors, and is the first proven channel class inhibitor. The results presented in Table 7 indicate that the combination of example 19 with T-20 is synergistic. No significant cytotoxicity was observed for the highest concentration of the combination drug.

TABLE 7 two drug combination study of example 19 with Enfuvirdine

^aExample 19 ratio to comparative compound.

^bThe lower limit of the asymptotic confidence interval greater than 1 indicates antagonism, the upper limit less than 1 indicates synergy, and the value 1 included in the interval indicates additivity. The 95% confidence intervals are shown in parentheses and represent variability in the data.

Pharmaceutical compositions and methods of use

The compounds of the invention can inhibit HIV integrase. HIV integrase inhibitors belong to a class of diketonic acid compounds that prevent viral integration in cells and inhibit HIV-1 replication (Hazuda et al Science 2000, 287, 646). Recently, HIV integrase inhibitors have been accepted into clinical trials for the treatment of AIDS and HIV infection (neamuli expert. opin. ther. patents 2002, 12, 709, paper and Burke Drugs fut.2002, 27, 1101).

Accordingly, another aspect of the present invention is a method of treating HIV infection in a human patient comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, in combination with a pharmaceutically acceptable carrier.

Another aspect of the present invention is a method of treating HIV infection in a human patient comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, with a therapeutically effective amount of at least one other agent useful in the treatment of AIDS or HIV infection selected from nucleoside HIV reverse transcriptase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors, and HIV integrase inhibitors.

Another aspect of the invention is a method wherein the agent is a nucleoside HIV reverse transcriptase inhibitor.

Another aspect of the invention is a method wherein the nucleoside HIV reverse transcriptase inhibitor is selected from abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine, or a pharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention is a method wherein the agent is a non-nucleoside HIV reverse transcriptase inhibitor.

Another aspect of the invention is a method wherein the non-nucleoside HIV reverse transcriptase inhibitor is selected from the group consisting of delavirdine, efavirenz and nevirapine, or a pharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention is a method wherein the agent is an HIV protease inhibitor.

Another aspect of the invention is a method wherein the HIV protease inhibitor is selected from the group consisting of amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and fosamprenavir, or a pharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention is a method wherein the agent is an HIV fusion inhibitor.

Another aspect of the invention is a method wherein the HIV fusion inhibitor is enfuvirdine or T-1249, or a pharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention is a method wherein the agent is an HIV attachment inhibitor.

Another aspect of the invention is a method wherein the agent is a CCR5 inhibitor.

Another aspect of the invention is a method wherein the CCR5 inhibitor is selected from Sch-C, Sch-D, TAK-220, PRO-140, and UK-427,857, or a pharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention is a method wherein the agent is a CXCR4 inhibitor.

Another aspect of the invention is a method wherein the CXCR4 inhibitor is AMD-3100, or a pharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention is a method wherein the agent is an HIV budding or maturation inhibitor.

Another aspect of the invention is a method wherein the inhibitor of budding or maturation is PA-457, or a pharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention is a method wherein the agent is an HIV integrase inhibitor.

Another aspect of the invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, in combination with at least one other agent useful in the treatment of AIDS or HIV infection selected from nucleoside HIV reverse transcriptase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors, and HIV integrase inhibitors, and a pharmaceutically acceptable carrier.

Another aspect of the invention is a composition wherein the agent is a nucleoside HIV reverse transcriptase inhibitor.

Another aspect of the invention is a composition wherein the nucleoside HIV reverse transcriptase inhibitor is selected from abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine, or a pharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention is a composition wherein the agent is a non-nucleoside HIV reverse transcriptase inhibitor.

Another aspect of the invention is a composition wherein the non-nucleoside HIV reverse transcriptase inhibitor is selected from the group consisting of delavirdine, efavirenz and nevirapine, or a pharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention is a composition wherein the agent is an HIV protease inhibitor.

Another aspect of the invention is a composition wherein the HIV protease inhibitor is selected from the group consisting of amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and fosamprenavir, or a pharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention is a composition wherein the agent is an HIV fusion inhibitor.

Another aspect of the invention is a method of composition wherein the HIV fusion inhibitor is enfuvirdine or T-1249, or a pharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention is a composition wherein the agent is an HIV attachment inhibitor.

Another aspect of the invention is a composition wherein the agent is a CCR5 inhibitor.

Another aspect of the invention is a composition wherein the CCR5 inhibitor is selected from Sch-C, Sch-D, TAK-220, PRO-140, and UK-427,857, or a pharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention is a method wherein the agent is a CXCR4 inhibitor.

Another aspect of the invention is a method wherein the CXCR4 inhibitor is AMD-3100, or a pharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention is a composition wherein the agent is an HIV budding or maturation inhibitor.

Another aspect of the invention is a composition wherein the inhibitor of budding or maturation is PA-457, or a pharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention is a composition wherein the agent is an HIV integrase inhibitor.

By "combination," "co-administration," "simultaneously," and similar terms with respect to the administration of a compound of formula I bearing at least one anti-HIV agent, it is meant that these components are part of a combination antiretroviral therapy or highly active antiretroviral therapy (HAART) as understood by practitioners in the AIDS and HIV infection arts.

By "therapeutically effective" is meant the amount of agent required to provide a meaningful patient benefit as recognized by physicians in the AIDS and HIV infection fields. In general, the goals of therapy are to inhibit viral load, restore and maintain immune function, improve quality of life, and reduce HIV-associated morbidity and mortality.

By "patient" is meant a person infected with the HIV virus and suitable for treatment as understood by physicians in the AIDS and HIV infection arts.

"treatment", "therapy", "regimen", "HIV infection", "ARC", "AIDS", and related terms are used as understood by practitioners in the AIDS and HIV infection arts.

The compounds of the present invention are generally administered in the form of a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and may contain conventional excipients. A therapeutically effective amount is that amount which is necessary to provide a meaningful patient benefit. The pharmaceutically acceptable carrier is a generally known carrier having acceptable safety. Compositions include all common solid and liquid forms, including capsules, tablets, lozenges, and powders as well as liquid suspensions, syrups, elixirs, and solutions. The compositions are prepared using conventional formulation techniques, and conventional excipients (e.g., binders and wetting agents) and vehicles (e.g., water and alcohols) are typically used for the compositions.

Solid compositions are typically formulated in dosage units, and preferably the compositions provide from about 1 to 1000 milligrams of active ingredient per dose. Some examples of dosages are 1 mg, 10 mg, 100 mg, 250 mg, 500 mg, and 1000 mg. Typically, other antiretroviral agents are always present in a unit range similar to those classes of agents used clinically. Typically 0.25-1000 mg/unit.

Liquid compositions are generally in the range of dosage units. Typically, the liquid composition will be in the unit dosage range of 1-100 mg/ml. Examples of some dosages are 1 mg/ml, 10 mg/ml, 25 mg/ml, 50 mg/ml, and 100 mg/ml. Typically, other antiretroviral agents are always present in a unit range similar to those classes of agents used clinically. Typically 1-100 mg/ml.

The present invention includes all conventional modes of administration; oral and parenteral methods are preferred. Generally, the dosing regimen will be similar to other antiretroviral agents used clinically. Typical daily doses are 1-100 mg/kg body weight per day. Generally, more compound is required for oral administration, while less is required for parenteral administration. The particular mode of administration may be determined by a physician using sound medical judgment.

The invention also includes methods of administering such compounds in combination therapy. That is, the compounds may be combined with, but used separately from, other agents used in the treatment of AIDS and HIV infection. Some of these agents include HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV cell fusion inhibitors, HIV integrase inhibitors, HIV nucleoside reverse transcriptase inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, HIV protease inhibitors, budding and maturation inhibitors, immunomodulators, and anti-infective drugs. In these combination methods, the compound of formula I is generally administered in combination with other agents at daily dosages of 1-100 mg/kg body weight per day. Other agents are typically administered in amounts used for treatment. The particular mode of administration may be determined by a physician using sound medical judgment.

Table 8 lists some agents suitable for the present invention that are effective in treating AIDS and HIV infection.

TABLE 8 antiviral Agents

Immunomodulator

Name of drug	Manufacturer(s)	Indications of
			AS-101	Wyeth-Ayerst	AIDS
Bromopilimine	PharmaciaUpjohn	Advanced AIDS
			Vinegar-mennan	CarringtonLabs，Inc.(IrVing，TX)	AIDS，ARC
CL246,738	AmericanCyanamidLederle Labs	AIDS, Kaposi's sarcoma
			EL10	Elan Corp，PLC(Gainesville，GA)	HIV infection
FP-21399	FukiImmunoPharm	Repression of HIV fusion with CD4+ cells

Name of drug	Manufacturer(s)	Indications of
			Gamma interferon	Genentech	ARC in combination with TNF (tumor necrosis factor)
Name of drug	Manufacturer(s)	Indications of
			Granulocyte macrophage colony stimulating factor	Genetics InstituteSandoz	AIDS
Granulocyte macrophage colony stimulating factor	Hoechst-RousselImmunex	AIDS
			Granulocyte macrophage colony stimulating factor	Schering-Plough	AIDS in combination with AZT
HIV core particle immunostimulants	Rorer	Seropositive HIV
			IL-2 Interleukin-2	Cetus	AIDS in combination with AZT
IL-2 Interleukin-2	Hoffman-LaRocheImmunex	AIDS, ARC, HIV, in combination with AZT
			IL-2 Interleukin-2 (Adeskin)	Chiron	AIDS, increased CD4 cell number
Immunoglobulin intravenous injection (human)	Cutter Biological(Berkeley，CA)	Pediatric AIDS in combination with AZT
			IMREG-1	Imreg(New Orleans，LA)	AIDS, Kaposi sarcoma, ARC, PGL
IMREG-2	Imreg(New Orleans，LA)	AIDS, Kaposi sarcoma, ARC, PGL

Name of drug	Manufacturer(s)	Indications of
			Ethiconol, diethyl dimercaptocarbamate	Merieux Institute	AIDS，ARC
Alpha-2 interferon	Schering Plough	Kaposi sarcoma, in combination with AZT, AIDS
			Methionine-enkephalin	TNIPharmaceutical(Chicago，IL)	AIDS，ARC
Name of drug	Manufacturer(s)	Indications of
			MTP-PE muramyl tripeptide granulocyte colony stimulating factor	Ciba-Geigy Corp.Amgen	Kaposi sarcoma AIDS in combination with AZT
Remune	Immune ResponseCorp.	Immunotherapeutic agent
			rCD4 recombinant soluble human CD4	Genentech	AIDS，ARC
rCD4-IgG hybrid		AIDS，ARC
			Recombinant soluble human CD4	Biogen	AIDS，ARC
Interferon alpha 2a	Hoffman-LaRoche and AZT combined use	Kaposi sarcoma, AIDS, ARC
			SK&F106528 soluble T4	Smith Kline	HIV infection
Thymopentin	ImmunobiologyResearch Institute(Annandale，NJ)	HIV infection
			Tumor necrosis factor; TNF	Genentech	ARC in combination with gamma interferon

Anti-infective agents

Name of drug	Manufacturer(s)	Indications of
			Clindamycin and primaquine	PharmaciaUpjohn	PCP
Fluconazole	Pfizer	Cryptococcal meningitis, candidiasis
			Lozenge nystatin lozenge	Squibb Corp.	Oral candidiasis prevention
Eflornithine hydrochloride injection eflornithine	Merrell Dow	PCP
			Name of drug	Manufacturer(s)	Indications of
Pentamidine Ethoxylicacid (IM)&IV)	LyphoMed(Rosemont，IL)	PCP treatment
			Trimethoprim		Antibacterial agents
Trimethoprim sulfate		Antibacterial agents
			Pietraxin	BurroughsWellcome	PCP treatment
Inhalation pentamidine besylate	FisonsCorporation	PCP prevention
			Spiromycin	Rhone-Poulencdiarrhea	Cryptosporidial

Name of drug	Manufacturer(s)	Indications of
			itraconazole-R1211(Intraconazole)	Janssen-Pharm.	Histoplasmosis; cryptococcal meningitis
Trimethotrexate	Warner-Lambert	PCP
			Roxithromycin	NeXstar，Sequus	Carbonic acidWestern sarcoma
Recombinant human erythropoietin	Ortho Pharm.Corp.	Severe anemia associated with AZT therapy
			Recombinant human growth hormone	Serono	AIDS-related wasting, cachexia
Megestrol acetate	Bristol-MyersSquibb	Treatment of AIDS-related anorexia
			Testosterone	Alza，Smith Kline	AIDS-related wasting
Total enteral nutrition	Norwich EatonPharmaceuticals	AIDS-related diarrhea and malabsorption

Description of the specific embodiments

Intermediate 1

2- (2- (methylthio) ethoxy) acetic acid 2-methylthio chloride is reacted at 22 DEG CA solution of the ethanol base (10.0 g, 0.108mol) in dry tetrahydrofuran (25 ml) was added dropwise over 30 minutes to a suspension of sodium hydride (9.54 g, 60% dispersion in mineral oil, 0.238 mol, washed twice with hexane) in dry tetrahydrofuran (250 ml). After 30 minutes, a solution of chloroacetic acid (10.25g, 0.108mol) in dry tetrahydrofuran (20ml) was added dropwise over 30 minutes at 22 ℃ and the resulting mixture was heated at reflux for 5 hours. The cooled mixture was treated with 250ml of 1N hydrochloric acid and sodium chloride was added to the aqueous phase until saturation. The organic phase was separated and the aqueous phase was washed with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was distilled in vacuo to give 11.27g (69% yield) of the title acid clear oil; bp 85-95 deg.C/0.3 torr (bulb to bulb distillation, air bath temperature).¹HNMR400MHz(CDCl₃)δppm：2.18(3H，s，SCH₃)，2.76(2H，t，J＝6.6Hz，CH₂)，3.77(2H，t，J＝6.6Hz，CH₂)，4.20(2H，s，OCH₂)。

Intermediate 2

Methyl 2- (2- (methylthio) ethoxy) acetate a solution of intermediate 1, 2- (2- (methylthio) ethoxy) acetic acid (11.27 g, 0.075 mol) in dry dichloromethane (50ml) was treated with oxalyl chloride (13.0 ml, 0.15 mol) followed by a drop of N, N-dimethylformamide and the resulting mixture was stirred at 22 ℃ for 5 hours. The solvent and excess reagent were then evaporated under reduced pressure and the residual acid chloride was added dropwise to a cold (0-5 ℃) mixture of methanol (30ml) and pyridine (10ml) in dichloromethane (50 ml). After 1 hour at 22 ℃, the solvent was evaporated under reduced pressure. The obtained residue was diluted with ethyl acetate, washed with 1N hydrochloric acid, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was distilled in vacuo to give 11.42g (93% yield) of the title ester as a clean oil; bp 65-75 deg.C/0.1 torr (reduced pressure micro-distillation, air bath temperature).¹HNMR 400MHz(CDCl₃)δppm：2.17(3H，s，SCH₃)，2.75(2H，t，J＝6.9Hz，CH₂)，3.74(2H，t，J＝6.9Hz，CH₂)，3.77(3H，s，OCH₃)，4.15(2H，s，OCH₂)。

Intermediate 3

Intermediate 22- (2- (methylthio) ethoxy) acetic acid methyl ester, (4.69 g, 28.6mmol) was added to a solution of methyl chloroamido aluminum (H.Geilen, C.Alonso-Alija, M.Hendrix, U.Niewohner and D.Schauss, Tetrahedron Lett., 2002, 43, 419-421) (0.114 mol; prepared from 6.30g (0.117mol) of ammonium chloride and 57.0ml (0.114mol) of a 2M solution of trimethylaluminum in toluene (50 ml)) and the resulting mixture was heated at 80 ℃ for 18 hours. The reaction mixture was then cooled to 0 ℃, treated dropwise with methanol (100ml), and stirred for an additional hour at 25 ℃. The solid formed was filtered and washed with methanol (300 ml). The combined filtrates were concentrated to give a white paste, which was diluted with isopropanol (160ml) and acetone (40ml) and stirred at 25 ℃ for 1 hour. The solid was then filtered off and the filtrate was concentrated in vacuo to give 3.50g (62% yield) of the title compound as an oil.¹HNMR 400MHz(DMSO-d₆)δppm：2.10(3H，s，SCH₃)，2.71(2H，t，J＝6.8Hz，CH₂)，3.66(2H，t，J＝6.8Hz，CH₂)，4.34(2H，s，OCH₂)。MS(ESI⁺)m/z 149[M+H⁺]。

Intermediate 4

Ethyl 5-benzyloxy-2- { (2- (methylthio) ethoxy) methyl } -6-oxo-1, 6-dihydropyrimidine-4-carboxylate diethyl oxalate (2.77 g, 19.0mmol) and ethyl benzyloxyacetate (3.69 g, 19.0mmol) in dry tetrahydrofuran (30 ml) were treated with sodium hydride (0.83 g, 60% dispersion in mineral oil, 20.9mmol) at 22 ℃ and then with ethanol (10(L), and the resulting mixture was stirred at 22 ℃ for 18 hours the tetrahydrofuran was evaporated under reduced pressure to give a thick orange slurry, then to the above adduct was added simultaneously a mixture of intermediate 3, 2- (2- (methylthio) ethoxy) acetamidine hydrochloride (3.50 g, 19.0mmol) in sodium ethoxide (9.5mmol, prepared from 0.22 g sodium in 25 ml ethanol), and the resulting mixture was heated at 60 ℃ for 3 hours. Acetic acid (2 ml) was added and the ethanol was evaporated under reduced pressure. The resulting residue was diluted with ethyl acetate, washed successively with saturated sodium bicarbonate and brine, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Chromatography on silica gel (gradient elution with 20-30% ethyl acetate in toluene) afforded 0.728 g (10% yield) of the title ester as a clear oil. ¹HNMR 400MHz(CDCl₃)δ(ppm)：1.33(3H，t，J＝7.1Hz，CH₃)，2.18(3H，s，SCH₃)，2.78(2H，t，J＝6.0Hz，CH₂)，3.78(2H，t，J＝6.0Hz，CH₂)，4.36(2H，q，J＝7.1Hz，OCH₂)，4.54(2H，s，OCH₂)，5.35(2H，s，OCH₂) 7.37(3H, m, arene), 7.48(2H, m, arene). HRMS (ESI)⁺)C₁₈H₂₃N₂O₅S[M+H⁺]The calculated value of (a): 379.1328: measured value: 379.1314.

intermediate 5

5-benzyloxy-2- { (2- (dimethylsulfonium) ethoxy) methyl } -6-oxo-1, 6-dihydropyrimidine-4-carboxylic acid ethyl ester iodide: intermediate 4, ethyl 5A solution of-benzyloxy-2- { (2- (methylthio) ethoxy) methyl } -6-oxo-1, 6-dihydropyrimidine-4-carboxylate, (0.555 g, 1.47mmol) in dichloromethane (10 mL) was treated with methyl iodide (2.0 mL, 21.5mmol) at 22 deg.C for 10 days. The solvent and excess reagent were evaporated to give the title compound (0.76 g) as an oil, which was used without further purification.¹HNMR 400MHz(CDCl₃)δ(ppm)：1.32(3H，t，J＝7.1Hz，CH₃)，3.26(6H，s，SCH₃)，4.02(2H，m，CH₂)，4.23(2H，m，CH₂)，4.34(2H，q，J＝7.1Hz，OCH₂)，4.69(2H，s，OCH₂)，5.23(2H，s，OCH₂) 7.35-7.5(5H, m, arene). MS (ESI)⁺)m/z 393[M+]。

Intermediate 6

3-benzyloxy-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxylic acid ethyl ester: a solution of intermediate 5, 5-benzyloxy-2- { (2- (dimethylsulfonium) ethoxy) methyl } -6-oxo-1, 6-dihydropyrimidine-4-carboxylic acid ethyl ester iodide, (0.76 g, 1.47mmol) in dry N, N-dimethylformamide (10 mL) was treated with powdered anhydrous potassium carbonate (2.5 g) at 22 deg.C and the resulting mixture was stirred for 48 h. The solid was then filtered and the filtrate was evaporated in vacuo. The residue was diluted with ethyl acetate, washed successively with 0.1N hydrochloric acid, saturated sodium bicarbonate and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and then chromatographed on silica gel (gradient elution with 20-50% ethyl acetate in toluene) to give 0.347 g (72% yield) of the title ester as white prisms; melting point 103 ℃ and 104 ℃ (ethyl acetate-hexane). ¹HNMR 400MHz(CDCl₃)δppm：1.34(3H，t，J＝7.1Hz，CH₃)，4.03(2H，t，J＝5.6Hz，CH₂)，4.11(2H，t，J＝5.6Hz，CH₂)，4.37(2H，q，J＝7.1Hz，OCH₂)，4.74(2H，s，OCH₂)，5.30(2H，s，OCH₂) 7.38(3H, m, arene), 7.50(2H, m, arene). C₁₇H₁₈N₂O₅Analytical calculation of (a): c61.81, H5.49, N8.48. Measurement value: c61.55, H5.53, N8.39.

Intermediate 7

3- (benzyloxy) -4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxylic acid intermediate 6, 3- (benzyloxy) -4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c][1，4]A solution of oxazine-2-carboxylic acid ethyl ester (0.300 g, 0.91mmol) in ethanol (10 mL) was treated with 3 mL (3.0mmol) of 1N sodium hydroxide and stirred at 25 ℃ for 30 min. The solution was then acidified with 1N hydrochloric acid, extracted with ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave 0.264g (96% yield) of the title acid as white crystals; melting point 171 deg.C (ethyl acetate).¹HNMR 400MHz(CDCl₃)δ(ppm)：4.03(2H，t，J＝5.3Hz，CH₂)，4.12(2H，t，J＝5.3Hz，CH₂)，4.73(2H，s，OCH₂)，5.53(2H，s，OCH₂) 7.35-7.42(3H, m, arene), 7.53(2H, m, arene). C₁₅H₁₄N₂O₅Analytical calculation of (a): c59.60, H4.67, N9.27. Measurement value: c59.35, H4.69, N9.10.

Intermediate 8

3-hydroxy-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxylic acid ethyl ester the intermediate 6, 3-benzyloxy-4-oxo-4, 6, 7, 9-carboxylic acid was dissolved in a mixture of ethyl acetate (60 ml) and ethanol (20 ml)Tetrahydropyrimidino [2, 1-c][1，4]A solution of oxazine-2-carboxylic acid ethyl ester (0.236 g, 0.714mmol) was treated with 1atm hydrogen at 25 deg.C over 10% activated palladium on carbon (0.10g) for 2.5 hours to give 0.160g (94% yield) of the title compound as white needle crystals; melting point 172 ℃ and 174 ℃ (ethyl acetate). ¹HNMR 400MHz(CDCl₃)δppm：1.47(3H，t，J＝7.3Hz，CH₃)，4.08(4H，m，2xCH₂)，4.54(2H，q，J＝7.3Hz，OCH₂)，4.72(2H，s，OCH₂)，10.75(1H，s，OH).C₁₀H₁₂N₂O₅Analytical calculation of (a): c50.00, H5.03, N11.66. Measurement value: c50.01, H4.95, N11.54.

Intermediate 9

2- (2- (methylthio) ethoxy) propionic acid 2-methylthioethanol (10.0 g, 0.108 mol) was added to sodium hydride (9.54 g, 60% dispersion in mineral oil, 0.238 mol, washed twice with hexane) and then reacted with 2-bromopropionic acid (16.6 g, 0.108 mol) to give 13.81 g (78% yield) of the title compound as a clear oil; bp: 80-90 deg.C/0.2 torr (reduced pressure micro-distillation, air bath temperature).¹HNMR 400MHz(CDCl₃)δppm：1.49(3H，d，J＝7.0Hz，CH₃)，2.18(3H，s，SCH₃)，2.76(2H，t，J＝6.6Hz，CH₂)，3.74(2H，t，J＝6.6Hz，CH₂)，4.07(1H，d，J＝7.0Hz，OCH)。

Intermediate 10

Methyl 2- (2- (methylthio) ethoxy) propanoate intermediate 9, 2- (2- (methylthio) ethoxy) propanoic acid, (13.70 g,0.083 moles) was reacted with oxalyl chloride and then methanol to give 14.27 g (96% yield) of the title ester as a clear oil; bp: 55-60 deg.C/0.3 torr (reduced pressure micro-distillation, air bath temperature).¹HNMR 400MHz(CDCl₃)δppm：1.42(3H，d，J＝7.0Hz，CH₃)，2.15(3H，s，SCH₃)，2.71(2H，t，J＝6.8Hz，CH₂)，3.56(1H，m，CH)，3.75(3H，s，OCH₃)，3.78(1H，m，CH)，4.15(1H，q，J＝7.0Hz，OCH)。

Intermediate 11

Intermediate 10, methyl 2- (2- (methylthio) ethoxy) propanoate, (10.00 g, 56.1mmol) was added to a solution of methyl chloroamidoaluminum (0.224 mol; prepared from 12.36 g (0.231mol) ammonium chloride and 112.0 ml (0.224mol) of 2M trimethylaluminum in toluene (100ml) as described in the preparation of intermediate 3) to give 7.70 g (69% yield) of the title compound as an oil. ¹HNMR 400MHz(D₂O)δppm：1.37(3H，d，J＝6.6Hz，CH₃)，2.01(3H，s，SCH₃)，2.65(2H，t，J＝5.6Hz，CH₂)，3.64(2H，m，CH₂)，4.30(1H，q，J＝6.6Hz，OCH)。MS(ESI⁺)m/z 163[M+H⁺]。

Intermediate 12

5-benzyloxy-2- {1- (2- (methylthio) ethoxy) ethyl } -6-oxo-1, 6-dihydropyrimidine-4-carboxylic acid ethyl ester diethyl oxalate (5.66 g, 38.7mmol) and ethyl benzyloxyacetate (7.52 g, 38.7mmol) in dry tetrahydrofuran (60 mL) were reacted at 22 deg.C with ethyl benzyloxyacetate (7.52 g, 38.7mmol)Sodium hydride (1.70 g of 60% dispersion in mineral oil, 42.5mmol) was treated and the condensation product reacted with a mixture of intermediate 11, 2- (2- (methylthio) ethoxy) propionamidine hydrochloride, (7.70 g, 38.7mmol) in sodium ethoxide (19.3mmol, prepared from 0.445 g of sodium) in ethanol (50 ml) to give after chromatography on silica gel 2.29 g (yield 15%) of the title ester as a clear oil.¹HNMR 400MHz(CDCl₃)δppm：1.33(3H，t，J＝7.1Hz，CH₃)，1.54(3H，d，J＝7.1Hz，CH₃)，2.16(3H，s，SCH₃)，2.7-2.8(2H，m，CH₂)，3.54(1H，m，CH)，3.86(1H，m，CH)，4.37(2H，q，J＝7.1Hz，OCH₂)，4.47(1H，q，J＝7.1Hz，OCH)，5.34(2H，ABq，J_AB＝11.0Hz，OCH₂) 7.37(3H, m, arene), 7.49(2H, m, arene). MS (ESI)⁺)m/z 393[M+H⁺]。

Intermediate 13

5-benzyloxy-2- {1- (2- (dimethylsulfonium) ethoxy) ethyl } -6-oxo-1, 6-dihydropyrimidine-4-carboxylic acid ethyl ester iodide A solution of intermediate 12, 5-benzyloxy-2- {1- (2- (methylthio) ethoxy) ethyl } -6-oxo-1, 6-dihydropyrimidine-4-carboxylic acid ethyl ester, (1.63 g, 4.15mmol) in dichloromethane (5 mL) was treated with iodomethane (5.0 mL, 53.9mmol) for 5 days at 22 deg.C as described for intermediate 5 preparation to give the title compound (2.22 g) as an oil which was used without further purification. ¹HNMR 400MHz(CDCl₃)δppm：1.32(3H，t，J＝7.1Hz，CH₃)，1.66(3H，d，J＝6.6Hz，CH₃)，3.15(3H，s，SCH₃)，3.32(3H，s，SCH₃)，3.4(1H，m，CH)，4.01(2H，m，CH₂)，4.37(2H，q，J＝7.1Hz，OCH₂)，4.45(1H，m，CH)，4.63(1H，q，J＝6.6Hz，OCH)，5.28(2H，OCH₂) 7.38(3H, m, arene), 7.50(2H, m, arene). MS (ESI⁺)m/z 407[M+]。

Intermediate 14

3- (benzyloxy) -9-methyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Intermediate 13, 5-benzyloxy-2- {1- (2- (dimethylsulfonium) ethoxy) ethyl } -6-oxo-1, 6-dihydropyrimidine-4-carboxylic acid ethyl ester iodide (2.22 g, 4.15mmol) in dry N, N-dimethylformamide (30 ml) was treated with powdered anhydrous potassium carbonate (6 g) at 22 ℃ and stirred for 40 hours. The solid was then filtered and the filtrate was concentrated in vacuo. The residue was diluted with ethyl acetate, washed with 0.1N hydrochloric acid, saturated sodium bicarbonate and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was chromatographed on silica gel (toluene-ethyl acetate 7: 3 elution) to give 1.0 g (70% yield) of the title ester as white crystals; melting point 48-50 deg.C (ethyl acetate-hexane).¹HNMR 400MHz(CDCl₃)δ(ppm)：1.33(3H，t，J＝7.1Hz，CH₃)，1.68(3H，d，J＝6.6Hz，CH₃)，3.91(2H，m，CH₂)，4.17-4.31(2H，m，CH₂)，4.37(2H，q，J＝7.1Hz，OCH₂)，4.73(1H，q，J＝6.6Hz，OCH)，5.30(2H，ABq，J_AB＝11.0Hz，OCH₂) 7.38(3H, m, arene), 7.50(2H, m, arene). C₁₈H₂₀N₂O₅Analysis calculated value: c62.78, H5.85, N8.13. Measurement value: c62.69, H6.01, N8.16.

Intermediate 15

3-hydroxy-9-methyl-4-oxo-4, 6, 7,9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxylic acid ethyl ester intermediate 14, 3-benzyloxy-9-methyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ] ][1，4]Oxazine-2-carboxylic acid ethyl ester, (0.610 g, 1.77mmol) was hydrogenolyzed in a mixture of ethyl acetate (75 ml) and ethanol (75 ml) at 25 ℃ with 10% activated palladium on carbon (0.20 g) under 1 atmosphere of hydrogen for 2 hours to give 0.430 g (95% yield) of the title ester as white crystals; melting point 119-.¹HNMR 400MHz(CDCl₃)δppm：1.46(3H，t，J＝7.1Hz，CH₃)，1.67(3H，d，J＝6.6Hz，CH₃)，3.90(2H，m，CH₂)，4.13-4.32(2H，m，CH₂)，4.51(2H，m，OCH₂) 4.70(1H, q, J ═ 6.6Hz, CH), 10.7(1H, broad peak, OH). C₁₁H₁₄N₂O₅Analytical calculation of (a): c51.96, H5.55, N11.01. Measurement value: c51.60, H5.61, N10.70.

Intermediate 16

3-benzyloxy-9-methyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxylic acid intermediate 14, 3-benzyloxy-9-methyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ]][1，4]Oxazine-2-carboxylic acid ethyl ester, (0.225 g, 0.65mmol) saponification as described for preparation of intermediate 7 gave 0.198 g (96% yield) of the title acid as white crystals; melting point 167-.¹HNMR 400MHz(CDCl₃)δppm：1.68(3H，d，J＝6.6Hz，CH₃)，3.93(2H，m，CH₂)，4.12-4.21(1H，m，CH)，4.27-4.35(1H，m，CH)，4.70(1H，q，J＝6.6Hz，OCH)，5.53(2H，ABq，J_AB＝11.1Hz，OCH₂) 7.39(3H, m, arene), 7.55(2H, m, arene). MS (ESI)⁺)m/z 317[M+H⁺]。C₁₆H₁₆N₂O₅Analytical calculation of (a): c60.75, H5.10, N8.86. Measurement value: c60.65, H5.05, N8.72.

Intermediate 17

2- (2- (methylthio) ethyl) -1, 3-dioxolane A solution of 3- (methylthio) propanal (5.2 g, 0.05 mol) and ethylene glycol (3.4g.0.055 mol) in 100ml of benzene was treated with 300 mg of p-toluenesulfonic acid and heated at reflux for 4 hours. The solution was cooled and decanted. Concentration and drying in vacuo afforded the title compound as a pale yellow oil. ¹H NMR(300MHz，CDCl₃)δppm：4.93(1H，t，J＝4.76Hz)3.74-4.03(4H，m)2.46-2.68(2H，m)2.08(3H，s)1.83-2.00(2H，m)。

Intermediate 18

4- (methylthio) -2- (2- (trimethylsilyloxy) ethoxy) butyronitrile intermediate 17, 2- (2- (methylthio) ethyl) -1, 3-dioxolane, (2.96g, 0.02mol), trimethylsilyl cyanide (1.98g, 0.02mol) and 20mg of zinc iodide in N₂Mix under protection and stir at room temperature for 16 hours. The mixture was then concentrated in vacuo to afford 4.9g (approximately 100% yield) of the title compound as a yellow oil.¹H NMR(300MHz，CDCl₃)δppm：4.37-4.49(1H，m)3.50-3.88(4H，m)2.57-2.74(2H，m)1.98-2.26(5H，m)0.06-0.22(9H，m)：LC/MS 198(-TMS+Na)。

Intermediate 19

4- (methylthio) -2- (2- (trimethylsilyloxy) ethoxy) butanamidine A solution of intermediate 18, 4- (methylthio) -2- (2- (trimethylsilyloxy) ethoxy) butyronitrile, (4.9g, 0.02mol) in 30 ml of methanol was saturated with ammonia. The flask was then sealed and heated in an oil bath at 80-90 ℃ for 16 hours. After cooling, the flask was opened and the mixture was concentrated in vacuo to give the title compound as a very viscous oil in essentially quantitative yield.¹H NMR(300MHz，CDCl₃)δppm：3.94-4.02(1H，m)3.76-3.94(3H，m)3.68-3.77(2H，m)3.52-3.62(2H，m)2.53-2.67(2H，m)2.07(3H，s)1.89-2.01(2H，m)；LC/MS 193(M+H)。

Intermediate 20

Ethyl 5- (benzyloxy) -2- (1- (2-hydroxyethoxy) -3- (methylthio) propyl) -6-oxo-1, 6-dihydropyrimidine-4-carboxylate ethyl 2- (benzyloxy) acetate (7.76 g, 0.04 mol) and diethyl oxalate (5.84 g, 0.04 mol) were treated with one equivalent of NaH and a few drops of ethanol in 80 ml of tetrahydrofuran. The resulting mixture was stirred for 1.5 hours, after which the solvent was removed under vacuum and replaced with 30 ml of ethanol. Intermediate 19, 2- (2-hydroxyethoxy) -4-methylthio) butamidine in 30 ml of ethanol was added to the mixture followed by NaH (60% in mineral oil, 800mg, 0.02 mol). Stirred at room temperature for 20 hours, and at 60 ℃ for 3 hours, then concentrated under reduced pressure. The residue was dissolved in CH ₂Cl₂Neutralized and washed with water. Will CH₂Cl₂The layers are over MgSO₄Dried, filtered and concentrated in vacuo. Chromatographing on silica gel using 4: 1 CH₂Cl₂(ii) a Diethyl ether and ethyl acetate gave 760 mg of the title compound (9% yield).¹H NMR(300MHz，CDCl₃)δppm：7.24-7.54(5H，m)5.17-5.36(2H，s)4.50(1H，m)4.30(2H，q，J＝7.32Hz)3.38-4.00(4H，m)2.59(2H，m)1.95-2.11(5H，m)1.20-1.36(3H，t，J＝7.32Hz)；LC/MS m/z 423(M+H)。

Intermediate 21

3- (benzyloxy) -9- (2- (methylthio) ethyl) -4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxylic acid ethyl ester in 10ml CH₂Cl₂Intermediate 20, 5- (benzyloxy) -2- (1- (2-hydroxyethoxy) -3- (methylthio) propyl) -6-oxo-1, 6-dihydropyrimidine-4-carboxylic acid ethyl ester of (527 mg, 1.25mmol) and Et₃N (505mg, 5mmol) in 2 ml CH was added₂Cl₂CH in (1)₃SO₂Solution of Cl (288mg, 2.5 mmol). It was stirred for 20 hours and then concentrated. The crude product was purified by chromatography on silica gel using 10: 1 CH₂Cl₂Diethyl ether was used as an eluent to give 265mg of the title compound (52% yield). (500MHz, CDCl)₃)δppm：7.31-7.55(5H，m)5.30(2H，s)4.75(1H，dd，J＝3.66Hz)4.32-4.40(2H，q，J＝7.17Hz)4.13-4.30(2H，m)3.75-3.97(2H，m)2.20-2.84(4H，m)2.06(3H，s)1.32(3H，t，J＝7.17Hz)；LC/MS m/z 405(M+H)。

Intermediate 22

3- (benzyloxy) -9- (2- (methylthio) ethyl) -4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxylic acid to the stirred intermediate 21, 3- (benzyloxy) -9- (2- (methylthio) ethyl) -4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c][1，4]To a solution of oxazine-2-carboxylic acid ethyl ester (97mg,. 0.2mmol) in 3ml of tetrahydrofuran was added lithium hydroxide (15mg,. 6mmol) in 3ml of water. After 20 minutes the reaction mixture was taken up in 1 Acidifying with N HCl and then with CH₂Cl₂And (4) extracting. Extracting with MgSO 2₄Dry, filter and concentrate to give 82 mg of the title compound (88% yield). LC/MS m/e 377.

Intermediate 23

2- (2-chloroethoxy) -2-methylpropanenitrile (Navalokina, R. et al J. org. chem. USSR (Engl. trans.), 1980, 16, 1382-1386.2) Ramalingam, K.U.S. Pat. No. 4,864,051, 1989.) A250 ml round bottom flask was charged with ZnCl₂(68.14 g, 0.5 mol), which is then melted by heating under vacuum. After returning to room temperature the material was placed in N₂And (4) in an atmosphere. Acetone cyanohydrin (45.66mL, 0.5mole) was added followed by 2-chloroethanol (50.24mL, 0.75mole) and the mixture was placed in a preheated oil bath (60 ℃). After stirring at 60 ℃ for 18-20 h, the reaction mixture was cooled, diluted with water (300mL), and CH₂Cl₂(5X100mL) washing. To merge CH₂Cl₂Drying the extract (Na)₂SO₄) Filtered and concentrated in vacuo to give a crude yellow liquid. Purification was accomplished by vacuum distillation (10mm Hg) using a Vigreux column. Fractions boiling between 65-75 ℃ were collected to give the desired product as a colourless oil (47.1g, 63.8% yield).¹H NMR(500MHz，CDCl₃)δppm：3.85(2H，t，J＝5.8Hz)，3.64(2H，t，J＝5.8Hz)，1.60(6H，s)。

Intermediate 24

2- (2-ethoxy-2-oxoethyl) -8, 8-dimethyl-2, 5, 6, 8-tetrahydro- [1, 2, 4- ]Oxadiazolo [3, 2-c ]][1，4]Oxazine-2-carboxylic acid ethyl ester to a stirred solution of intermediate 23, 2- (2-chloroethoxy) -2-methylpropanenitrile (14.7 g, 0.10 mol) and NaI (1.5 g, 10mmol) in ethanol (50ml) was added an aqueous solution of hydroxylamine (18.4 g, 0.30 mol) (50%) to produce an exothermic reaction. After this time, the reaction mixture was heated at 80 ℃ for 2 hours. Cooled to room temperature and the solvent removed. The residue obtained is dissolved in 1: 1 ethanol/H₂O (100mL) and cooled in an ice bath. To this was added acetylene dicarboxylic acid diethyl ester (17.6 ml, 0.110 mol) over 10 minutes. The reaction mixture was warmed to room temperature and stirred for 1 hour. After this time, it was diluted with ethyl acetate (250mL) and washed with H₂O (2X100mL), brine (50mL), Na₂SO₄Dried, filtered and concentrated to give a crude yellow oil. Flash chromatography on silica gel eluting with 20-40% ethyl acetate/hexanes afforded the title compound as a viscous pale yellow oil (15.29g, 48.6% yield).¹H NMR(500MHz，CDCl₃)δppm：4.35-4.28(2H，m)，4.18-4.12(2H，m)，3.60-3.56(1H，m)，3.51-3.47(1H，m)，3.30(1H，d，J＝16.2Hz)，2.94(1H，d，J＝16.2Hz)，1.52(3H，s)，1.51(3H，s)，1.29(3H，t，J＝7.0Hz)，1.24(3H，t，J＝7.0Hz)。LCMS(M+H)C₁₄H₂₃N₂O₇The calculated value of (a): 315.16, respectively; measurement value: 315.33.

intermediate 25

3-hydroxy-9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxylic acid ethyl ester intermediate 24, 2- (2-ethoxy-2-oxoethyl) -8, 8-dimethyl-2, 5, 6, 8-tetrahydro- [1, 2, 4- ]Oxadiazolo [3, 2-c ]][1，4]A solution of oxazine-2-carboxylic acid ethyl ester (31.16 g) in 1, 2, 4-trimethylbenzene (200 ml) was heated at 180 ℃ for 5 hours. The resulting black colored reaction solution was cooled and then concentrated to give a dark brown paste, which was taken up in ethyl acetate (250 m)L) in combination with 0.5M Na₂CO₃Aqueous (4X50mL) extraction. The organic layer was discarded and the aqueous layer was acidified by careful addition of concentrated HCl (20mL) followed by CH₂Cl₂(4X50 mL). To merge CH₂Cl₂Layer drying (Na)₂SO₄) Filtered and concentrated to give a blackish paste, which was dissolved in ether (100mL) and allowed to stand in an open flask at room temperature. The resulting brown/light yellow solid was filtered to give the title compound. The mother liquor containing the product was reprocessed to yield additional material (combined yield of two steps-18-20%).¹H NMR(500MHz，CDCl₃)δ：10.55(1H，s)，4.45(2H，q，J＝7.0Hz)，4.02(4H，s)，1.61(6H，s)，1.43(3H，t，J＝7.0Hz)。HRMS(M+H)C₁₂H₁₇N₂O₅The calculated value of (a): 269.1138, respectively; measurement value: 269.1149.C₁₂H₁₆N₂O₅Analytical calculation of (a): c, 53.72; h, 6.01; n, 10.44. Measurement value: c, 53.71; h, 6.04; and N, 10.30.

Intermediate 26

3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxylic acid ethyl ester to intermediate 25, 3-hydroxy-9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ][1，4]To a stirred solution of oxazine-2-carboxylic acid ethyl ester (2.68g, 10mmol) and benzyl bromide (1.43 mL, 12mmol) in DMF (40 mL) was added K₂CO₃(2.07 g, 20 mmol). After stirring at room temperature for 48 hours, the reaction mixture was diluted with ether (100mL) and washed with water (3X30mL) and brine (20 mL). The organic layer was dried (Na)₂SO₄Activated carbon), filtered and concentrated to give a yellow solid. Trituration with hexanes/diethyl ether (9: 1) gave the title compound as an off-white solid (2.79g, 78% yield).¹H NMR(500MHz，CDCl₃)δppm：7.48-7.45(2H，m)，7.37-7.30(3H，m)，5.25(2H，s)，4.33(2H，q，J＝7.3Hz)，4.05-3.99(4H，m)，1.62(6H，s)，1.29(3H，t，J＝7.3Hz)。HRMS(M+H)C₁₉H₂₃N₂O₅The calculated value of (a): 359.1607, respectively; measurement value: 359.1611.C₁₉H₂₂N₂O₅Analytical calculation of (a): c, 63.67; h, 6.18; n, 7.81; measurement value: c, 63.63; h, 6.16; n, 7.78.

Intermediate 27

3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxylic acid intermediate 26, 3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ]][1，4]Oxazine-2-carboxylic acid ethyl ester (2.93 g, 8.2mmol) and LiOH. H₂A mixture of O (0.84 g, 20mmol) in 4: 1 ethanol/tetrahydrofuran (50 mL) was stirred at room temperature for 2 h, then concentrated in vacuo. The resulting yellow residue was treated with 1N HCl (25mL) to form a precipitate, which was filtered and dried in vacuo to give the title compound as a white powder (2.68g, 99% yield). ¹H NMR(500MHz，CDCl₃)δppm：7.54-7.48(2H，m)，7.37-7.27(3H，m)，5.44(2H，s)，4.05-3.93(4H，m)，1.60(6H，s)。HRMS(M+H)C₁₇H₁₉N₂O₅The calculated value of (a): 331.1294, respectively; measurement value: 331.1308.C₁₇H₁₈N₂O₅Analytical calculation of (a): c, 61.81; h, 5.49; n, 8.48; measurement value: c, 61.84; h, 5.36; and N, 8.25.

Intermediate 28

To a solution of monopotassium phosphate (140 g, 1.11 mol) in water (250 ml) was added 3-pentanone (75.8 g, 0.88 mol), followed by a solution of sodium cyanide (54 g, 1.10 mol) in water (250 ml), and the resulting mixture was stirred for 3 hours. The mixture was extracted with ether (1x250mL, then 2x100mL) and the combined ether layers were washed with 1.0N HCl (200 mL). The ether solution was dried (Na)₂SO₄) Filtered and concentrated in vacuo. The crude product was purified by vacuum distillation (bp 87 ℃, 10mmHg) to give the title compound (72.4g, 3% yield) as a clear oil.¹H NMR(500MHz，CDCl₃)δppm：2.71(1H，s)，1.82(2H，q，J＝7.5Hz)，1.76(2H，q，J＝7.5Hz)，1.10(6H，t，J＝7.5Hz).¹³C NMR(500MHz，CDCl₃)δppm：121.21，73.53，32.81，8.27。

Intermediate 29

2- (2-chloroethoxy) -2-ethylbutyronitrile Zinc chloride (68.1g, 0.5mol) was melted in vacuo as described for the synthesis of intermediate 23. The molten zinc was cooled and the evacuated flask was purged with nitrogen. The flask was charged with intermediate 28, 2-ethyl-2-hydroxybutyronitrile (40.3 g, 0.5mol) and 2-chloroethanol (50.5 ml, 0.75mmol) and then stirred at 60 ℃ for 20 h. The reaction mixture was diluted with water (250 ml) and extracted with dichloromethane (1x250mL, 4x100 mL). The combined organic layers were dried (sodium sulfate), filtered and concentrated in vacuo. The crude product was purified by vacuum distillation (bp 83 ℃, 10mmHg) to give the title compound (52g) comprising unreacted intermediate 28. ¹H NMR(500MHz，CDCl₃)δppm：3.82(2H，t，J＝5.8Hz)，3.64(2H，t，J＝5.8Hz)，1.83(4H，J＝7.3Hz)，1.03(6H，t，J＝7.6Hz)。

Intermediate 30

Diethyl 2- (2, 2-diethyl-3-iminomorpholinooxy) but-2-enedioate a solution of the product mixture (0.171 mol) obtained in the synthesis of intermediate 29, 2- (2-chloroethoxy) -2-ethylbutyronitrile in absolute ethanol (150 ml) was added dropwise over 15 minutes to a solution of hydroxylamine (50% aqueous solution, 33.8 ml, 0.51 mol), sodium carbonate (9.1 g, 0.086 mol) and sodium iodide (2.55 g, 0.017 mol). The mixture was heated at 80 ℃ for 3 hours. The reaction was then concentrated to a thick slurry and azeotroped in vacuo with ethanol/water (1: 1, 100mL), water (100mL) and finally ethanol (100 mL). The residue was taken up in ethanol/water (1: 1, 160mL), cooled (0 deg.C) and treated with diethyl acetylenedicarboxylate (30.1mL, 0.188 mol). The reaction was stirred at room temperature for 2 hours, then diluted with water (200mL) and ethyl acetate (200 mL). The organic layer was separated, washed with water (200mL) and brine (100mL), then dried (sodium sulfate), filtered and concentrated in vacuo. The crude product was chromatographed on silica gel eluting with 10% to 40% ethyl acetate in ethane to give the title compound (25.7g) as a yellow oil.

Intermediate 31

9, 9-diethyl-3-hydroxy-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c) ][1，4]Intermediate 30, 2- (2, 2-diethyl-3-iminomorpholinooxy) diethyl but-2-enedioate (25.7 g) in 1, 2, 4-trimethylbenzene (100 ml) was heated at reflux (180 ℃ C.) for 16 h. The solvent was then removed in vacuo and the resulting oil was placed in a refrigerator until crystals began to form. The oil-crystal mixture was triturated with ether (50mL) and the solid collected by filtration and washed with a small volume of ether to form the titleCompound (9.02 g). A second crop (1.62g) was obtained from the filtrate.¹H NMR(500MHz，CDCl₃)δppm：10.54(1H，s)，4.44(2H，q，J＝7.0Hz)，4.00(4H，m)，2.00(2H，m)，1.92(2H，m)，1.42(3H，t，J＝7.0Hz)，0.85(6H，t，J＝7.3Hz).¹³C NMR(500MHz，CDCl₃)δppm：169.53，157.82，151.40，147.58，125.35，87.27，62.62，58.35，43.24，31.06，14.17，7.79。HRMS[M+H]⁺ C₁₄H₂₁N₂O₅The calculated value of (a): 297.14506, respectively; measurement value: 297.1464.

intermediate 32

2- (3-Chloropropoxy) -2-methylpropanenitrile Using the procedure described for the synthesis of intermediate 23, 2- (2-chloroethoxy) -2-methylpropanenitrile zinc chloride (68.1g, 0.5mol) was melted. The molten zinc was cooled and the flask purged with nitrogen. The flask was charged with acetone cyanohydrin (46 ml, 0.5mol) and 3-chloropropanol (64 ml, 0.75mmol), and the reaction mixture was stirred at 60 ℃ for 30 hours. The mixture was then diluted with water (200 ml) and extracted with dichloromethane (1x200mL and 3x100 mL). The combined organic layers were dried (sodium sulfate), filtered and concentrated in vacuo. The crude product was purified by vacuum distillation (bp 78-84 ℃ C., 10mmHg) to give a 2: 1 mixture of the title compound (41g) and residual 3-chloropropanol. ¹H NMR(500MHz，CDCl₃)δppm：3.72(2H，t，J＝5.8Hz)，3.63(2H，t，J＝6.4Hz)，2.04(2H，m)，1.57(6H，br s)。

Intermediate 33

2- (2- (3-chloropropoxy) propan-2-yl) -5-hydroxyEthyl 6-oxo-1, 6-dihydropyrimidine-4-carboxylate A solution of intermediate 32, 2- (3-chloropropyloxy) -2-methylpropanenitrile (0.186 mol) in absolute ethanol (40 ml) was added dropwise over 15 minutes to hydroxylamine (50% in water, 17ml, 0.278mol), 20 ml of H₂O, sodium carbonate (9.91 g, 0.093 mol) and sodium iodide (2.80 g, 0.019 mol) in a cold (0 ℃) solution. (in an alternative method, sodium carbonate is removed from the mixture). The mixture was stirred at room temperature for 30 minutes, then additional hydroxylamine (17mL, 0.278mol) was added. The reaction was then heated at 80 ℃ for 16 hours. The mixture was concentrated to a thick slurry, which was azeotroped with ethanol/water (1: 1, 100mL) in vacuo. The resulting residue was taken up in ethanol/water (1: 1, 200mL), cooled (0 deg.C), and treated by dropwise addition of acetylene dicarboxylic acid diethyl ester (30.1mL, 0.188mol) over 10 minutes. The reaction was stirred at room temperature for 2.5 hours, then diluted with water (300mL) and ethyl acetate (300 mL). The separated organic layer was washed with water (100mL) and brine (100mL), then dried (sodium sulfate), filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 10% to 40% ethyl acetate in hexane to give 21.2 g of a yellow oil. A solution of this oil (15.6g) in 1, 2, 4-trimethylbenzene (300mL) was heated at reflux (180 ℃ C.) for 2.5 hours, after which the solvent was removed in vacuo. The resulting oil was taken up in ethyl acetate (300mL) and extracted with saturated aqueous sodium bicarbonate (1x200mL, then 4x100 mL). The combined aqueous layers were acidified to pH 1-2 using 6NHCl and then extracted with ethyl acetate (3 × 150 mL). The organic extract was dried (sodium sulfate), filtered, and then concentrated in vacuo. The resulting oil was triturated with ether (50mL) and the resulting solid collected by filtration and washed with a small volume of ether to give the title compound (2.05 g). A second batch (0.70g) was obtained from the filtrate. ¹H NMR(500MHz，CDCl₃)δppm：10.83(1H，br)，10.02(1H，br)，4.46(2H，q，J＝7.0Hz)，3.66(2H，t，J＝6.1Hz)，3.58(2H，t，J＝5.8Hz)，2.06(2H，m)，1.55(6H，s)，1.44(3H，t，J＝7.0Hz)。

Intermediate 34

3- (benzoyloxy) -10, 10-dimethyl-4-oxo-6, 7, 8, 10-tetrahydro-4H-pyrimido [2, 1-c][1，4]OxazazemA solution of intermediate 33, 2- (2- (3-chloropropoxy) propan-2-yl) -5-hydroxy-6-oxo-1, 6-dihydropyrimidine-4-carboxylic acid ethyl ester (0.064 g, 0.2mmol) in pyridine (1ml) was treated with benzoic anhydride (0.047 g, 0.2mmol) and stirred at 60 ℃ for 1 hour. The solvent was removed and the residue taken up in N, N-dimethylformamide (1mL) and treated with potassium carbonate (0.036g, 0.2 mmol). The mixture was stirred at 80 ℃ for 1 hour, and the solvent was removed to give the title compound.

Intermediate 35

3- (benzyloxy) -10, 10-dimethyl-4-oxo-6, 7, 8, 10-tetrahydro-4H-pyrimido [2, 1-c][1，4]OxazazemA suspension of intermediate 33, 2- (2- (3-chloropropoxy) propan-2-yl) -5-hydroxy-6-oxo-1, 6-dihydropyrimidine-4-carboxylic acid ethyl ester (0.205 g, 0.64mmol) and anhydrous potassium carbonate (0.361 g, 2.6mmol) in anhydrous dimethylformamide (4 ml) was stirred at 60 ℃ for 5 h. The reaction mixture was treated with benzyl bromide (0.122g, 0.71mmol) and stirred for 16 h. Thereafter, 2mL of H was added₂O and the mixture was stirred for an additional 24 hours. The solvent was removed using a rotary evaporator, and the resulting residue was suspended in 0.5N hydrochloric acid (16 mL). The crude product was extracted with ethyl acetate (2 × 15mL), then dried (sodium sulfate), filtered and concentrated to dryness by rotary evaporator to give 0.299 g (yield > 100%) of the title compound as a solid. LC/MS [ M + H ]]⁺＝345.21。

Intermediate 36

3-hydroxy-10, 10-dimethyl-4-oxo-6, 7, 8, 10-tetrahydro-4H-pyrimido [2, 1-c][1，4]OxazazemIntermediate 33, ethyl 2- (2- (3-chloropropoxy) propan-2-yl) -5-hydroxy-6-oxo-1, 6-dihydropyrimidine-4-carboxylate (7.01 g, 22mmol) and anhydrous potassium carbonate (9.12 g, 66mmol) in anhydrous dimethylformamide (50ml) was stirred at 80 ℃ for 20 h. The solvent was removed by rotary evaporator and the residue was dissolved in water (50mL) and the pH was adjusted to 1 using 6.0N HCl. The solution was extracted with ethyl acetate (4 × 25 mL). The combined organic layers were dried (sodium sulfate) and filtered. The solvent was removed by rotary evaporator to give the title compound (5.53g, 89% yield) as a brown solid:¹H NMR(500MHz，CDCl₃)δppm10.49(1H，s)，4.56(2H，br)，4.43(2H，q，J＝7.2Hz)，3.69(2H，t，J＝6.4Hz)，1.93-1.99(2H，m)，1.61(6H，s)，1.42(3H，t，J＝7.2Hz)；¹³C NMR(126MHz，CDCl₃)δppm 169.33，158.30，153.39，148.73，124.45，82.85，62.60，60.71，38.79，27.67，27.35，14.15；HRMS(ESI)C₁₃H₁₉N₂O₅calculated value of (M + H): 283.1294, measurement: 283.1305.

intermediate 37

(4-Fluoronaphthalen-1-yl) methylamine hydrochloride A solution of 1-cyano-4-fluoronaphthalene (1.05g, 6.12mmol) and 1.5mL of HCl (aq.) in absolute ethanol (50mL) was stirred under an atmosphere of hydrogen (balloon) with 10% palladium on carbon (0.20g) for 16 h. The catalyst was removed by filtration through celite and the filtrate was concentrated in vacuo. The resulting solid was triturated with ether and collected by filtration to give the title compound (0.575g, 44% yield) as an off-white solid.

Intermediate body 38

Methyl 2- (aminomethyl) -5-fluorobenzoate trifluoroacetate methyl 2- ((tert-butoxycarbonyl) methyl) -5-fluorobenzoate prepared according to a literature procedure was treated with trifluoroacetic acid to give the title compound. The yield is 100%;¹H NMR(300MHz，DMSO-d6)δppm：3.89(3H，s)4.32(2H，q，J＝5.61Hz)7.51-7.71(2H，m)7.78(1H，dd，J＝9.33，2.38Hz)8.13(2H，brs)；LC/MS m/z 184(M+H)。

intermediate 39

To 4-fluoro-2- (methylcarbamoyl) benzylcarbamic acid tert-butyl ester (7.70 g, 27.3 mmol; prepared from 2-bromo-5-fluorobenzoic acid using literature methods) in CH₂Cl₂(100 ml) solution CF was added₃CO₂H (25 ml), and the mixture was stirred at room temperature for 15 minutes. It is concentrated in vacuo and the residue is triturated with diethyl ether to give 8.0g (99% yield) of the title compound as a white powder.¹H NMR(300MHz，D₂O)δppm：2.93(3H，s)4.20(2H，s)7.35(1H，dt，J＝8.5，3Hz)7.42(1H，dd，J＝9.0，2.7Hz)7.57(1H，dd，J＝8.4，5.5Hz)；LC/MSm/z 183(M+H)。

Intermediate 40

2- (aminomethyl) -N-cyclopropyl-5-fluorobenzamide trifluoroacetic acid tert-butyl 2- (cyclopropylcarbamoyl) -4-fluorobenzylcarbamate (130 mg, 0.42mmol) prepared according to the literature procedure in CH₂Cl₂The solution (5 mL) was stirred with trifluoroacetic acid (3mL) at room temperature for 10 minutes, then concentrated in vacuo to give 140mg (100% yield) of the title compound as a foam:¹H NMR(DMSO-d6，300MHz)δppm：0.62(2H，m，CH₂)，0.73(2H，m，CH₂)，2.86(1H，m，CH)，4.02-4.07(2H，ABq，NCH₂)，7.46(2H，m，Ar-Hs)，7.58(1H，m，Ar-H)，8.11(3H，br，NH₃)，8.81(1H，d，J＝4.4Hz，NH)；LC/MS m/z 209(M+H)。

intermediate 41

(5-fluoro-2-methylphenyl) (morpholino) methanone morpholine (870 mg, 10mmol) and triethylamine (1.1 g, 10.8mmol) in CH ₂Cl₂(15 ml) solution 5-fluoro-2-methylbenzoyl chloride (1.72 g, 10mmol) in CH was added dropwise₂Cl₂(5 ml) solution and the mixture was stirred for 15 minutes. The mixture was then washed with water and dried (MgSO)₄) The organic phase was filtered and concentrated to obtain 2.19g (98% yield) of the title compound as a solid:¹H NMR(500MHz，CDCl₃)δppm：2.27(3H，s)3.24(2H，d，J＝4Hz)3.58(2H，s)3.79(4H，dd，J＝18，3.8Hz)6.88(1H，dd，J＝8.2，2.8Hz)6.92-7.05(1H，m)7.18(1H，dd，J＝8.4，5.3Hz)。

intermediate body 42

(2- (bromomethyl) -5-fluorophenyl) (morpholino) methanone A mixture of intermediate 41, (5-fluoro-2-methylphenyl) (morpholino) methanone (2.1 g, 9.5mmol) and N-bromosuccinimide (2.0 g, 11mmol) was placed in CCl₄(30 ml) was heated under reflux. To the mixture was added benzoyl peroxide (242mg, 1mmol), and the mixture was heated under reflux for 2 hours. After cooling, the insoluble material was filtered and the filtrate was subjected to column chromatography (SiO)₂0-10% in CH₂Cl₂Diethyl ether) to yield 1.1g (38% yield) of the title compound as a clear oil:¹H NMR(300MHz，CDCl₃)δppm：3.31(2H，t，J＝4.94Hz)3.55-4.02(6H，m)4.56(2H，dd，J＝128.81，9.51Hz)6.89(1H，dd，J＝8.23，2.74Hz)6.96-7.12(1H，m)7.33-7.49(1H，m)；LC/MS m/z 302(M+H)。

intermediate 43

To a solution of intermediate 42, (2- (bromomethyl) -5-fluorophenyl) (morpholino) methanone (1.0 g, 3.32mmol) in dimethylformamide (10 ml) was added sodium azide (230 mg, 3.5mmol), and the mixture was stirred under a nitrogen atmosphere for 1 hour. The solvent was evaporated in vacuo and the residue was dissolved in CH ₂Cl₂Then, it is washed with water. Drying (Na)₂SO₄) The organic phase is filtered, concentrated and the residue is purified by column chromatography (SiO)₂，CH₂Cl₂) Purification yielded 770mg (88% yield) of the title compound as oil:¹H NMR(300MHz，CDCl₃)δppm：3.27(2H，s)3.51-3.65(2H，m)3.66-3.97(4H，m)4.38(2H，brs)6.92(1H，dd，J＝8.2，2.7Hz)7.07(1H，dt，J＝8.5，3Hz)7.34(1H，dd，J＝8.4，5.5Hz)；LC/MS m/z 265(M+H)。

intermediate 44

(2- (aminomethyl) -5-fluorophenyl) (morpholino) methanone hydrochloride to a solution of intermediate 43, (2- (azidomethyl) -5-fluorophenyl) (morpholino) methanone (770 mg, 2.92mmol) in ethanol (20 mL) was added 4N HCl (1 mL) and 10% Pd-C (100 mg), and the mixture was washed with 1atmH₂Hydrogenation was carried out for 3 hours. The catalyst was removed by filtration and the filtrate was concentrated. Subjecting the residue to C18 reverse phase silica gel column chromatography (YMC ODS, 0-5% CH)₃CN/H₂O) to yield 350mg (yield 44%) of the title compound, (2- (aminomethyl) -5-fluorophenyl) (morpholino) -methanone hydrochloride as a white powder:¹H NMR(300MHz，DMSO-d6)δppm：3.0-4.0(8H，m)，3.78(2H，t，J＝5Hz)，7.32(1H，dd，J＝8.8，2.6Hz)，7.35-7.44(1H，t，J＝8.5，3Hz)，7.75(1H，dd，J＝8.8，5.5Hz)；LC/MS m/z 239(M+H)。

intermediate 45

To a solution of 5-fluoro-2-methyl-benzenesulfonyl chloride (4.18 g, 20mmol) in tetrahydrofuran (25 ml) was added dropwise a solution of dimethylamine in tetrahydrofuran (2M, 25 ml, 50mmol) over 15 minutes and the mixture was stirred for 5 minutes. The insoluble material was filtered and the filtrate was concentrated. Subjecting the residue to column chromatography (SiO)₂5% in CH₂Cl₂Diethyl ether of (iv) to form 4.3g (yield 90%) of the title compound as a clear oil: ¹H NMR(500MHz，CDCl₃)δppm：2.57(3H，s)2.82(3H，s)2.82(3H，s)7.12-7.18(1H，m)7.28(1H，dd，J＝8.2，5.5Hz)7.59(1H，dd，J＝8.2，2.1Hz)；LC/MC m/z 218(M+H)。

Intermediate 46

2-bromomethyl-5-fluoro-N, N-dimethyl-benzenesulfonamide intermediate 45, 5-fluoro-2, N-trimethyl-benzenesulfonamide, (435 mg, 2.0mmol) and N-bromosuccinimide (391 mg, 2.2mmol) are placed in CCl at 80-90 ℃ under nitrogen atmosphere₄The mixture in (20 ml) was stirred for 5 minutes. To the mixture was added 2, 2' -azobisisobutyronitrile (AIBN, 100 mg) and stirring was continued at 80-90 ℃ for 30 minutes. After cooling, the insoluble precipitate was filtered and the filtrate was concentrated and purified by column chromatography (SiO)₂，CH₂Cl₂) Purification to yield 440mg (74% yield) of the title compound;¹H NMR(500MHz，CDCl₃)δppm：2.87(6H，s)4.86(2H，s)7.28(1H，dd，J＝8.55，2.75Hz)7.61-7.65(2H，m)；LC/MC m/z 296/298(M+H)。

intermediate 47

A mixture of intermediate 46, 2-bromomethyl-5-fluoro-N, N-dimethyl-benzenesulfonamide (880 mg, 2.97mmol) and sodium azide (200 mg, 3mmol) in dimethylformamide (4 ml) was stirred at 55-60 ℃ for 30 minutes before the solvent was removed in vacuo. The residue is in CH₂Cl₂Partition between water, wash the organic phase with water and dry (Na)₂SO₄) Filtered and concentrated to form 670mg (yield 87%) of the title compound as a yellow oil;¹H NMR(500MHz，CDCl₃)δppm：2.84(6H，s)4.78(2H，s)7.29-7.34(1H，m)7.59-7.64(2H，m)。

intermediate 48

To a solution of intermediate 47, 2-azidomethyl-5-fluoro-N, N-dimethyl-benzenesulfonamide (660 mg, 2.6mmol) in tetrahydrofuran (10 ml) and water (2 ml) was added triphenylphosphine (740 mg, 2.8mmol), and the mixture was stirred under nitrogen atmosphere for 1 hour. Tetrahydrofuran was evaporated in vacuo and the residue and a mixture of 6N HCl (3mL) in MeOH (5mL) was heated at 80 ℃ for 20 h. Using it with CH ₂Cl₂Washing with dilute NH₄Basification of the aqueous phase with OH and use of CH₂Cl₂And (4) extracting. Drying (Na)₂SO₄) The organic extract was filtered and concentrated to yield 210mg (0.91mmol, 35% yield) of the title compound;¹H NMR(500MHz，CDCl₃)δppm：2.84(6H，s)4.10(2H，s)7.23-7.29(1H，m)7.53-7.60(2H，m)；LC/MS m/z 233(M+H)。

intermediate 49

To a solution of 5-fluoro-2-methyl-benzenesulfonyl chloride (4.18 g, 20mmol) in acetone (20 ml) under nitrogen atmosphere was added 40% aqueous methylamine solution (4.5 ml, 60mmol) and the mixture was stirred for 5 minutes. Acetone was removed in vacuo and CH was used₂Cl₂The aqueous residue is extracted. Drying (Na)₂SO₄)CH₂Cl₂Extracting with water, filtering, concentrating, and mixingThe residue was purified by column chromatography (SiO)₂10% in CH₂Cl₂Diethyl ether of (1) to form 3.9g (19.2mmol, 96% yield) of the title compound as a white solid;¹H NMR(500MHz，CDCl₃)δppm：2.59(3H，s)，2.67(3H，d，J＝5.5Hz)，4.41(1H，brs)，7.13-7.20(1H，m)，7.29(1H，dd，J＝8.2，5.5Hz)，7.69(1H，J＝8.6，2.1Hz)；LC/MS m/z 204(M+H)。

intermediate 50

The title compound may be prepared from intermediate 49, 5-fluoro-2, N-dimethyl-benzenesulfonamide following the procedure described for intermediate 46 and by column chromatography (SiO)₂5% in CH₂Cl₂Diethyl ether in (iv) was purified.¹H NMR(500MHz，CDCl₃)δppm：2.64(3H，d，J＝5.19Hz)4.91(1H，d，J＝3.66Hz)4.98(2H，s)7.26-7.30(1H，m)7.54(1H，dd，J＝8.6，5.2Hz)7.73(1H，dd，J＝8.4，2.6Hz)；LC/MS m/z 282/284。

Intermediate 51

The title compound can be prepared from intermediate 50, 2-bromomethyl-5-fluoro-N-methyl-benzenesulfonamide following the procedure described for intermediate 47, and by column chromatography (SiO) as ₂5% Ether-CH₂Cl₂) And (5) purifying.¹H NMR(500MHz，CDCl₃)δppm：2.65(3H，d，J＝5.19Hz)4.81(2H，s)4.86(1H，d，J＝4.6Hz)7.27-7.33(1H，m)7.49(1H，dd，J＝8.2，5.2Hz)7.76(1H，dd，J＝8.2，2.8Hz)。

Intermediate body 52

2- (aminomethyl) -5-fluoro-N-methylbenzenesulfonamide hydrochloride to a solution of intermediate 51, 2-azidomethyl-5-fluoro-N-methyl-benzenesulfonamide (560 mg, 2.3mmol) in ethanol (10 ml) was added 6N HCl (1 ml) and 10% Pd-C (100 mg) and the reaction solution was purified using 1atm H₂The mixture was hydrogenated for 14 hours. The catalyst was removed by filtration through celite and the filtrate was concentrated in vacuo to yield 630mg (yield > 100%) of the title compound.¹H NMR(500MHz，DMSO-D6)δppm：4.36(2H，d，J＝5.2Hz)7.63-7.70(2H，m)7.77-7.83(1H，m)8.11(1H，d，J＝4.9Hz)8.41(3H，s)；LC/MS m/z 219(M+H)。

Intermediate 53

5-fluoro-2-methyl-benzenesulfonamide to a solution of 5-fluoro-2-methyl-benzenesulfonyl chloride (4.18 g, 20mmol) in acetone (20 mL) was added dropwise concentrated NH₄OH (3 ml) and the resulting mixture was stirred for 5 minutes. The acetone was removed in vacuo and the precipitate was filtered, washed thoroughly with water and dried in vacuo to yield 3.7g (98% yield) of the title compound as a white solid;¹H NMR(500MHz，DMSO-D6)δppm：2.55(3H，s)7.33-7.40(1H，m)7.40-7.46(1H，m)7.54(2H，s)7.59(1H，dd，J＝9.2，2.7Hz)；LC/MS m/z 190(M+H)。

intermediate body 54

The title compound may be prepared from intermediate 53, 5-fluoro-2-methyl-benzenesulfonamide following the procedure described for intermediate 46, and by column chromatography (SiO)₂5% Ether/CH₂Cl₂) And (5) purifying.¹H NMR(500MHz，CDCl₃)δppm：5.01(2H，s)5.16(2H，brs)7.25-7.31(1H，m)7.53(1H，dd，J＝8.5，5.2Hz)7.80(1H，dd，J＝8.5，2.7Hz).LC/MS m/z 268/270(M+H)。

Intermediate 55

2-azidomethyl-5-fluoro-N-methyl-benzenesulfonamide the title compound may be prepared from intermediate 54, 2-bromomethyl-5-fluoro-benzenesulfonamide following the procedure described for the preparation of intermediate 47. ¹H NMR(300MHz，CDCl₃)δppm：4.82(2H，s)5.18(2H，s)7.27(1H，m)7.45(1H，dd，J＝8.4，5.5Hz)7.79(1H，dd，J＝8.4，2.6Hz).LC/MSm/z 253(M+Na)。

Intermediate 56

The title compound can be prepared from intermediate 55, 2-azidomethyl-5-fluoro-N-methyl-benzenesulfonamide following the procedure described for the preparation of intermediate 48.¹H NMR(500MHz，DMSO-D6)δppm：4.05(2H，s)5.05(3H，br)7.44(1H，dt，J＝8.5，3Hz)7.58(1H，dd，J＝9.2，2.7Hz)7.66(1H，dd，J＝8.5，5.5Hz).LC/MS m/z 205(M+H)。

Intermediate 57

5- (2-bromo-5-fluoro-phenyl) -2-methyl-2H-tetrazole A mixture of 5- (2-bromo-5-fluoro-phenyl) -1H-tetrazole (1.0 g, 4.12mmol), methyl iodide (1.12 g, 10mmol) and potassium carbonate (1.5 g) in dimethylformamide (5 mL) is stirred at room temperature for 16 hours and then concentrated in vacuo. Subjecting the residue to column chromatography (SiO)₂，CH₂Cl₂) Purification gave 650mg (yield 61%) of the title compound as a white powder.¹H NMR(500MHz，CDCl₃)δppm：4.45(3H，s)7.03-7.11(1H，m)7.63(1H，dd，J＝8.9，3.1Hz)7.69(1H，dd，J＝8.9，5.5Hz)；¹³C NMR(126MHz，CDCl₃)δppm：39.86，116.28，118.66，118.76，130.13，135.73，161.74，163.53；LC/MS m/z 257/259。

Intermediate 58

4-fluoro-2- (2-methyl-2H-tetrazol-5-yl) -benzonitrile A mixture of intermediate 57, 5- (2-bromo-5-fluoro-phenyl) -2-methyl-2H-tetrazole (650 mg, 2.53mmol) and CuCN (224 mg, 2.5mmol) in dimethylformamide (4 mL) was placed in a sealed tube and heated at 110 ℃ for 20H. After cooling, the insoluble material was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in CH₂Cl₂In (1), diluting the NH with 4N aqueous HCl and₄OH washed and then dried (MgSO)₄) Filtered and concentrated. Subjecting the solid residue to column chromatography (SiO)₂，CH₂Cl₂) Purification gave 375mg (73% yield) of the title compound as an off-white solid; ¹H NMR(500MHz，CDCl₃)δppm：4.48(3H，s)7.29(1H，dd，J＝7.6，2.8Hz)7.85(1H，dd，J＝8.6，5.2Hz)8.00(1H，dd，J＝9.0，2.6Hz)；LC/MS m/z 204。

Intermediate 59

(4-fluoro-2- (2-methyl-2H-tetrazol-5-yl) phenyl) methylamine hydrochloride A solution of intermediate 58, 4-fluoro-2- (2-methyl-2H-tetrazol-5-yl) -benzonitrile (330 mg, 1.62mmol) in ethanol (15 mL) was combined with 6N HCl (1 mL) and 10% Pd-C (200 mg) under a nitrogen atmosphere. The mixture was then stirred in hydrogen (1atm) for 3 hours. After removal of the catalyst, the filtrate was concentrated in vacuo to yield 360mg (91% yield) of the title compound as an off-white solid;¹H NMR(500MHz，DMSO-D6)δppm：4.42(2H，d，J＝2.75Hz)4.49(3H，s)7.48-7.56(1H，m)7.78(1H，dd，J＝8.7，5.7Hz)7.86(1H，dd，J＝9.8，2.8Hz)8.45(3H，s)；LC/MS m/z 208。

intermediate body 60

5- (2-bromo-5-fluoro-phenyl) -1-methyl-2H-tetrazole A mixture of 5- (2-bromo-5-fluoro-phenyl) -1H-tetrazole (1.0 g, 4.12mmol), methyl iodide (1.12 g, 10mmol) and potassium carbonate (1.5 g) in dimethylformamide (5 mL) is stirred at room temperature for 16 hours and then concentrated in vacuo. Subjecting the residue to column chromatography (SiO)₂，CH₂Cl₂) Purification afforded 350mg (33% yield) of the title compound as white crystals.¹H NMR(500MHz，CDCl₃)δppm：4.00(3H，s)7.18-7.25(2H，m)7.72(1H，dd，J＝8.4，5.0Hz)；¹³C NMR(126MHz，CDCl₃)δppm：34.59，117.73，119.58，120.43，127.57，135.11，153.43，161.69.LC/MS m/z 257/259。

Intermediate 61

4-fluoro-2- (1-methyl-2H-tetrazol-5-yl) -benzonitrile.¹H NMR(300MHz，CDCl₃)δppm：4.13(3H，s)7.38-7.49(2H，m)7.86-7.97(1H，m)；LC/MS m/z204(M+H)。

Intermediate 62

(4-fluoro-2- (1-methyl-2H-tetrazol-5-yl) phenyl) methylamine hydrochloride.¹H NMR(500MHz，DMSO-D6)δppm：4.05(2H，s)4.09(3H，s)7.58-7.67(1H，m)7.77(1H，dd，J＝9.3，2.6Hz)7.87(1H，dd，J＝8.7，5.7Hz)8.38(3H，s)；LC/MSm/z 208。

Intermediate 63

Triethylamine (1.5 g, 15mmol) was added to a cold stirred solution of 3-m-tolyl-3-trifluoromethyl-diazirine (2.0 g, 10mmol, prepared using the method described in Doucet-Personeni C. et al, J.Med.Chem., 2001, 44, 3203 and Nassal, M.Liebigs Ann.Chem.1983, 1510-Buckoor K et al, J.Med.Chem., 2002, 45, 4038-46) in ethanol (20 ml). To the mixture was added tert-butyl hypochlorite (3.25g, 30mmol) and the mixture was stirred for 5 minutes. The mixture was poured into 10% aqueous sodium sulfite (100mL) and extracted with ether. The ether extract was washed with brine and dried (MgSO) ₄) Filtered and concentrated. Subjecting the residue to column chromatography (SiO)₂Pentane) to afford 1.6g (80% yield) of the title compound.¹H NMR(300MHz，CDCl₃)δppm：2.33(3H，s)6.90-7.03(2H，m)7.15-7.31(2H，m)。

Intermediate 64

3- (3-Bromomethyl-phenyl) -3-trifluoromethyl-3H-diazepan to intermediate 63, 3-m-tolyl-3-trifluoromethyl-3H-diazepan (200 mg, 1mmol) in CCl₄To the solution (4 ml) was added N-bromosuccinimide (200 mg, 1.1mmol, recrystallized from water) and the stirred mixture was heated at 85 ℃. AIBN (50mg) was added thereto, and the mixture was heated under reflux for an additional 2.5 hours. After cooling, the mixture was subjected to column chromatography (SiO)₂Pentane) to form 150mg (yield 54%) of the title compound as a clear oil.¹H NMR(300MHz，CDCl₃)δppm：4.42(2H，s)7.10-7.17(2H，m)7.31-7.45(2H，m)。

Intermediate 65

2- [3- (3-trifluoromethyl-diaziridin-3-yl) -benzyl]A mixture of intermediate 64, 3- (3-bromomethyl-phenyl) -3-trifluoromethyl-3H-diazepane (140 mg, 0.5mmol) and potassium phthalimide (95 mg, 0.5mmol) in dimethylformamide (1.5 ml) was stirred at room temperature for 3 hours. Dimethylformamide was removed in vacuo. The residue is treated with CH₂Cl₂Extracting, washing with water, and drying (Na)₂SO₄) Filtered and concentrated. The residue obtained is subjected to column chromatography (SiO) ₂，1∶1 CH₂Cl₂Pentane) to provide 140mg (yield 82%) of the title compound as a solid;¹H NMR(300MHz，CDCl₃)δppm：4.80(2H，s)7.09-7.21(2H，m)7.32(1H，t，J＝7.9Hz)7.41-7.49(2H，m)7.66-7.71(2H，m)7.81-7.85(2H，m)；LC/MS m/z 346(M+H)。

intermediate 66

(3- (3- (trifluoromethyl) diaziridin-3-yl) phenyl) methylamine intermediate 65, 2- [3- (3-trifluoromethyl-diaziridin-3-yl) -benzyl at room temperature]A stirred solution of (E) -isoindole-1, 3-dione (150 mg, 0.43mmol) in ethanol (2 mL) was treated with hydrazine hydrate (0.4mL) and the solution was stirred for 3.5 hours. After removal of ethanol in vacuo, the residue was taken up in CH₂Cl₂And water. Acidifying the aqueous phase with diluted HCl and CH₂Cl₂And (6) washing. Basification of the aqueous phase with diluted NaOH, addition of CH₂Cl₂And (4) extracting. Drying the organic extract (MgSO)₄) Filtered and concentrated to give 50 mg (54% yield) of a 1: 1 mixture of (3- (3- (trifluoromethyl) diaziridin-3-yl) phenyl) methylamine and (3- (3- (trifluoromethyl) -3H-diazaspin-3-yl) phenyl) methylamine;¹H NMR(300MHz，CDCl₃) δ ppm: 3.85(2H, s)3.88(2H, s)7.08(2H, s)7.31-7.40(4H, m)7.43-7.50(1H, m, J ═ 6.2Hz)7.54(1H, s); LC/MS M/z 216(M + H diazirine) and 218(M + H diazirine).

Intermediates 67 to 68

To 2, 4-difluorobenzonitrile (10 g, 72mmol) dissolved in tetrahydrofuran (20 ml) and dimethylformamide (40 ml) was added 1, 2, 4-triazole sodium salt (6.3 g, 70mmol) and the mixture was stirred at 90 ℃ for 3 hours, after which the mixture was filtered and the solvent was removed. The resulting residue was adsorbed onto silica gel and intermediates 67 and 68 were separated by flash chromatography, eluting with 0% to 30% ethyl acetate/hexanes.

Intermediate 67

4-fluoro-2- (1H-1, 2, 4-triazol-1-yl) benzonitrile colorless, needle crystals (2.46 g, 18% yield)¹H NMR(500MHz，CDCl₃)δ：8.89(1H，s)，8.19(1H，s)，7.85(1H，dd，J＝8.7，5.6Hz)，7.60(1H，dd，J＝8.8，2.4Hz)，7.28-7.24(1H，m)。LCMS(M+H)C₉H₆N₄Calculated value of F: 189.05, respectively; measurement value: 189.13.

intermediate 68

4- (1H-1, 2, 4-triazol-1-yl) -2-fluorobenzonitrile white solid (0.746 g, 6% yield)¹H NMR(500MHz，CDCl₃)δ：8.66(1H，s)，8.15(1H，s)，7.79(1H，dd，J＝8.5，6.7Hz)，7.69(1H，dd，J＝9.5，1.8Hz)，7.65-7.63(1H，m)。LCMS(M+H)C₉H₆N₄Calculated value of F: 189.05, respectively; measurement value: 189.13.

intermediate 69

(4-fluoro-2- (1H-1, 2, 4-triazol-1-yl) phenyl) methanamine hydrochloride intermediate 67, 4-fluoro-2- (1H-1, 2, 4-triazol-1-yl) benzonitrile (2.46 g, 13.13mmol) was dissolved in hot ethanol (150 ml). To this was added 1N HCl (15 mL) followed by 10% Pd-C (200 mg). Using 55psi H in a Parr Oscillator₂The mixture was treated for 4 hours, then filtered through celite and the solvent removed under reduced pressure. The residue obtained is taken up in ethyl acetate and waterAre distributed among the devices. The aqueous phase was separated and lyophilized to give the title compound as a white powder (2.96g, 99% yield).¹H NMR(500MHz，CD₃OD)δppm：9.51(1H，s)，8.63(1H，s)，7.85(1H，dd，J＝8.5，5.8Hz)，7.68(1H，dd，J＝8.8，2.4Hz)，7.49(1H，td，J＝8.3，2.4Hz)，4.20(2H，s)。LCMS(M+H)C₉H₁₀N₄Calculated value of F: 193.08, respectively; measurement value: 193.16.

intermediate 70

(2-fluoro-4- (1H-1, 2, 4-triazol-1-yl) phenyl) methanamine hydrochloride the title compound may be prepared from intermediate 68 following the procedure described for the synthesis of intermediate 69. White powder (79% yield). ¹H NMR(500MHz，CD₃OD)δppm：9.25(1H，s)，8.46(1H，s)，7.80(1H，dd，J＝8.6，5.8Hz)，7.64(1H，dd，J＝8.8，2.4Hz)，7.44(1H，td，J＝8.3，2.6Hz)，4.17(2H，s)。LCMS(M+H)C₉H₁₀N₄Calculated value of F: 193.08, respectively; measurement value: 193.16.

intermediates 71-74

Intermediates 71-74 were prepared using the procedure described for the synthesis of intermediates 67-70.

Intermediate 71

4-fluoro-2-morpholinobenzonitrile¹H NMR(500MHz，CDCl₃)δppm：7.55(1H，dd，J＝8.5，6.4Hz)，6.71(1H，td，J＝8.1，2.3Hz)，6.67(1H，dd，J＝11.0，2.4Hz)，3.88(4H，t，J＝4.6Hz)，3.22(4H，t，J＝4.6Hz)。LCMS(M+H)C₁₁H₁₂N₂Calculated OF: 207.09, respectively; measurement value: 207.19.

intermediate 72

4-morpholino-2-fluorobenzonitrile.¹H NMR(500MHz，CDCl₃)δppm：7.42(1H，dd，J＝8.8，7.6Hz)，6.63(1H，dd，J＝8.8，2.4Hz)，6.56(1H，dd，J＝12.8，2.4Hz)，3.84(4H，t，J＝4.9Hz)，3.28(4H，t，J＝4.9Hz)。LCMS(M+H)C₁₁H₁₂N₂Calculated OF: 207.09, respectively; measurement value: 207.19.

intermediate 73

(4-fluoro-2-morpholinophenyl) methylamine hydrochloride.¹H NMR(500MHz，CDCl₃)δppm：7.54(1H，t，J＝7.3Hz)，7.20(1H，dd，J＝10.5，2.0Hz)，7.05-7.02(1H，m)，4.28(2H，s)，3.93(4H，bs)，3.03(4H，bs)。LCMS(M+H)C₁₁H₁₆N₂Calculated OF: 211.12, respectively; measurement value: 211.23.

intermediate body 74

(2-fluoro-4-morpholinophenyl) methylamine hydrochloride.¹H NMR(500MHz，CD₃OD)δppm：7.73(1H，t，J＝8.2Hz)，7.62(1H，d，J＝7.6Hz)，7.58(1H，d，J＝8.2Hz)，4.26(2H，s)，4.11(4H，t，J＝4.4Hz)，3.65(4H，t，J＝4.4Hz)。LCMS(M+H)C₁₁H₁₆N₂Calculated OF: 211.12, respectively; measurement value: 211.23.

intermediate 75

4-fluoro-2- (1, 1-dioxo-1. lamda.)⁶-[1，2]Thiazinan-2-yl) benzonitrile to 2, 4-difluorobenzonitrile (10.0 g, 72mmol) and 1, 1-dioxo-1. lambda⁶-[1，2]Thiazin-2-ane (8.84 g, 65.4mmol) to a 1: 1 mixture of tetrahydrofuran/dimethylformamide (40 mL) was added potassium carbonate (9.0 g, 65.4 mmol). The mixture was stirred at 90 ℃ for 18 hours, then filtered and concentrated. By flash chromatography (SiO)₂) The residue was purified, eluting with 10% -50% ethyl acetate/hexane, then recrystallized from hot ethyl acetate/hexane to give the title compound as white needles (0.537g, 3% yield). ¹H NMR(500MHz，CD₃OD)δppm：7.70(1H，dd，J＝8.8，5.8Hz)，7.30(1H，dd，J＝8.8，2.4Hz)，7.15-7.12(1H，m)，3.27(2H，t，J＝5.3Hz)，3.33(2H，t，J＝6.1Hz)，2.40-2.35(2H，m)，2.05-2.01(2H，m)。LCMS(M+H)C₁₁H₁₆N₂Calculated OF: 255.06, respectively; measurement value: 255.19.

intermediate 76

(4-fluoro-2- (1, 1-dioxo-1. lamda.)⁶-[1，2]Thiazinan-2-yl) phenyl) methylamine hydrochloride the intermediate 75, 4-fluoro-2- (1, 1-dioxo-1. lambda⁶-[1，2]Thiazinan-2-yl) benzonitrile (1.37 g, 5.4mmol) was dissolved in ethanol (120 ml). 1N HCl (20 ml) and a catalytic amount of 10% Pd-C were added. The mixture was shaken under 55psi of hydrogen for 4 hours and then passedCelite was filtered and concentrated to give the title compound as a white solid (1.58g, 100% yield).¹H-NMR(300MHz，CD₃OD)δppm：7.61(1H，dd，J＝8.4，6.2Hz)，7.38(1H，dd，J＝9.3，2.7Hz)，7.28(1H，td，J＝8.2，2,7Hz)，7.26(2H，dd，J＝21.4，13.7Hz)，3.93-3.84(1H，m)，3.50-3.41(3H，m)，2.40-2.31(2H，m)，2.04-1.96(2H，m)。LCMS[M+H]⁺ C₁₁H₁₆N₂O₆Calculation of FS: 259.087, respectively; measurement value: 259.24.

intermediates 77 to 78

To a solution of 1H-1, 2, 3-triazole (3.5 g, 50.7mmol) in tetrahydrofuran (10 mL) and dimethylformamide (20 mL) was added NaH (1.3 g, 51mmol, 95%) in portions. The mixture was stirred at room temperature for 30 minutes. 2, 4-difluorobenzonitrile (7.6 g, 55mmol) was added and the mixture was stirred at 85 ℃ for 3 hours. The white mixture was concentrated and purified by flash chromatography, eluting with 0% to 10% ethyl acetate/hexanes to give intermediates 77 and 78.

Intermediate 77

4-fluoro-2-1, 2, 3-triazol-2-yl-benzonitrile white needle crystals (0.34 g, 3% yield). 1H-NMR (300MHz, CDCl) ₃)δppm：7.92(2H，s)，7.88-7.79(2H，m)，7.19-7.12(1H，m)。LCMS[M+H]+C₉H₆N₄Calculated value of F: 189.05, respectively; measurement value: 189.12.

intermediate 78

2-fluoro-4-1, 2, 3-triazol-2-yl-benzonitrile white solid (0.097)G, 1% yield).¹H-NMR(300MHz，CDCl₃)δppm：8.03-7.95(2H，m)，7.86(2H，s)，7.74-7.69(1H，m)。

Intermediate 79

4-fluoro-2-1, 2, 3-triazol-2-yl-benzylamine hydrochloride intermediate 77, 4-fluoro-2-1, 2, 3-triazol-2-yl-benzonitrile (0.34 g, 1.8mmol) was dissolved in ethanol (50 ml). 1N HCl (10 mL) and a catalytic amount of 10% Pd-C were added. The mixture was placed in 55psiH₂After shaking for 4 hours under conditions, it was filtered through celite and concentrated to give the title compound as the corresponding HCl salt. Yellow solid (0.402 g, 98% yield).¹H-NMR(500MHz，CD₃OD)δppm：8.13(2H，s)，7.87(1H，dd，J＝4.9，2.6Hz)，7.73(1H，dd，J＝4.9，2.6Hz)，7.34(1H，td，J＝8.2，2.7Hz)，4.35(2H，s)。LCMS[M+H]⁺C₉H₁₀N₄Calculated value of F: 193.08, respectively; measurement value: 193.16.

intermediate 80

(2-fluoro-4- (2H-1, 2, 3-triazol-2-yl) phenyl) methylamine: the title compound may be prepared from intermediate 78, 2-fluoro-4-1, 2, 3-triazol-2-yl-benzonitrile according to the method providing intermediate 79.¹H-NMR(300MHz，CD₃OD)δppm：8.05-7.96(2H，m)，8.00(2H，s)，7.68(1H，t，J＝8.2Hz)，4.26(2H，s)。LCMS[M+H]⁺ C₉H₁₀N₄Calculated value of F: 193.08, respectively; measurement value: 193.14.

intermediates 81 to 84

A solution of 2, 4-difluorobenzonitrile (7.07 g, 50.8mmol) and 3-methyl-1H-1, 2, 4-triazole (4.22 g, 50.8mmol) in N, N-dimethylformamide (45 ml) was treated with powdered anhydrous potassium carbonate (10 g), and the resulting mixture was stirred at 22 ℃ for 18 hours. The solid was then filtered and the filtrate was concentrated in vacuo. The residue was diluted with ethyl acetate, washed with water and brine, then dried over anhydrous magnesium sulfate and concentrated. The resulting mixture was purified by a combination of silica gel chromatography (gradient elution of ethyl acetate in hexanes) and reverse phase silica gel chromatography to afford intermediates 81-84.

Intermediate 81

4-fluoro-2- (3-methyl-1H-1, 2, 4-triazol-1-yl) benzonitrile white crystals (ethyl acetate-hexane); mp: 117 ℃ and 118 ℃.¹HNMR 400MHz(CDCl₃)δppm：2.54(3H，s，CH₃) 7.24(1H, m, CH), 7.62(1H, dd, J ═ 2.5Hz and J ═ 9.1Hz, CH), 7.84(1H, dd, J ═ 5.6Hz and J ═ 8.6Hz, CH), 8.82(1H, s, CH)₁₀H₇FN₄Analytical calculation of (a): c59.40, H3.49, N27.71; measurement value: c59.25, H3.32, N27.81.

Intermediate 82

4-fluoro-2- (5-methyl-1H-1, 2, 4-triazol-1-yl) benzonitrile white crystals (ethyl acetate-hexane); mp: 120 ℃ and 121 ℃.¹HNMR 400MHz(CDCl₃)δppm：2.56(3H，s，CH₃) 7.30(1H, dd, J-2.5 Hz and J-8.1 Hz, CH), 7.39(1H, m, CH), 7.91(1H, dd, J-5.5 Hz and J-8.6 Hz, CH), 8.06(1H, s, CH)₁₀H₇FN₄Analytical calculation of (a): c59.40, H3.49, N27.71; measurement value: c59.35, H3.70, N27.77.

Intermediate 83

2-fluoro-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) benzonitrile white crystals (ethyl acetate-hexane); mp: 133 ℃ and 134 ℃.¹HNMR 400MHz(CDCl₃)δppm：2.52(3H，s，CH₃) 7.61(1H, dd, J2 Hz and J9.1 Hz, CH), 7.67(1H, dd, J2 Hz and J9.6 Hz, CH), 7.79(1H, dd, J6.5 Hz and J8.6 Hz, CH), 8.56(1H, s, CH)₁₀H₇FN₄Analytical calculation of (a): c59.40, H3.49, N27.71; measurement value: c59.42, H3.24, N28.41.

Intermediate 84

2-fluoro-4- (5-methyl-1H-1, 2, 4-triazol-1-yl) benzonitrile white crystals (ethyl acetate-hexane); mp: 89-90 ℃.¹HNMR 400MHz(CDCl₃)δppm：2.69(3H，s，CH₃) 7.49-7.55(2H, m, 2xCH), 7.83(1H, dd, J ═ 6.8Hz and J ═ 8.8Hz, CH), 8.00(1H, s, CH)₁₀H₇FN₄Analytical calculation of (a): c59.40, H3.49, N27.71; measurement value: c59.17, H3.22, N28.01.

Intermediate 85

(4-fluoro-2- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl) methanamine hydrochloride intermediate 81, 4-fluoro-2- (3-methyl-1H-1, 2, 4-triazol-1-yl) benzonitrile (0.680 g, 3.36mmol) was hydrogenated to give 0.720 g (88% yield) of the title hydrochloride salt as a white solid.¹HNMR 400MHz(DMSO-d₆)δppm：2.40(3H，s，CH₃)，4.02(2H，m，NCH₂) 7.50(1H, m, CH), 7.62(1H, dd, J ═ 2.8Hz and J ═ 9.3Hz, CH), 7.84(1H, dd, J ═ 6.1Hz and J ═ 9.1Hz, CH), 9.00(1H, s, CH). HRMS (ESI)⁺)C₁₀H₁₂FN₄[M+H⁺]The calculated value of (a): 207.1046, respectively; measurement value: 207.1047.

intermediate 86

(4-fluoro-2- (5-methyl-1H-1, 2, 4-triazol-1-yl) phenyl) methylamine hydrochloride intermediate 82, 4-fluoro-2- (5-methyl-1H-1, 2, 4-triazol-1-yl) benzonitrile (0.244 g, 1.20mmol) was hydrogenated to give 0.290 g (100% yield) of the title hydrochloride salt as a white solid.¹HNMR 400MHz(DMSO-d₆)δppm：2.42(3H，s，CH₃)，3.78(2H，m，NCH₂) 7.58(1H, m, CH), 7.67(1H, dd, J ═ 2.8Hz and J ═ 9.3Hz, CH), 7.90(1H, dd, J ═ 6.0Hz and J ═ 8.6Hz, CH), 8.22(1H, s, CH). HRMS (ESI) ⁺)C₁₀H₁₂FN₄[M+H⁺]The calculated value of (a): 207.1046, respectively; measurement value: 207.1041.

intermediate 87

(2-fluoro-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl) methylamine hydrochloride intermediate 83, 2-fluoro-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) benzonitrile (0.220 g, 1.09mmol) was hydrogenated to give 0.260 g (98% yield) of the title hydrochloride salt as a white solid.¹HNMR 400MHz(DMSO-d₆)δppm：2.38(3H，s，CH₃)，4.09(2H，m，NCH₂) 7.75-7.8(2H, m, 2xCH), 7.83(1H, dd, J ═ 2Hz and J ═ 9Hz, CH), 9.29(1H, s, CH). MS (ESI)⁺)m/e 207[M+H⁺]。

Intermediate 88

4-fluoro-2-imidazol-1-yl-benzonitrile to a solution of imidazole (4.45 g, 65.4mmol) in tetrahydrofuran (30 ml) and dimethylformamide (10 ml) was added potassium carbonate (9.95 g, 72mmol) and the mixture was stirred at room temperature for 30 min. 2, 4-Difluorobenzonitrile (10.0 g, 72mmol) was added thereto, and the mixture was stirred at 90 ℃ for 3 hours and then at room temperature for 2 days. The mixture was filtered and concentrated, and the residue was purified by flash chromatography (SiO)₂) Purification, eluting with 20% to 70% ethyl acetate/hexanes, gave the title compound as white needles (1.1g, 9% yield).¹H-NMR(500MHz，CDCl₃)δppm：7.94(1H，s)，7.84(1H，dd，J＝8.7，5.6Hz)，7.37(1H，t，J＝8.7，5.6Hz)，7.37(1H，t，J＝1.4Hz)，7.29(1H，t，J＝1.1Hz)，7.27-7.21(2H，m)。LCMS[M+H]⁺ C₁₀H₇N₃Calculated value of F: 188.058, respectively; measurement value: 188.12.

intermediate 89

(4-fluoro-2- (1H-imidazol 1-yl) phenyl) methylamine) hydrochloride following the procedure which affords intermediate 79, starting from intermediate 88, 4-fluoro-2-imidazole- 1-Yl-benzonitrile the title compound can be prepared. A yellow solid, which is a solid,¹H-NMR(500MHz，CD₃OD)δppm：9.39(1H，s)，7.98(1H，d，J＝1.5Hz)，7.92-7.89(2H，m)，7.63-7.59(2H，m)，4.11(2H，s)。LCMS[M+H]⁺ C₁₀H₁₁N₃calculated value of F: 192.09, respectively; measurement value: 192.15.

intermediate 90

1- (2-cyano-5-fluoro-phenyl) -1H-1, 2, 4-triazole-3-carboxylic acid methyl ester to a solution of 1H-1, 2, 4-triazole-3-carboxylic acid methyl ester (27g, 215mmol) in dimethylformamide (170 mL) was added sodium hydride (5.53 g, 95%, 217mmol) and the mixture was stirred for 30 min. 2, 4-difluorobenzonitrile (30 g, 217mmol) was added thereto, and the resulting mixture was stirred at room temperature for 60 hours. The mixture was diluted with water, filtered and the solid removed. The solution was extracted with ethyl acetate and washed with water (3X's) and brine, then dried (Na)₂SO₄) And concentrated. By flash chromatography (SiO)₂) The resulting residue was purified with 30% tetrahydrofuran/20% CH₂Cl₂Elution with 50% hexanes gave the title compound as white needles (5.34g, 10% yield).¹H-NMR(300MHz，CDCl₃)δppm：8.92(1H，s)，7.85(1H，dd，J＝8.8，5.5Hz)，7.67(1H，dd，J＝8.8，2，6Hz)，7.34-7.27(1H，m)，40.3(3H，s)。LCMS[M+H]⁺ C₁₁H₈N₄FO₂The calculated value of (a): 247.06, respectively; measurement value: 247.11.

intermediate 91

1- (2- (aminomethyl)Methyl 5-fluorophenyl) -1H-1, 2, 4-triazole-3-carboxylate the title compound may be prepared from intermediate 90, 1- (2-cyano-5-fluoro-phenyl) -1H-1, 2, 4-triazole-3-carboxylic acid methyl ester.¹H-NMR(300MHz，CD₃OD)δppm：9.15(1H，s)，7.80(1H，dd，J＝8.8，5.9Hz)，7.71(1H，dd，J＝8.8，2.6Hz)，7.46(1H，td J＝8.2，2.6Hz)，4.19(2H，s)，4.03(3H，s)。LCMS[M+H]⁺ C₁₁H₁₂N₄O₂The calculated value of (a): 251.09, respectively; measurement value: 251.17.

Intermediate 92

3-fluoro-2- (1, 1-dioxo-1. lamda.)⁶-[1，2]Thiazinan-2-yl) benzonitrile to 1, 1-dioxo-1. lambda. dissolved in tetrahydrofuran (8 ml) and dimethylformamide (2 ml)⁶-[1，2]To a solution of thiazin-2-ane (1.90 g, 14.4mmol) was added sodium hydride (0.36 g, 95%, 14.4mmol), and the mixture was stirred for 20 minutes. 2, 3-difluorobenzonitrile (2.0 g, 14.4mmol) was added thereto, and the mixture was stirred at 90 ℃ for 2 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with water and brine and then concentrated. The solid residue was triturated with 1: 1 ethyl acetate/hexane to give the title compound as a pale brown solid (0.47g, 13% yield).¹H-NMR(500MHz，CDCl₃)δppm：7.47-7.45(1H，m)，7.32-7.36(2H，m)，4.08-4.02(1H，m)，3.57(1H，td，J＝13.0，3,7Hz)，3.40-3.34(1H，m)，3.32-3.27(1H，m)，2.44-2.32(2HF，m)，2.04-1.97(2H，m)，1.90-1.84(1H，m)。LCMS[M+H]⁺ C₁₁H₁₂N₂FO₂Calculated value of S: 255.28, respectively; measurement value: 255.13.

intermediate 93

3-fluoro-2- (1, 1-dioxo-1. lamda.)⁶-[1，2]Thiazinan-2-yl) benzylamine hydrochloride following the procedure which provides intermediate 79, from intermediate 92, 3-fluoro-2- (1, 1-dioxo-1. lambda⁶-[1，2]Thiazinan-2-yl) benzonitrile the title compound can be prepared. A white solid, a solid which is,¹H-NMR(500MHz，CD₃OD)δppm：7.56-7.52(1H，m)，7.40-7.34(2H，m)，4.31(2H，s)，3.98-3.93(1H，m)，3.68-3.64(1H，m)，3.42-3.39(2H，m)，2.42-2.37(2H，m)，2.03-1.92(2H，m)。LCMS[M+H]⁺ C₁₁H₁₆N₂O₂calculation of FS: 259.09, respectively; measurement value: 259.18.

intermediate 94

3-fluoro-2-1, 2, 4-triazol-1-yl-benzonitrile A mixture of 2, 3-difluorobenzonitrile (2.27 g, 16.3mmol) and triazole sodium salt (1.33 g, 14.8mmol) in tetrahydrofuran (5 ml) and dimethylformamide (10 ml) was stirred at 85 ℃ for 4 hours. After concentration, the residue was purified by flash chromatography (SiO) ₂) Purify, elute with 25% -50% ethyl acetate/hexanes. The isolated product was recrystallized from hot ethyl acetate/hexane to give the title compound as white needle crystals (1.51g, 54% yield).¹H-NMR(500MHz，CDCl₃)δppm：8.50(1H，d，J＝2.4Hz)，8.25(1H，s)，7.69-7.67(1H，m)，7.60-7.57(2H，m)。LCMS[M+H]⁺ C₉H₆N₄Calculated value of F: 189.16, respectively; measurement value: 189.14.

intermediate 95

(3-fluoro-2- (1H-1, 2, 4-triazol-1-yl) phenyl) methylamine the title compound may be prepared from intermediate 94, 3-fluoro-2-1, 2, 4-triazol-1-yl-benzonitrile.¹H-NMR(500MHz，CD₃OD)δppm：9.61(1H，d，J＝2.9Hz)，8.79(1H，s)，7.82-7.74(1H，m)，7.67-7.57(2H，m)，4.14-4.13(2H，m)。LCMS[M+H]⁺ C₉H₁₀N₄Calculated value of F: 193.08, respectively; measurement value: 193.16.

intermediate 96

5-fluoro-2- (1H-1, 2, 4-triazol-1-yl) benzonitrile A suspension of 2, 5-difluorobenzonitrile (4.5 g, 32.35mmol) and 1, 2, 4-triazole sodium salt (3.6 g, 40mmol) in dimethylformamide (40 ml) was heated at 80 ℃ for 15 hours. The reaction mixture is then cooled with CH₂Cl₂Diluted (200mL), washed with water (3X30mL) and brine (30mL), then dried (Na)₂SO₄) Filtered and concentrated to give a white solid which was purified by flash column chromatography (SiO)₂) Purification using 1: 1 to 3: 1 ethyl acetate/hexanes gave the title compound (2.98 g, 49% yield) as a white powder.¹HNMR(500MHz，CDCl₃)δ：8.70(1H，s)，8.18(1H，s)，7.76(1H，dd，J＝9.0，4.8Hz)，7.55(1H，dd，J＝7.3，2.8Hz)，7.51-7.47(1H，m)。LCMS(M+H)C₉H₆FN₄The calculated value of (a): 189.17, respectively; measurement value: 189.10.

intermediate 97

(5-fluoro-2- (1H-1, 2, 4-triazol-1-yl) phenyl) methylamineIntermediate 96, 5-fluoro-2- (1H-1, 2, 4-triazol-1-yl) benzonitrile (2.94 g, 15.59mmol) in ethanol (100 mL) and 1N HCl (50 mL) was dissolved by bubbling N ₂Degassing is carried out. Then, 10% Pd/C was added, the flask was evacuated, and H was bubbled through three times₂In H₂The atmosphere (40psi) was placed on a Parr shaker. After 6 hours, the reaction mixture was filtered, concentrated, and the aqueous solution was lyophilized to give the title compound (4.07g, 98%) as a white powder. LCMS (M + H) C₉H₁₀FN₄The calculated value of (a): 193.09, respectively; measurement value: 193.15.

intermediate 98

2- (1H-1, 2, 4-triazol-1-yl) benzonitrile A suspension of 2-fluorobenzonitrile (3.0 g, 25mmol) and 1, 2, 4-triazole sodium salt (2.4 g, 27mmol) in tetrahydrofuran (7 ml) and dimethylformamide (14 ml) was stirred at 95 ℃ for 18H. After cooling and concentration, the product is treated with hot CH₂Cl₂Hexane (1: 1) crystallization gave the title compound as a white solid (4.25g, 100% yield).¹H-NMR(300MHz，CDCl₃)δppm：8.74(1H，s)，8.16(1H，s)，7.82(1H，dd，J＝4.9，1.3Hz)，7.77-7.25(2H，m)，7.57-7.51(1H，m)。LCMS[M+H]⁺C₉H₇N₄The calculated value of (a): 171.06, respectively; measurement value: 171.12.

intermediate 99

(2- (1H-1, 2, 4-triazol-1-yl) phenyl) methanamine hydrochloride intermediate 98, 2- (1H-1, 2, 4-triazol-1-yl) benzonitrile (4.25g, 25mmol) was dissolved in ethanol (50 mL) and 1N HCl (25 mL). Adding 10 percent of the mixturePd-C (1 g), and the mixture was heated at 50psi H₂Shake for 2 hours. After filtration through celite and concentration, the residue was triturated with ether and the title compound was collected as a white solid. (3.94 g, 75% yield). ¹H-NMR(300MHz，CD₃OD)δppm：9.01(1H，s)，8.32(1H，s)，7.78-7.64(4H，m)，4.15(2H，s)。LCMS[M+H]⁺ C₉H₁₁N₄The calculated value of (a): 175.09, respectively; measurement value: 175.17.

intermediate 100

2- (1, 1-dioxo-1. lamda.)⁶-[1，2]Thiazinan-2-yl) benzonitrile sodium hydride (0.675 g, 25mmol, 95%) was added to 1, 1-dioxo [1, 2 ]]Thiazine (3.37 g, 25mmol) in dimethylformamide (35 ml) and the mixture stirred at room temperature for 15 min. 2-fluorobenzonitrile (3.37 ml, 31.3mmol) was added and the mixture was stirred at 80 ℃ for 18 h. The mixture was cooled, diluted with water, and extracted with ethyl acetate. The organic phase was washed with water and brine and then dried (Na)₂SO₄) And concentrated. Subjecting the residue to flash chromatography (SiO)₂) Purify, elute with 10% -100% ethyl acetate/hexanes. The isolated solid was recrystallized from hot ethyl acetate/hexane (2: 1) to give the title compound as white crystals (4.15g, 70% yield).¹H-NMR(300MHz，CDCl₃)δppm：7.70(1H，dd，J＝7.7，1.1Hz)，7.64-7.53(2H，m)，7.41(1H，td，J＝7.3，1.6Hz)，3.72(2H，t，J＝5.5Hz)，3.32(2H，t，J＝6.0Hz)，2.40-2.32(2H，m)，2.05-1.97(2H，m)。LCMS [M+H]⁺C₁₁H₁₂N₂O₂Calculated value of S: 237.06, respectively; measurement value: 237.10.

intermediate body 101

2- (1, 1-dioxo-1. lamda.)⁶-[1，2]Thiazinan-2-yl) benzylamine hydrochloride the intermediate 100, 2- (1, 1-dioxo-1. lambda⁶-[1，2]Thiazinan-2-yl) benzonitrile (2.63 g, 11.14mmol) was dissolved in ethanol (150 ml) and 1N HCl (13 ml). To this was added 10% Pd-C (0.5g) and H at 55psi₂The mixture was shaken for 24 hours. Filtration through celite and concentration gave the title compound as a white solid (2.93g, 95% yield). ¹H-NMR(300MHz，CD₃OD)δppm：7.61-7.47(4H，m)，4.30(2H，q，J＝13.7Hz)，3.96-3.87(1H，m)，3.49-3.36(3H，m)，2.40-2.31(2H，m)，2.05-1.96(2H，m)。LCMS[M+H]⁺C₁₁H₁₇N₂SO₂The calculated value of (a): 241.10, respectively; measurement value: 241.10.

intermediate body 102

(3, 5-Difluoropyridin-2-yl) methylamine hydrochloride A mixture of 3, 5-difluoromethylpyridinylnitrile (1.4 g, 10mmol), concentrated HCl (12 mL) and 10% Pd-C (200 mg) in 1: 1 ethanol/tetrahydrofuran was shaken under an atmosphere of hydrogen (50psi) for 5 h. The reaction mixture was filtered and the ethanol was removed in vacuo. The remaining solution was lyophilized to give an off-white solid (2.16g, 100% yield). LCMS (M + H) C₆H₇F₂N₂The calculated value of (a): 145.06, respectively; measurement value: 145.12.

intermediate 103

(5-chloro-pyridine)Pyridin-2-yl) methylamine A solution of 5-chloromethylpyridynitrile (3.8 g, 27.43mmol), concentrated HCl (3 mL), and 10% Pd-C (1.0g) in ethanol (100mL) was shaken under an atmosphere of hydrogen (40psi) for 2 hours. The reaction mixture was filtered, concentrated and the resulting residue taken up in saturated NaHCO₃In (50mL), with CH₂Cl₂(4X25 mL). To merge CH₂Cl₂Layer drying (Na)₂SO₄) Filtered and concentrated to give the title compound as a yellow oil (2.0g, 51% yield). LCMS (M + H) C₆H₈ClN₂The calculated value of (a): 143.04, respectively; measurement value: 143.07.¹HNMR(500MHz，CDCl₃)δppm：8.56-8.51(1H，br d)，7.66-7.60(1H，m)，7.28-7.14(1H，m)，3.97(2H，s)，1.72(2H，s)。

intermediate body 104

2- (bromomethyl) -5-fluorobenzonitrile, N₂By reacting 5-fluoro-2-methylbenzonitrile (28.51 g, 211mmol), NBS (41.31 g, 232mmol) and AIBN (2.5 g, 15mmol) in CCl ₄(845 ml) for 10 minutes, and then the reaction was heated at reflux for 8 hours. After standing overnight at room temperature, the reaction mixture was filtered and the filter cake was washed with CCl₄(500mL) washed. The combined filtrates were evaporated to give a yellow oil. By flash chromatography (SiO)₂) Using 5-25% ethyl acetate/hexanes as eluent, the title compound (29.74 g, 66% yield) was obtained as a pale yellow oil.¹H NMR(500MHz，CDCl₃)δ：7.55(1H，dd，J＝8.6，5.2Hz)，7.37(1H，dd，J＝7.9，2.8Hz)，7.32-7.28(1H，m)，4.61(2H，s)。

Intermediate 105

2- ((1, 3-Dioxoisoindolin-2-yl) methyl) -5-fluorobenzonitrile to a stirred solution of intermediate 104, 2- (bromomethyl) -5-fluorobenzonitrile (29.72 g, 139mmol) and phthalimide (32.69 g, 222mmol) in dimethylformamide (300 ml) was added Cs₂CO₃(67.87 g, 208 mmol). After vigorous stirring for 1 hour, the reaction mixture was poured into water (1.2L). The precipitated product was filtered and washed with water (600mL) and methanol (150mL) to give a white solid. The solid was taken up in 1L of water/methanol (2: 1) and K was added thereto₂CO₃(12g) And the mixture was stirred at 40 ℃. After 30 minutes, the mixture was cooled and filtered. The filter cake was washed with water (500mL) and dried in vacuo to give the title compound (38.91g, 94% yield) as a white powder.¹H NMR(500MHz，CDCl₃)δ：7.89(2H，dd，J＝5.5，3.1HZ)，7.76(5.5，3.1Hz)，7.41(1H，dd，J＝8.6，5.2Hz)，7.38(1H，dd，J＝7.9，2.8Hz)，7.24(1H，td，J＝8.2，2.8Hz)，5.06(2H，s)。LCMS(M+H)C₁₆H₁₀FN₂O₂The calculated value of (a): 281.07, respectively; measurement value: 281.15.

Intermediate 106

Tert-butyl 2-cyano-4-fluorobenzylcarbamate A suspension of intermediate 105, 2- ((1, 3-dioxoisoindolin-2-yl) methyl) -5-fluorobenzonitrile (5.6 g, 20mmol) in dimethylformamide (20 ml) was warmed until dissolved. Tetrahydrofuran (100mL) was added to the reaction solution, and the mixture was placed in a preheated (70 ℃ C.) oil bath. Hydrazine monohydrate was added thereto, and the reaction was stirred for 8 hours. The resulting white slurry was left at room temperature overnight. To the slurry was added di-tert-butyl dicarbonate (6.55 g, 30mmol), and the mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with ether (100ml), filtered and the filtrate was washed with water at 40 ℃And (5) treating with activated carbon. After filtration and concentration, the crude product was purified by flash chromatography using 20-30% ethyl acetate/hexanes as the eluent to provide the title compound (2.88g, 58% yield) as a pale yellow powder.¹H NMR(500MHz，CDCl₃)δ：9.46(1H，br s)，7.61(1H，dd，J＝7.9，2.1Hz)，7.34(1H，dd，J＝8.2，4.6Hz)，7.22(1H，td，J＝8.6，2.4Hz)，4.71(2H，s)，1.59(9H，s)。LCMS(M+H)C₁₃H₁₆FN₂O₂The calculated value of (a): 251.12, respectively; measurement value: 251.22.

intermediate 107

Intermediate 106, 2-cyano-4-fluorobenzylcarbamic acid tert-butyl ester, (1.9 g, 7.591mmol) was charged in a round bottom flask at room temperature and then treated with trifluoroacetic acid (20 ml). After 1 hour, the reaction mixture was concentrated to give a yellow oil, which was dissolved in CHCl ₃To yield the title compound (2.01g, 100% yield) as a pale yellow solid. LCMS (M + H) C₈H₈FN₂The calculated value of (a): 151.07, respectively; measurement value: 151.08.

intermediate 108

(2, 5-dibromo-4-fluorophenyl) methylamine 2, 5-dibromo-4-fluorobenzyl bromide (0.350 g, 1mmol) was added to 7M NH₃the/MeOH solution was heated in a sealed tube at 100 ℃ for 2 hours. The reaction mixture was cooled and concentrated to give a white solid, which was dissolved in CH₂Cl₂In combination with Et₃Treated with N (1mL) and then concentrated. The resulting residue was taken up in ethyl acetate (25)mL) were triturated together, filtered and concentrated to give the title compound (0.291g) as a pale yellow oil. HRMS (M + H) C₇H₇Br₂Calculated value of FN: 283.94, respectively; measurement value: 283.93.

intermediate 109

4-fluoro-2-methylsulfanyl-benzylamine, in N₂4-fluoro-2- (methylthio) benzonitrile (1.67 g, 0.1 mol) was dissolved in 20mL of tetrahydrofuran under an atmosphere and 10mL of 2M BH₃.Me₂And S, processing. It was heated at 60 ℃ for 2 hours. The heating was discontinued and 5mL of MeOH was carefully added followed by 4mL of 6N HCl. Addition of additional H₂O (20mL), followed by the addition of ethyl acetate. The layers were separated. The aqueous layer was made alkaline with 1N NaOH and CH₂Cl₂And (4) extracting. Drying the extract (MgSO)₄) Filtered, concentrated and dried in vacuo to give 1.3g of the title compound as a solid (yield 76%). ¹H NMR(500MHz，CDCl₃)δppm：7.20-7.31(1H，m)6.90(1H，dd，J＝2.4Hz)6.75-6.86(1H，m)3.86(2H，s)2.47(3H，s)；LC/MS m/z 172。

Intermediate body 110

2- (aminomethyl) -5-fluoroaniline hydrochloride 2-amino-4-fluorobenzonitrile (FritzHunziker et al Eur. J. Med. chem.1981, 16, 391) (0.300 g, 1.68mmol) was dissolved in acetic anhydride (5 ml) and the solution was stirred at 23 ℃ for 18 hours. An additional portion of acetic anhydride (3mL) was added to dissolve the N- (2-cyano-5-fluorophenyl) acetamide. Palladium (10% on activated carbon) was then added and the mixture was taken up in H₂(34psi) for 72 hours. Filtered off on kieselguhrPd-C was removed and the filtrate was concentrated in vacuo to give the diethylamide: LCMS (M + H)⁺m/z 225. It was heated at reflux with HCl (6N, 10mL) for 30 min. The acid was removed under reduced pressure to give a solid which was crystallized from MeOH-ether to give the title compound (0.120g, 51% yield).¹H NMR(400MHz，MeOD)δppm：7.51(1H，m)，6.96(2H，m)，4.20(2H，s)。

Intermediate 111

4-fluoro-2- (2-oxopyrrolidin-1-yl) benzonitrile 2-bromo-4-fluorobenzonitrile (1.00 g, 5.00mmol), 2-pyrrolidone (0.46 ml, 6.00mmol), Cs contained in dioxane (6 ml) was added₂CO₃(2.28 g, 7.0mmol) and 9, 9-dimethyl-4, 5-bis (diphenylphosphino) xanthene (xanthphos) (0.231 g, 0.40mmol) were degassed with argon in a 48 ml pressure vessel for 15 minutes. Introduction of Pd₂dba₃And the reaction mixture was heated at 105 ℃ for 48 hours. The mixture was cooled, diluted with ethyl acetate or dioxane and then filtered through celite. The resulting mixture was concentrated in vacuo and chromatographed on silica gel using a hexane: ethyl acetate (3: 7) gradient as eluent to give the title compound as a white solid (0.887g, 87% yield): ¹H NMR(400MHz，CDCl₃)δppm：7.69(1H，dd，J＝5.8，8.6Hz)，7.22(1H，dd，J＝2.5，9.6Hz)，7.07(1H，ddd，J＝2.5，7.6，8.6Hz)，3.96(2H，t，.J＝7.0Hz)，2.62(2H，t，J＝8.1Hz)，2.30-2.22(2H，m)；LCMS(⁺ESI，M+H⁺)m/z205。

Intermediate body 112

4-fluoro-2- (2-oxopiperidin-1-yl) benzonitrileThe title compound may be prepared following the procedure which provides intermediate 111.¹H NMR(400MHz，CDCl₃)δppm：7.71(1H，dd，J＝5.7，8.7Hz)，7.14-7.06(1H，m)，7.08(1H，dd，J＝2.4，9.0Hz)，3.65(2H，t，.J＝5.7Hz)，2.60(2H，t，J＝6.3Hz)，2.05-1.95(4H，m)；LCMS(⁺ESI，M+H⁺)m/z 219。

Intermediate 113

4-fluoro-2- (2-oxoazepan-1-yl) benzonitrile the title compound may be prepared according to the procedure which provides intermediate 111.¹H NMR(400MHz，CDCl₃)δppm：7.68(1H，dd，J＝5.8，8.6Hz)，7.08(1H，ddd，J＝2.5，7.6，8.6Hz)，7.01(1H，dd，J＝2.5，9.0Hz)，3.77-3.76(2H，m)，2.75-2.72(2H，m)，1.91-1.86(6H，m)；LCMS(⁺ESI，M+H⁺)m/z 233。

Intermediate body 114

N- (2-cyano-5-fluorophenyl) -N-methylacetamide the title compound may be prepared according to the procedure which affords intermediate 111.¹H NMR(400MHz，CDCl₃)δppm：7.79-7.75(1H，m)，7.32-7.19(1H，m)，7.10-7.07(1H，m)，3.42(0.6H，brs)，3.30(2.4H，s)，2.32(0.6H，brs)，1.91(2.4H，s)；LCMS(⁺ESI，M+H⁺)m/z 193；HPLC：94％(220nm)。

Intermediate 115

2- (2-oxoazetidin-1-yl) benzonitrile the title compound may be prepared according to the procedure which provides intermediate 111.¹H NMR(400MHz，DMSO-d₆)δppm：8.02(1H，d，J＝8.4Hz)，7.76(1H，dd，J＝1.5，7.8Hz)，7.69-7.65(1H，m)，7.23(1H，s)，4.04(2H，t，J＝4.8Hz)，3.16(2H，t，J＝4.8Hz)。LCMS(⁺ESI，M+H⁺)m/z 173。

Intermediate body 116

2- (2-oxooxazolidin-3-yl) benzonitrile the title compound may be prepared according to the procedure which provides intermediate 111.¹H NMR(400MHz，CDCl₃)δppm：7.71(1H，dd，J＝1.5，7.6Hz)，7.68-7.63(1H，m)，7.58(1H，d，J＝7.6Hz)，7.38(1H，dt，J＝1.3，7.6Hz)，4.57(2H，t，J＝7.8Hz)，4.21(2H，t，J＝7.8Hz)；LCMS(⁺ESI，M+H⁺)m/z 189。

Intermediate 117

4-fluoro-2- (2-oxooxazolidin-3-yl) benzonitrile 2-bromo-4-fluorobenzonitrile (1.00 g, 5.00mmol), 2-oxazolidinone (0.390 g, 4.50mmol), K, contained in dioxane (10 ml) is added₂CO₃A48 ml pressure vessel of (0.970 g, 7.0mmol) and xantphos (0.231 g, 0.40mmol) was degassed with argon for 15 minutes. Adding Pd₂dba₃(0.140g, 0.15mmol) and then the reaction mixture was heated at 70 ℃ for 18 hours. The mixture was cooled, diluted with dioxane and filtered through celite. Mixing the obtained mixture Concentrated in vacuo and chromatographed on silica gel using a gradient of hexane: ethyl acetate (1: 1) to (3: 7) as eluent to give the title compound as a white solid (0.460g, 50% yield):¹H NMR(400MHz，CDCl₃)δppm：7.73(1H，dd，J＝5.8，8.6Hz)，7.43(1H，dd，J＝2.5，9.6Hz)，7.11(1H，ddd，J＝2.5，7.5，8.7Hz)，4.60(2H，t，J＝7.1Hz)，4.29(2H，t，J＝7.1HJz)；LCMS(⁺ESI，M+H⁺)m/z 207。

intermediate 118

3- (2- (aminomethyl) -5-fluorophenyl) oxazolidin-2-one hydrochloride.¹H NMR(400MHz，MeOD)δppm：7.73(1H，dd，J＝6.0，8.6Hz)，7.43(1H，dd，J＝2.5，9.5Hz)，7.11(1H，ddd，J＝2.5，7.5，8.6Hz)，4.64(2H，t，J＝7.7Hz)，4.17(2H，t，J＝7.7Hz)，4.14(2H，s)；LCMS(⁺ESI，M+H⁺)m/z 211。

Intermediate 119

4-fluoro-2- (2-oxoazetidin-1-yl) benzonitrile the title compound may be prepared according to the procedure providing intermediate 117.¹H NMR(400MHz，CDCl₃)δppm：8.06(1H，dd，J＝10.7，2.6Hz)，7.58(1H，dd，J＝8.6，6.3Hz)，7.87(1H，td，J＝8.6，2.5Hz)，4.25(2H，t，J＝5.0Hz)，3.26(2H，t，J＝5.0Hz)；LCMS(⁺ESI，M+H⁺)m/z 191。

Intermediate body 120

1- (2- (aminomethyl) -5-fluorophenyl) azetidin-2-one hydrochloride.¹H NMR(400MHz，DMSO/D₂0)δppm：7.54(1H，dd，(t)，J＝8.6Hz)，7.25(1H，dd，J＝10.8，2.5Hz)，7.17(1H，td，J＝8.6，2.5Hz)，4.12(2H，s)，3.79(2H，t，J＝4.6Hz)，3.09(2H，t，J＝4.6Hz)；LCMS(⁺ESI，M+H⁺)m/z 195。

Intermediate 121

(R) -2- (2- ((tert-butyldimethylsilyloxy) methyl) -5-oxopyrrolidin-1-yl) -4-fluorobenzonitrile the title compound can be prepared according to the procedure which provides intermediate 111.¹HNMR(400MHz，CDCl₃)δppm：7.68(1H，dd，J＝5.8，8.8Hz)，7.19(1H，dd，J＝2.5，9.1Hz)，7.11-7.07(1H，m)，4.46-4.42(1H，m)，3.55(2H，d，J＝3.3Hz)，2.72-2.52(2H，m)，2.43-2.33(1H，m)，2.09-2.01(1H，m)，0.81(9H，s)，-0.04(3H，s)，-0.07(3H，s)；LCMS(⁺ESI，M+H⁺)m/z 349。

Intermediate body 122

(S) -2- (2- ((tert-butyldimethylsilyloxy) methyl) -5-oxopyrrolidin-1-yl) -4-fluorobenzonitrile the title compound can be prepared according to the procedure which provides intermediate 111.¹HNMR(400MHz，CDCl₃)δppm：7.68(1H，dd，J＝5.8，8.6Hz)，7.19(1H，dd，J＝2.5，9.4Hz)，7.11-7.07(1H，m)，4.46-4.43(1H，m)，3.55(2H，d，J＝3.3Hz)，2.72-2.52(2H，m)，2.43-2.33(1H，m)，2.09-2.01(1H，m)，0.81(9H，s)，-0.04(3H，s)，-0.07(3H，s)；LCMS(⁺ESI，M+H⁺)m/z 349。

Intermediate 123

4-fluoro-2- (thiazol-2-ylamino) benzonitrile the title compound may be prepared according to the method providing intermediate 111.¹H NMR(400MHz，DMSO-d₆)δppm：9.21(1H，s)，8.39-8.35(1H，m)，7.97(1H，d，J＝5.0Hz)，7.23-7.13(3H，m)；LCMS(⁺ESI，M+H⁺)m/z 220。

Intermediate body 124

4-fluoro-2- (5-methyl-1, 3, 4-thiadiazol-2-ylamino) benzonitrile the title compound may be prepared according to the procedure which provides intermediate 111.¹H NMR(400MHz，DMSO-d₆)δppm：8.30(1H，dd，J＝6.5，8.8Hz)，7.96(1H，s)，7.26-7.19(2H，m)，2.64(3H，s)；LCMS(⁺ESI，M+H⁺)m/z 235。

Intermediate 125

1- (2- (aminomethyl) -5-fluorophenyl) piperidin-2-one hydrochloride to intermediate 112, 4-fluoro-2- (2-oxopiperidin-1-yl) benzonitrile (150 mg, 0.69mmol) in H₂Ethanol (10 ml) and 10% palladium were added to the O (10 ml) stirred solutionActivated carbon (50 mg) and 1N HCl (2.1 mL, 20.6 mmol). The reaction is carried out in a Parr System at H₂Shaking (40psi) for 1 hour under an atmosphere. The Pd/C catalyst was then removed by filtration through celite and the filtrate was concentrated in vacuo to give a solid. Toluene (2X50mL) was added to the solid and the solution was evaporated in vacuo. LCMS (M + H)⁺m/z 170。

Intermediate 126

1-bromo-4-fluoro-2-methoxybenzene to a mixture of 2-bromo-5-fluorophenol (10 g, 50.8mmol) and methyl iodide (11.2 g, 78.7mmol) in dimethylformamide (100 ml) was added potassium carbonate (10.9 g, 79mmol), and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with water (100 ml) and extracted with diethyl ether (50mLx 3). The combined extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give 11.3 g of 1-bromo-4-fluoro-2-methoxybenzene amber oil.

Intermediate 127

4-fluoro-2-methoxybenzonitrile to a solution of intermediate 126, 1-bromo-4-fluoro-2-methoxybenzene (9.0 g) in N-methylpyrrolidone (100 ml, Sure Seal; Aldrich) was added CuCN (6.6 g, 73.7mmol, 1.8 eq; Aldrich), and the mixture was stirred at 180 ℃ under an anhydrous nitrogen atmosphere for 5.5 hours. After cooling, 14% NH was added ₄Aqueous OH (330mL) and stirring was continued at room temperature for 45 min. The mixture was extracted with diethyl ether (100ml x3) and the combined extracts were sequentially diluted with dilute NH₄Aqueous OH, dilute HCl and brine, then dried (MgSO)₄) Concentration to provide the title compound (5.2g, 85% yield, 2 steps) as a white solid:¹H NMR(CDCl₃，500MHz)δppm：3.91(3H，s，OMe)，6.69(1H，dd，J＝2.3Hz，J＝10.5Hz，Ar-H)，6.72(1H，dt，J＝2.5Hz，J＝J＝8.0Hz，Ar-H)，7.55(1H，dd，J＝6.5Hz，J＝8.5Hz，Ar-H)；¹³CNMR(CDCl₃125.8Hz) delta ppm: 56.49, 98.16, 100.06, 100.27, 108.31, 108.50, 115.83135.37, 135.46, 163.25, 163.34165.47, 167.50 analytical samples were obtained by trituration with diethyl ether: c₈H₆Analytical calculation of FNO: c63.57, H4.00, N9.26; measurement value: c63.36, H3.91, N9.16.

Intermediate 128

4-fluoro-2-methoxybenzylamine hydrochloride to a mixture of intermediate 127, 4-fluoro-2-methoxybenzonitrile (800 mg, 5.3mmol) and concentrated HCl (0.53 ml, 6.36mmol, 1.2eq) in ethanol (20 ml) was added 10% Pd-C (100 mg; Aldrich) and the mixture was hydrogenated at room temperature under 1atm of hydrogen for 15 h. Additional amounts of concentrated HCl (1mL) and 10% Pd-C (200mg) were added to the mixture and the reaction was allowed to continue for an additional 40 hours. The mixture was filtered through celite and the filtrate was concentrated to dryness in vacuo. The residue was triturated with ether to give the title compound (895mg, 88% yield) as a white powder: ¹H NMR(CDCl₃，500MHz)δppm：3.84(3H，s，OMe)，3.91(2H，d，J＝5.5Hz，N-CH₂)，6.81(1H，dt，J＝2.5Hz，J＝J＝8.5Hz，Ar-H)，6.99(1H，dd，J＝2.5Hz，J＝11.3Hz，Ar-H)，7.47(1H，dd，J＝7Hz，J＝8.5Hz，Ar-H)；¹³CNMR(CDCl₃，125.8Hz)δppm：36.76，56.03，99.30，99.51106.28，106.45，117.93，117.95，131.60，131.69，158.56，158.64，162.28，164.22。HRMS(ESI)C₈H₁₁Calculated value of FNO (M + H): 156.0825, measurement: 156.0830.

intermediate 129

4-fluoro-2-hydroxybenzonitrile intermediate 127, 4-fluoro-2-methoxybenzonitrile (4.53 g, 30mmol) and AlCl₃A mixture of (5.0 g, 37.6 mmol; Aldrich) in dry toluene (30mL) was stirred at about 130 deg.C for 18 hours. After cooling, ice water (. about.50 mL) was added and the resulting mixture was extracted with ether (20mLx 2). The combined extracts were washed sequentially with water and brine, then dried (MgSO)₄) Concentration in vacuo afforded the title compound (3.90g, 28.5mmol, 95% yield) as a white solid:¹H NMR(DMSO-d6，300MHz)δppm：6.74-6.84(2H，m，Ar-Hs)，7.71(1H，dd，J＝7Hz，J＝8.5Hz，Ar-H)，11.64(1H，s，OH)；¹³C NMR(DMSO-d6，75.5Hz)δppm：95.13102.45，102.78，106.53，106.83 115.53，134.68，134.84，161.41，161.58，163.00，166.35.HRMS(ESI-)C₇H₃calculated NOF (M-H): 136.0199, measurement: 136.0199.

intermediate body 130

4-fluoro-2- (2-morpholino-2-oxoethoxy) benzonitrile to a solution of intermediate 129, 4-fluoro-2-hydroxybenzonitrile (685 mg, 5mmol) in dimethylformamide (8 ml, Sure Seal; Aldrich) was added NaH (200 mg, 5 mmol; 60% oil dispersion; Aldrich) and the mixture was stirred under a nitrogen anhydrous atmosphere for 5 minutes. 4- (2-chloroacetyl) morpholine (900 mg, 5.5mmol, 1.1 eq; Avocado Organics) was added and stirring continued at room temperature for 21 h. The reaction was quenched by careful addition of water (30 ml). The obtained mixture is treated with CH ₂Cl₂(25mLx 2). The combined extracts were washed with brine and driedDried (MgSO)₄) And concentrated. The residue was triturated to give 1.10g (4.17mmol, 83% yield) of the title compound as a white solid:¹HNMR(CDCl₃，500MHz)δppm：3.63(2H，t，J＝4Hz，NCH₂)，3.67(1H，m，OCH)，3.72(1H，m，OCH)，4.86(2H，s，OCH₂)，6.80-6.86(2H，m，Ar-Hs)，7.61(1H，dd，J＝8.5Hz，6.1Hz，Ar-H)；¹³C NMR(CDCl₃，125.77Hz)δppm：42.63，46.04，66.80，68.33，98.45，98.47，101.57，101.79，109.56，109.74，115.42，135.48，135.57，161.26，161.35，114.79，165.23，167.28。HRMS C₁₃H₁₄N₂O₃calculated value of F (M + H): 265.0988, measurement: 265.0998.

intermediate 131

2- (2- (aminomethyl) -5-fluorophenoxy) -1-morpholinoethanone hydrochloride a solution of intermediate 130, 4-fluoro-2- (2-morpholino-2-oxoethoxy) benzonitrile (500 mg, 1.89mmol) in warm ethanol (30 mL) and ethyl acetate (30 mL) was combined with concentrated HCl (0.32mL, 3.78mmol, 2 eq). 10% Pd-C (100 mg; Aldrich) was added thereto, and the mixture was hydrogenated under hydrogen gas at 1atm at room temperature for 20 hours. An additional amount of 10% Pd-C (50mg) was added to the mixture and stirring was continued for an additional 7 hours. The mixture was filtered through celite and the filtrate was concentrated to dryness in vacuo. The residue was triturated with ethyl acetate then ethanol to give the title compound (168mg, 29% yield) as an off-white powder:¹H NMR(CD₃OD，500MHz)δppm：3.55(2H，t，J＝5Hz，NCH₂)，3.62(2H，t，J＝5Hz，NCH₂)，3.70(2H，t，J＝5Hz，OCH₂)，3.75(2H，t，J＝5Hz，OCH₂)，4.17(2H，s，NCH₂)，5.17(2H，s，OCH₂)，6.82(1H，dt，J＝2.5，8.5Hz，Ar-H)，7.05(1H，dd，J＝2.5，10.5Hz，Ar-H)，7.43(1H，dd，J＝6.5，8.5Hz，Ar-H)；¹³C NMR(CD₃OD，125.77Hz)δppm：39.40，42.49，44.97，66.11，66.46，66.59，101.38，101.59，108.40，108.57，118.40，132.53，132.62，158.43，158.52，63.87，165.83，168.27。HRMS(ESI)C₁₃H₁₈N₂O₃calculated value of F (M + H): 269.1301, measurement: 269.1301.

intermediate 132

Dimethyl-carbamic acid 2-cyano-5-fluoro-phenyl ester in N₂A stirred solution of intermediate 129, 4-fluoro-2-hydroxybenzonitrile (685 mg, 5.00mmol), dimethylcarbamoyl chloride and triethylamine (606 mg, 6mmol) in dichloroethane (10ml) was heated at reflux for 20 hours under ambient conditions. The cooled mixture was diluted with dichloroethane (10mL), washed with water and brine. The organic layer was separated and dried (Na) ₂SO₄) Concentrating, and subjecting the residue to column chromatography (SiO)₂5% Ethyl acetate-CH₂Cl₂) Purification afforded 700mg (67% yield) of the title compound as a white crystalline solid:¹HNMR(CDCl₃，500MHz)δppm：3.03(3H，s，NMe)，3.15(3H，s，NMe)，6.99(1H，dt，J＝2.5Hz，8.5Hz，Ar-H)，7.23(1H，dd，J＝2.5Hz，9.5Hz，Ar-H)，7.61(1H，dd，J＝9Hz，6Hz，Ar-H)；¹³C NMR(CDCl₃，125.77Hz)δppm：36.76，37.06，102.84，102.86，111.59，111.79，113.24，113.42，114.99，134.36，134.45，152.54，155.06，155.16，164.26，166.31。HRMS(ESI)C₁₀H₁₀N₂O₂calculated value of F (M + H): 209.0726, measurement: 209.0722.

intermediate 133

To a solution of intermediate 132, 2-cyano-5-fluoro-phenyl dimethyl-carbamate (340 mg, 1.63mmol) in ethyl acetate (20 ml) and ethanol (20 ml) was added concentrated HCl (0.4 ml) and 10% Pd-C (100 mg), and the mixture was hydrogenated under 55psi of hydrogen in a Parr shaker for 20 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated in vacuo to give an oil, which was partitioned between ethyl acetate (10mL) and water (10 mL). After separation, the aqueous phase was washed with additional ethyl acetate (5 mL). The combined extracts were concentrated to dryness in vacuo. The residual oil was triturated with ether to provide 145mg (38% yield) of the title compound as a brown powder:¹HNMR(CD₃OD，500MHz)δppm：3.06(3H，s，NMe)，3.21(3H，s，NMe)，4.11(2H，s，NCH₂)，7.13(2H，m，Ar-Hs)，7.60(1H，m，Ar-H)；¹³CNMR(CD3OD，125.77Hz)δppm：36.03，36.25 37.58，110.79，110.99，113.26，113.43，122.32，132.18，132.25，151.55，154.72，162.69，164.67。HRMS(ESI)C₁₀H₁₃N₂O₂calculated value of F (M + H): 213.1039, measurement: 213.1039.

intermediate 134

2- (benzyloxy) -4-fluorobenzonitrile benzyl alcohol (13 ml, 125mmol) was slowly added to a stirred suspension of NaH (95%, 2.86 g, 113mmol) in toluene (200 ml) at room temperature. After 30 minutes, 2, 4-difluorobenzonitrile (15.3 g, 110 mmol; Aldrich) was added simultaneously and stirring was continued overnight (18 hours). Thereafter, the reaction mixture was washed with water (2 × 25mL) and brine (25 ml). The organic layer was dried (Na) ₂SO₄) Filtering and concentrating to obtain white slurry, and mixing the white slurry with waterTrituration with hexanes and filtration afforded the title compound as a white solid (20.34 g, 81% yield).¹H NMR(500MHz，CDCl₃)：7.59-7.55(1H，m)，7.45-7.34(5H，m)，6.75-6.71(2H，m)，5.19(2H，s)；¹³C NMR(125.76MHz，DMSO-d6)δppm：71.16，98.75，101.54，101.75，108.66，108.84，115.83，127.16，128.58，128.94，135.03，135.44，135.54，162.22，162.31，165.26，167.29。LCMS C₁₄H₁₁Calculated values of FNO: 228.2, respectively; measurement value: 228.0.

intermediate 135

A solution of intermediate 134, 2- (benzyloxy) -4-fluorobenzonitrile (9.03 g, 39.7mmol) in ethanol (100ml) and ethyl acetate (100ml) was stirred under hydrogen (60psi) with 10% palladium on carbon (1.67 g) and concentrated hydrochloric acid (12 ml, 144mmol) for four days. The catalyst was removed by filtration through celite and the filtrate was concentrated. The crude product was triturated with ether and the resulting solid collected by filtration to give the title compound (5.24g, 74% yield) as a light orange solid.¹H NMR(500MHz，DMSO-D6)δppm：10.81(1H，s)，8.18(3H，s)，7.36(1H，t，J＝7.3Hz)，6.79(1H，dd，J＝10.8，2.6Hz)，6.66(1H，dt，J＝8.5，2.3Hz)，3.90(2H，d，J＝5.2Hz)。

Intermediate 136

(2, 2-diethoxyethyl) (o-tolyl) sulfane sodium metal (1.6g, 66mmol) was dissolved in ethanol (50 ml) at 23 ℃. 2-Methylthiophenol (8.1 ml, 68mmol) was slowly added to the solution, andbromoacetaldehyde diethyl acetal (9.50 ml, 63mmol) was then added. The reaction mixture was stirred at reflux for 18 hours. The solvent is then evaporated in vacuo using H₂The residue was washed with O (100mL) and extracted with diethyl ether (100 mL). The organic solution was dried (MgSO ₄) Concentrated in vacuo and purified by distillation to give the title compound (13.48 g, 82% yield):¹H NMR(400MHz，CDCl₃)δppm：7.33(1H，d，J＝7.9Hz)，7.16-7.08(3H，m)，4.65(1H，t，J＝5.6Hz)，3.66(2H，q，J＝7.0Hz)，3.55(2H，q，J＝7.0Hz)，3.09(2H，d，J＝5.6Hz)，2.38(3H，s)，1.20(6H，t，J＝7.0Hz)。LCMS(M+H)⁺m/z 241(t＝2.65min.)。

intermediate 137

7-methylbenzo [ b ]]To a solution of intermediate 136, (2, 2-diethoxyethyl) (o-tolyl) sulfane (0.58 g, 2.41mmol) in chlorobenzene (20 ml) was added polyphosphoric acid. The reaction mixture was stirred at reflux for 18 hours. Water (100mL) was then added, followed by CH₂Cl₂(2X50mL) organic material was extracted. The organic solution was dried (MgSO₄) Concentration in vacuo afforded 335 mg (94% yield) of the title compound:¹H NMR(400MHz，CDCl₃)δ：7.68(1H，d，J＝7.8Hz)，7.43(1H，d，J＝5.4Hz)，7.36(1H，d，J＝5.4Hz)，7.30(1H，dd，J＝7.8，7.1Hz)，7.14(1H，d，J＝7.1Hz)，2.58(3H，s)；LCMS(M+H)⁺m/z 148。

intermediate 138

7- (bromomethyl) benzo [ b ]]Thiophene to intermediate 137, 7-methylbenzo [ b ]]Thiophene (1.0 g)6.5mmol) of CCl₄To the solution (20 ml) was added benzoyl peroxide (1.1g, 4.54mmol) followed by NBS (1.15g, 6.5mmol) in portions. The reaction mixture was stirred at reflux while being irradiated with a 250W lamp. The reaction mixture was stirred at reflux for 3 hours. The solution was cooled, filtered and the solvent evaporated in vacuo. The residue was purified by silica gel column chromatography using hexane as eluent to give the title compound (0.570g, 33% yield):¹H NMR(400MHz，CDCl₃)δ：7.80(1H，dd，J＝7.8，1.7Hz)，7.49(1H，d，J＝5.4Hz)，7.40-7.33(3H，m)，4.78(2H，s)。LCMS(M+H)⁺m/z 209。

intermediate 139

Benzo [ b ]]Thien-7-ylmethylamine hydrochloride to intermediate 138, 7- (bromomethyl) benzo [ b]To thiophene (0.20g, 0.96mmol) was added a solution of methanol saturated with ammonia (30 mL). The reaction mixture was heated in a steel autoclave at 70 ℃ for 18 hours. The solvent was evaporated in vacuo and the residue dissolved in MeOH (10 ml). HCl (1M in ethanol, 1ml) was added to the solution and the solvent was removed in vacuo to give the title compound (0.177 g, 99% yield); LCMS (M + H) ⁺m/z164。

Intermediate 140-148

The synthesis of intermediates 140 and 148 provides representative methods for the synthesis of other compounds of the invention.

Intermediate body 140

N- { 4-fluoro-2- (methylcarbamoyl) benzyl } -3-benzyloxy-9-methyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidineAnd [2, 1-c ]][1，4]Oxazine-2-carboxamide intermediate 27, 3-benzyloxy-9-methyl-4-oxo-4, 6, 7, 9-tetrahydropyrimido [2, 1-c][1，4]A mixture of oxazine-2-carboxylic acid (0.172 g, 0.54mmol) and intermediate 39, 2- (aminomethyl) -5-fluoro-N-methylbenzamide trifluoroacetate (0.177 g, 0.60mmol) in methyl chloride (10 ml) was treated with triethylamine (0.17 ml, 1.22mmol) at 22 ℃ and then with benzotriazol-1-yloxy-tri-pyrrolidinyl-phosphonium hexafluorophosphate (PyBOP) (0.340 g, 0.65 mmol). After 3 hours, the reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was chromatographed on silica gel (elution gradient ethyl acetate 50-100% in toluene) to give 0.260 g (100% yield) of the title amide as a white solid.¹HNMR400MHz(CDCl₃)δ(ppm)：1.70(3H，d，J＝6.6Hz，CH₃)，3.01(3H，d，J＝4.7Hz，NCH₃)，3.89(2H，m，CH₂)，4.14(1H，m，CH)，4.29(1H，m，CH)，4.53(2H，d，J＝6.7Hz，NCH₂)，4.69(1H，q，J＝6.6Hz，OCH)，5.35(2H，s，OCH₂) 6.69(1H, width q, NH), 7.09(1H, m, arene), 7.16(1H, m, arene), 7.32(3H, m, arene), 7.42(1H, m, arene), 7.47(2H, m, arene), 8.61(1H, width t, NH). HRMS (ESI) ⁺)C₂₅H₂₆FN₄O₅[M+H⁺]The calculated value of (a): 481.1887: measurement value: 481.1884.

intermediate 141

N- (4-Fluorobenzyl) -3- (benzyloxy) -9- (2- (methylthio) ethyl) -4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamides in N₂Intermediate 22(82mg, 0.22mmol) and O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (152mg, 0.4mmol) were added to 1mL dimethyl methyl formate (DMT) under ambient conditionsThe solution in amide was stirred for 20 minutes. 4-Fluorobenzylamine (38mg, 0.3mmol) was then added and stirring continued for 16 h. Dimethylformamide was evaporated under reduced pressure and the remaining residue was dissolved in CH₂Cl₂In (1). The resulting solution was washed with dilute HCl. The solvent was removed under reduced pressure and the crude product was passed through chromatography (SiO)₂Ethyl acetate) to provide the title compound (70mg, yield ═ 66%). LC/MS M/e 484(M + H).

Intermediate body 142

3- (benzyloxy) -2- (6-fluoro-1-oxoisoindoline-2-carbonyl) -9, 9-dimethyl-6, 7-dihydropyrimido [2, 1-c)][1，4]Oxazin-4 (9H) -one to intermediate 27, 3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino- [2, 1-c][1，4]Oxazine-2-carboxylic acid (1.65 g, 5mmol) CH₂Cl₂(15 ml) to the stirred suspension was added a catalytic amount of dimethylformamide and 10 ml of 2M in CH ₂Cl₂Oxalyl chloride of (1). After 30 minutes, the resulting clear yellow solution was concentrated to give a light brown solid. Dissolving the solid in CH₂Cl₂(50 mL) and added to intermediate 107, 2- (aminomethyl) -5-fluorobenzonitrile trifluoroacetate (1.77 g, 5.97mmol) and diethylisopropylamine (2.6 mL, 15mmol) in CH₂Cl₂(100 ml) of the mixture. After 1 hour, the clear brown reaction mixture was concentrated and the resulting residue was dissolved in ethyl acetate (200mL) and then washed sequentially with water (25mL), 1N HCl (25mL), water (25mL) and brine (25 mL). The combined aqueous layers were washed with CH₂Cl₂(3x50 ml). The combined organic phases were dried (Na)₂SO₄) Filtered, concentrated, and purified by flash chromatography (SiO)₂) Purification using 30-50% ethyl acetate/hexanes as eluent gave the title compound (0.331g, 14% yield) as a yellow powder.¹H NMR(500MHz，CDCl₃)δ：7.48-7.45(1H，m)，7.88(2H，d，J＝7.9Hz)，7.30(2H，d，J＝7.0Hz)，7.12(2H，t，J＝7.6Hz)，7.05-7.01(1H，m)，5.22(2H，s)，4.77(2H，s)，4.06(4H，s)，1.59(6H，s)。HRMS(M+H)C₂₅H₂₃FN₃O₅The calculated value of (a): 464.1622, respectively; measurement value: 464.1628.

intermediate 143

N- (4-fluoro-2- (methylcarbamoyl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide A25 ml round bottom flask was charged with intermediate 27, 3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino- [2, 1-c ][1，4]Oxazine-2-carboxylic acid (0.991 g, 3.0mmol), intermediate 39, 2- (aminomethyl) -5-fluoro-N-methylbenzamide trifluoroacetate (1.185 g, 4.0mmol), 4-dimethylaminopyridine (DMAP, 1.1 g, 9.0mmol) and O- (7-azabenzotriazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate (HATU, 1.722 g, 4.5 mmol). Dimethylformamide (20mL) was added, and the mixture was stirred at room temperature for 1 hour. Thereafter, the reaction mixture was diluted with ethyl acetate (100mL) and washed with water (3X25mL) and brine (25 mL). The organic layer was dried (Na)₂SO₄) Filtering, concentrating, and performing flash chromatography (SiO)₂) Purification, eluting with hexane/ethyl acetate (1: 1 to 1: 3) followed by ethyl acetate, gave the title compound as an off-white solid (1.48 g, 100% yield).¹H NMR(500MHz，CDCl₃)δppm：8.49(1H，t，J＝6.1Hz)，7.48-7.46(2H，m)，7.43(1H，dd，J＝8.5，5.5Hz)，7.31-7.27(3H，m)，7.12(1H，dd，J＝8.9，2.7Hz)，7.05(1H，td，J＝8.2，2.7Hz)，6.52(1H，br s)，5.26(2H，s)，4.53(2H，d，J＝6.4Hz)，4.01(2H，t，J＝4.9Hz)，3.96(2H，t，J＝4.9Hz)，2.97(3H，d，J＝4.9Hz)，1.62(6H，s)。HRMS(M+H)C₂₆H₂₈FN₄O₅The calculated value of (a): 495.2044, respectively; measurement value: 495.2032.

intermediate body 144

N- (4-fluoro-2-hydroxybenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Intermediate 27, 3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino- [2, 1-c)][1，4]A solution of oxazine-2-carboxylic acid (1.50 g, 4.54mmol) and HATU (2.07 g, 5.45mmol) in dry dimethylformamide was stirred at room temperature for 20 minutes under nitrogen. To this solution was added intermediate 135, 2-hydroxy-4-fluoro-benzylamine hydrochloride (1.05g, 5.9mmol), followed by DMAP (1.39g, 11.4mmol), and the reaction mixture was stirred at 60 ℃ for 90 minutes. The solvent was removed in vacuo and the residue was purified by flash column chromatography (SiO) ₂) The crude residue was purified, eluting with 40% -60% ethyl acetate in hexanes, to give the title compound (1.31 g, 64% yield) as a solid.¹H NMR(500MHz，CDCl₃)δppm：9.69(1H，br s)，8.18(1H，t，J＝6.3Hz)，7.44(2H，dd，J＝6.6，2.6Hz)，7.30-7.35(3H，m)，7.00(1H，dd，J＝8.2，6.7Hz)，6.68(1H，dd，J＝10.4，2.4Hz)，6.54(1H，dt，J＝8.2，2.4Hz)，5.29(2H，s)，4.36(2H，d，J＝6.7Hz)，3.97-4.05(4H，m)，1.61(6H，s)。

Intermediate 145

N- (4-fluoro-2- (2-oxopiperidin-1-yl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazin-4 (9H) -one in CH₃Intermediate 27, 3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ] in CN/dimethylformamide (5 mL: 1mL)][1，4]Oxazine-2-carboxylic acid (80 mg, 0.242mmol) was added to intermediate 125, 1- (2- (aminomethyl) -5-fluorophenyl) piperidin-2-one hydrochloride (69 mg, 0.266mmol), benzotriazol-1-yl-oxy-tri-pyrrolidinyl-phosphonium hexafluorophosphate (PyBOP) (139 mg, 0.266mmol) and diisopropylethylamine (169 μ L, 0.968 mmol). The reaction mixture was stirred at 23 ℃ for 3 hours. The solvent was then removed in vacuo and aqueous HCl (1N, 25mL) was added. It was extracted with ethyl acetate (3X25 mL). The combined organic fractions were dried (MgSO)₄) Filtered and concentrated in vacuo. The crude product was purified on a Biotage system using a silica gel column using hexane/ethyl acetate (1: 1) to (1: 5) as eluent to give 114 mg (88% yield) of the title compound. ¹HNMR 400MHz(DMSO)δppm：8.73(1H，dd，(t)，J＝6.0Hz)，7.46(2H，m)，7.35(4H，m)，7.18(1H，dd，J＝9.8，3.0Hz)7.0(1H，m)，5.10(2H，s)，4.43(1H，dd，J＝15.0，7.08Hz)，4.06(1H，dd，J＝15.0，5.56)，4.02(2H，t，J＝5.0Hz)，3.90(2H，t，J＝5.0Hz)，3.64(1H，m)，3.44(1H，m)，2.45(1H，m)，2.35(1H，m)，1.86(4H，m)，1.56(6H，s)。LCMS(M+H)⁺m/z 535。

Intermediate 146

N- (4-fluoro-2- (2-oxoazetidin-1-yl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide to intermediate 27, 3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c][1，4]Oxazine-2-carboxylic acid (0.142 g, 0.430mmol) in CH₃CN dimethylformamide (30 ml: 5 ml) was added to the intermediate 120, 1- (2- (aminomethyl) -5-fluorophenyl) azetidin-2-one hydrochloride (0.100 g, 0.43mmol), (benzotriazol-1-yloxy) tris(dimethylamino) phosphonium hexafluorophosphate (0.207 g, 0.470mmol) and diisopropylethylamine (280. mu.L, 1.72 mmol). The reaction mixture was stirred at 23 ℃ for 18 hours. The solvent was removed in vacuo and 1N HCl (50mL) was added. It was extracted with ethyl acetate (2X50 ml). The combined organic extracts were dried (MgSO)₄) Filtered and concentrated in vacuo. The residue was purified on a Biotage system using a silica gel column with ethyl acetate as eluent to give the title compound (0.157 g, 72% yield).¹H NMR(400MHz，MeOD)δppm：7.88(1H，d，J＝8.3Hz)，7.76(1H，d，J＝8.0Hz)，7.58-7.30(4H，m)，7.10(1H，dd，J＝10.2，2.5Hz)，6.90(1H，m)，5.20(2H，s)，4.55(2H，s)，4.04(2H，m)，3.96(2H，m)，3.78(2H，t，J＝4.2Hz)，3.10(2H，t，J＝4.2Hz)，1.58(6H，s)；LCMS(M+H)⁺m/z 506。

Intermediate 147

N- (benzo [ b ]]Thien-7-ylmethyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c) ][1，4]Oxazine-2-carboxamide to intermediate 27, 3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c][1，4]Oxazine-2-carboxylic acid (0.200 g, 0.60mmol) in CH₃CN to dimethylformamide (30 ml: 5 ml) was added intermediate 139, benzo [ b ]]Thiophen-7-ylmethylamine hydrochloride (0.069 g, 0.266mmol), benzotriazol-1-yl-oxy-tri-pyrrolidinyl-phosphonium hexafluorophosphate (PyBOP) (0.347 g, 0.670mmol), and diisopropylethylamine (420. mu.L, 2.40 mmol). The reaction mixture was stirred at 23 ℃ for 60 hours. The solvent was then removed in vacuo and 1N HCl (50mL) was added. It was extracted with ethyl acetate (2X50 ml). The combined organic extracts were dried (MgSO)₄) Filtered and concentrated in vacuo. The residue was purified on a Biotage system using silica gel column with a hexane: ethyl acetate (1: 1) to (1: 5) gradient as eluent to give the titleTitle compound (0.279 g, 87% yield):¹HNMR(400MHz，DMSO-d₆)δ：9.11(1H，dd，J＝5.6Hz)，7.81(1H，m)，7.77(1H，d，J＝5.6Hz)，7.52(1H，d，J＝5.6Hz)，7.48-7.26(6H，m)，5.09(2H，s)，4.67(2H，d，J＝5.2Hz)，4.04(2H，m)，3.90(2H，m)，1.58(6H，s)。LCMS(M+H)⁺m/z 476。

intermediate 148

N- (4-fluoro-2- (methylcarbamoyl) benzyl) -3- (benzyloxy) -10, 10-dimethyl-4-oxo-6, 7, 8, 10-tetrahydro-4H-pyrimido [2, 1-c)][1，4]OxazazemIntermediate 35, 3- (benzyloxy) -10, 10-dimethyl-4-oxo-6, 7, 8, 10-tetrahydro-4H-pyrimido [2, 1-c) ][1，4]OxazazemA solution of the-2-carboxylic acid in dry dimethylformamide (4 ml) was treated with HATU (0.278 g, 0.70mmol) and stirred for 10 min. The reaction mixture was treated with 2- (aminomethyl) -5-fluoro-N-methylbenzamide trifluoroacetate (0.24 g, 0.8mmol) followed by dimethylaminopyridine (0.121 g, 0.97mmol) and stirred at 60 ℃ for 4 h. After this time, the solvent was removed in vacuo and the remaining residue was dissolved in ethyl acetate (15mL) and washed with 1.0N HCl (15 mL). The organic layer was dried (sodium sulfate), filtered and concentrated to dryness. Subjecting the crude product to flash column chromatography (SiO)₂) Purification, eluting with ethyl acetate. The product containing fractions were pooled, concentrated to dryness, and triturated with ether to afford 0.366 g of the title compound as a white glassy solid.¹H NMR(500MHz，d₆-acetone) δ ppm: 8.71-8.82(1H, m), 7.84-7.95(1H, br), 7.47-7.62(4H, m), 7.27-7.40 (c) ((1H, m))5H，m)，7.20(1H，dt，J＝8.5，2.7Hz)，5.15-5.21(2H，br s)，4.48-4.60(4H，m)，2.96(2H，s)，2.94(2H，s)，1.62-1.64(6H，s)。

Intermediate 149-174

Intermediate 149-174 was prepared following the coupling procedure described for intermediate 140-148.

Intermediate 149

N- (4-fluorobenzyl) -3- (benzyloxy) -9-methyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]The title compound can be prepared from intermediate 16, 3-benzyloxy-9-methyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ] ][1，4]Oxazine-2-carboxylic acid and 4-fluorobenzylamine.¹HNMR 400MHz(CDCl₃)δ(ppm)：1.67(3H，d，J＝6.6Hz，CH₃)，3.91(2H，m，CH₂)，4.12-4.35(2H，m，CH₂)，4.52(2H，d，J＝5.9Hz，NCH₂)，4.70(1H，q，J＝6.6Hz，OCH)，5.33(2H，s，OCH₂) 7.02(2H, m, arene), 7.25(2H, m, arene), 7.35(3H, m, arene), 7.47(2H, m, arene), 7.71(1H, broad t, NH).

Intermediate 150

N- (4-fluoro-2- (methylcarbamoyl) benzyl) -3- (benzyloxy) -4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide may be prepared from intermediate 7, 3- (benzyloxy) -4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c][1，4]Oxazine-2-carboxylic acid and intermediate 39, 2- (aminomethyl) -5-fluoro-N-methylbenzamide the title compound was prepared. White colourA crystal; mp: 189 deg.C and 190 deg.C (ethyl acetate).¹HNMR 400MHz(CDCl₃)δ(ppm)：3.01(3H，d，J＝4.5Hz，NCH₃)，4.00(2H，m，CH₂)，4.08(1H，m，CH)，4.50(2H，d，J＝6.6Hz，NCH₂)，4.71(2H，s，OCH₂)，5.38(2H，s，OCH₂) 6.88(1H, width q, NH), 7.07(1H, m, arene), 7.16(1H, dd, J ═ 2.5Hz and J ═ 8.6Hz, arene), 7.30-7.44(6H, m, arene), 8.55(1H, width t, NH)₂₄H₂₃FN₄O₅Analytical calculation of (a): c61.80, H4.97, N12.01. Measurement value: c61.84, H4.82, N12.00.

Intermediate 151

N- (4-fluoro-2- (1H-1, 2, 4-triazol-1-yl) benzyl) -3- (benzyloxy) -9-ethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide, synthesis of 3- (benzyloxy) -9-ethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c][1，4]Oxazine-2-carboxylic acid (synthesized using the methods described for syntheses or intermediates 7 and 16) and intermediate 69, (4-fluoro-2- (1H-1, 2, 4-triazol-1-yl) phenyl) methylamine may be used to prepare the title compound. White needle-shaped crystals; mp: 155 ℃ and 157 ℃ (ethyl acetate). ¹HNMR 400MHz(CDCl₃)δ(ppm)：1.03(3H，t，J＝7.5Hz，CH₃)，1.97-2.02(1H，m，CH)，2.29-2.32(1H，m，CH)，.3.83-3.88(2H，m，CH₂)，4.15-4.31(2H，m，CH₂)，4.44(2H，m，CH₂)，4.53(1H，m，CH)，5.34(2H，s，OCH₂) 7.08(1H, dd, J ═ 2.5Hz and J ═ 8.6Hz, arenes), 7.20(1H, m, arenes), 7.29-7.31(3H, m, arenes), 7.47(2H, m, arenes), 7.74(1H, dd, J ═ 6.1Hz and J ═ 8.6Hz, arenes), 8.02(1H, s, CH), 8.41(1H, s, CH), 8.55(1H, wide t, NH). C₂₆H₂₅FN₆O₄Analytical calculation of (a): c61.89, H4.99, N16.65. Measurement value: c61.67, H5.13, N16.61.

Intermediate body 152

N- (4-fluoro-2- (3-methyl-1H-1, 2, 4-triazol-1-yl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide may be prepared from intermediate 27, 3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino- [2, 1-c][1，4]Oxazine-2-carboxylic acid and intermediate 85, (4-fluoro-2- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl) methylamine the title compound was prepared. White crystals; mp: 203 deg.C (ethyl acetate).¹HNMR 400MHz(CDCl₃)δ(ppm)：1.65(6H，s，2xCH₃)，2.50(3H，s，CH₃)，4.03(4H，m，2xCH₂)，4.46(2H，d，J＝6.6Hz，NCH₂)，5.31(2H，s，OCH₂) 7.06(1H, dd, J ═ 3 Hz and J ═ 8.6Hz, arenes), 7.16(1H, m, arenes), 7.30-7.34(3H, m, arenes), 7.50(2H, m, arenes), 7.74(1H, dd, J ═ 6.0Hz and J ═ 8.6Hz, arenes), 8.28(1H, s, CH), 8.45(1H, wide t, NH). C₂₇H₂₇FN₆O₄Analytical calculation of (a): c62.54, H5.25, N16.21. Measurement value: c62.48, H5.31, N16.29.

Intermediate 153

N- (2-fluoro-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide the intermediate 27, 3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino- [2,1-c][1，4]oxazine-2-carboxylic acid and intermediate 87, (2-fluoro-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl) methylamine the title compound was prepared. White crystals; mp: 183 ℃ and 185 ℃ (ethyl acetate).¹HNMR 400MHz(CDCl₃)δ(ppm)：1.65(6H，s，2xCH₃)，2.52(3H，s，CH₃)，4.05(4H，m，2xCH₂)，4.64(2H，d，J＝6.1Hz，NCH₂)，5.33(2H，s，OCH₂) 7.29-7.55(8H, m, arene), 7.84(1H, width t, NH), 8.45(1H, s, CH). C₂₇H₂₇FN₆O₄Analytical calculation of (a): c62.54, H5.25, N16.21. Measurement value: c62.41, H5.40, N16.23.

Intermediate 154

2- ((3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamido) methyl) -5-fluorobenzoic acid methyl ester can be prepared from intermediate 27, 3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino- [2, 1-c][1，4]Oxazine-2-carboxylic acid and intermediate 38, 2- (aminomethyl) -5-fluorobenzoic acid methyl ester the title compound was prepared.¹H NMR(CDCl₃500MHz) δ ppm: 1.61(6H, s, gem-Me), 3.88(3H, s, OMe), 3.97(2H, t, J ═ 5.5Hz, CH) ₂)，4.02(2H，t，J＝5.5Hz，CH₂)，4.73(2H，d，J＝6.7Hz，NCH₂)，5.25(2H，s，OCH₂)，7.19(1H，dt，J＝3，8.5Hz，Ar-H)，7.27-7.31(3H，m，Ar-Hs)，7.48-7.50(2H，m，Ar-Hs)，7.61(1H，dd，J＝5.5，8.5Hz，Ar-H)，7.66(1H，dd，J＝3，9.5Hz，Ar-H).LC/MSm/z 496(M+H)。

Intermediate 155

N- (2- (cyclopropylcarbamoyl) -4-fluorobenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide the title compound can be prepared from intermediate 27, 3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimido- [2, 1-c ] [1, 4] oxazine-2-carboxylic acid and intermediate 40, 2- (aminomethyl) -N-cyclopropyl-5-fluorobenzamide. LC/MSm/z 521(M + H).

Intermediate body 156

N- (4-fluoro-2- (morpholine-4-carbonyl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide may be prepared from intermediate 27, 3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino- [2, 1-c][1，4]Oxazine-2-carboxylic acid and intermediate 44, (2- (aminomethyl) -5-fluorophenyl) (morpholino) methanone the title compound was prepared.¹HNMR(CDCl₃，500MHz)δppm：1.59(6H，s)，3.29(2H，brs)，3.57(2H，m)，3.74(4H，s)，3.98(4H，m)，5.26(2H，s)，6.88(1H，dd，J＝8.2，2.7Hz)，7.03(1H，dt，J＝8.5，2.5Hz)，7.24-7.33(3H，m)，7.42(2H，dd，J＝8.6，5.3Hz)，7.47(2H，dd，J＝7.5，2.0Hz)，8.18(1H，t，J＝6.4Hz)；LC/MS m/z 551(M+H)。

Intermediate 157

N- (4-fluoro-2- (2-morpholino-2-oxoethoxy) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide derivativesTo obtain the intermediate 27, 3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino- [2, 1-c][1，4]Oxazine-2-carboxylic acid and intermediate 131, 2- (2- (aminomethyl) -5-fluorophenoxy) -1-morpholinoethanone the title compound was prepared. ¹H NMR(CDCl₃，500MHz)δppm：1.59(6H，s，gem-Me)，3.38，3.54(4H，br，NCH₂)，3.62(4H，m，OCH₂)，3.96(2H，m，NCH₂)，4.01(2H，m，OCH₂)，4.55(2H，s，OCH₂)，4.55(2H，d，J＝4.3Hz，NCH₂)，5.17(2H，s，OCH₂)，6.53(1H，dd，J＝10，2.1Hz，Ar-H)，6.63(1H，dt，J＝2.5，8Hz，Ar-H)，7.23-7.26(1H，m，Ar-H)，7.28-7.30(3H，m，Ar-Hs)，7.42-7.44(2H，m，Ar-Hs)，8.00(1H，t，J＝5.5Hz，NH)；¹³C NMR(CDCl₃，125.77Hz)δppm：27.74，38.76，42.30，42.98，45.38，58.06，66.55，66.78，66.91，74.72，76.27，100.40，100.61，108.07，108.23，122.56，128.37，128.49，128.84，130.88，130.96，139.69，141.36，141.98，156.70，157.02，157.10，159.58，162.04，163.99，162.86，165.79。HRMS(ESI)C₃₀H₃₄N₄O₇Calculated value of F (M + H): 581.2412, measurement: 581.2393.

intermediate 158

Dimethyl-carbamic acid 2- { [ (3-benzyloxy-9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydro-pyrimido [2, 1-c)][1，4]Oxazine-2-carbonyl) -amino]5-fluoro-phenyl methyl ester, from intermediate 27, 3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino- [2, 1-c][1，4]Oxazine-2-carboxylic acid and intermediate 133, 2- (aminomethyl) -5-fluorophenyl dimethylcarbamate the title compound was prepared.¹H NMR(CDCl₃500MHz) δ ppm: 1.58(6H, s, gem-Me), 2.92, 3.05(2s, NMe), 3.96(2H, m, NCH)₂)，4.00(2H，m，OCH₂)，4.48(2H，d，J＝5.5Hz，NCH₂)，5.26(2H，s，OCH₂)，6.84(1H，dd，J＝2.5Hz，9Hz，Ar-H)，6.87(1H，dt，J＝2.5Hz，8Hz，Ar-H)，7.25-7.33(4H，m，Ar-Hs)，7.53(2H，d，J＝～7Hz，Ar-Hs)，7.78(1H，brt，J＝5Hz，NH)；¹³C NMR(CDCl₃，125.77Hz)δppm：27.68，36.61，36.89，37.97，42.97，58.06，74.73，76.23，110.58，110.77，113.06，113.23，126.55，126.58，128.31，128.45，128.91，131.23，131.31，136.76，140.70，142.00，150.60，150.69，154.50，156.30，159.79，161.40，163.37，162.43。HRMS(ESI)C₂₇H₃₀N₄O₆Calculated value of F (M + H): 525.2149, measurement: 525.2163.

intermediate 159

N- (4-fluoro-2- (2-oxopyrrolidin-1-yl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide may be prepared from intermediate 27, 3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino- [2, 1-c][1，4]Oxazine-2-carboxylic acid and 1- (2- (aminomethyl) -5-fluorophenyl) pyrrolidin-2-one (derived from the reduction of intermediate 111, 4-fluoro-2- (2-oxopyrrolidin-1-yl) benzonitrile) the title compound was prepared.¹HNMR 400MHz(MeOD)δppm：7.44(3H，m)，7.33(3H，m)，7.11(1H，dd，J＝9.2，3.0Hz)7.03(1H，m)，5.21(2H，s)，4.43(2H，s)，4.08(2H，t，J＝5.0Hz)，3.98(2H，t，J＝5.0Hz)，3.85(2H，t，J＝7.1Hz)，2.58(2H，t，J＝8.0Hz)，2.23(2H，m)，1.61(6H，s)。LCMS(M+H)⁺m/z 521。

Intermediate body 160

N- (4-fluoro-2- (2-oxoazepan-1-yl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c) ][1，4]Oxazine-2-carboxamide may be prepared from intermediate 27, 3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino- [2, 1-c][1，4]Oxazine-2-carboxylic acid and 1- (2- (aminomethyl) -5-fluorophenyl) azepan-2-one (derived from the reduction of intermediate 113, 4-fluoro-2- (2-oxoazepan-1-yl) benzonitrile) the title compound was prepared.¹HNMR 400MHz(DMSO)δppm：8.80(1H，dd，(t)，J＝6.0Hz)，7.46(2H，m)，7.36(4H，m)，7.08(1H，dd，J＝9.8，2.8Hz)，7.0(1H，m)，5.09(2H，s)，4.43(1H，dd，J＝15.2，7.1Hz)，4.06(1H，dd，J＝15.2，5.0Hz)，4.02(2H，t，J＝5.0Hz)，3.90(2H，t，J＝5.0Hz)，3.77(1H，m)，3.51(1H，m)，2.70(1H，m)，2.51(2H，m)，1.76(6H，m)，1.56(6H，s)。LCMS(M+H)⁺m/z 549。

Intermediate 161

N- (2- (2-oxooxazolidin-3-yl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide may be prepared from intermediate 27, 3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino- [2, 1-c][1，4]Oxazine-2-carboxylic acid and 3- (2- (aminomethyl) phenyl) oxazolidin-2-one (derived from the reduction of intermediate 116, 2- (2-oxooxazolidin-3-yl) benzonitrile) the title compound was prepared.¹H NMR(400MHz，DMSO-d₆)δppm：8.90(1H，t，J＝6.0Hz)，7.58-7.32(7H，m)，7.22(2H，t，J＝7.5Hz)，5.08(2H，s)，4.48(2H，t，J＝7.8Hz)，4.44(2H，d，J＝6.0Hz)，4.06-3.97(4H，m)，3.88(2H，m)，1.56(6H，s)；LCMS(M+H)⁺m/z 505。

Intermediate 162

N- (2- (2-oxoazetidin-1-yl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide may be prepared from intermediate 27, 3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino- [2, 1-c][1，4]Oxazine-2-carboxylic acid and 1- (2- (aminomethyl) phenyl) azetidin-2-one (derived from the reduction of intermediate 115, 2- (2-oxoazetidin-1-yl) benzonitrile) to prepare the title compound. ¹H NMR(400MHz，CDCl₃)δppm：8.67(1H，brt，J＝6.3Hz)，7.60(1H，dd，J＝1.3，7.6Hz)，7.53-7.50(1H，dd，m)，7.34-7.24(5H，m)，7.18(1H，ddd(dt)，J＝1.2，7.4Hz)，7.10(1H，dd，J＝1.2，8.0Hz)，5.27(2H，s)，4.60(2H，d，J＝6.3Hz)，4.01-3.95(4H，m)，3.71(2H，t，J＝4.5Hz)，3.10(2H，t，J＝4.5Hz)，1.60(6H，s)；LCMS(⁺ESI，M+H⁺)m/z 489。

Intermediate 163

N- (4-fluoro-2- (thiazol-2-ylamino) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide may be prepared from intermediate 27, 3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino- [2, 1-c][1，4]Oxazine-2-carboxylic acid and N- (2- (aminomethyl) -5-fluorophenyl) thiazol-2-amine (derived from the reduction of intermediate 123, 4-fluoro-2- (thiazol-2-ylamino) benzonitrile) the title compound was prepared.¹H NMR(400MHz，DMSO-d6)δppm：9.92(1H，s)，9.10(1H，t，J＝6.3Hz)，8.19(1H，dd，J＝2.8，12.3Hz)，7.41-7.38(2H，m)，7.32-7.28(5H，m)，6.99(1H，d，J＝3.8Hz)，6.71(1H，ddd(dt)，J＝2.8，8.3)，5.05(2H，s)，4.45(2H，d，J＝6.3Hz)，4.01-3.98(2H，m)，3.88-3.85(2H，m)，1.54(6H，s)LCMS(⁺ESI，M+H⁺)m/z 536。

Intermediate 164

N- (4-fluoro-2- (5-methyl-1, 3, 4-thiadiazol-2-ylamino) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide may be prepared from intermediate 27, 3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino- [2, 1-c][1，4]Oxazine-2-carboxylic acid and N- (2- (aminomethyl) -5-fluorophenyl) -5-methyl-1, 3, 4-thiadiazol-2-amine (derived from the reduction of intermediate 124, 4-fluoro-2- (5-methyl-1, 3, 4-thiadiazol-2-ylamino) benzonitrile) the title compound was prepared. LCMS (⁺ESI，M+H⁺)m/z 551。

Intermediate 165

N- (4-fluoro-2- (2-oxooxazolidin-3-yl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide may be prepared from intermediate 27, 3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino- [2, 1-c ][1，4]Oxazine-2-carboxylic acid and 3- (2- (aminomethyl) -5-fluorophenyl) oxazolidin-2-one (derived from the reduction of intermediate 117, 4-fluoro-2- (2-oxooxazolidin-3-yl) benzonitrile) the title compound was prepared.¹H NMR(400MHz，MeOD)δppm：9.48(1H，dd，J＝8.6，6.5Hz)，7.41(2H，m)，7.32(3H，m)，7.22(1H，dd，J＝9.6，2.5Hz)，7.08(1H，td，J＝8.6，2.7Hz)，5.21(2H，s)，4.57(2H，t，J＝7.7Hz)，4.50(2H，s)，4.07(4H，m)，3.99(2H，m)，1.61(6H，s)。LCMS(M+H)⁺m/z 523。

Intermediate 166

(R) -N- (2- (2- ((tert-butyldimethylsilyloxy) methyl) -5-oxopyrrolidin-1-yl) -4-fluorobenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide may be prepared from intermediate 27, 3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino- [2, 1-c][1，4]Oxazine-2-carboxylic acid and (S) -1- (2- (aminomethyl) -5-fluorophenyl) -5- ((tert-butyldimethylsilyloxy) methyl) pyrrolidin-2-one (derived from the reduction of intermediate 122, (R) -2- (2- ((tert-butyldimethylsilyloxy) methyl) -5-oxopyrrolidin-1-yl) -4-fluorobenzonitrile) the title compound was prepared.¹HNMR 400mhz (dmso) δ ppm: 8.82(1H, width s), 7.47(2H, m), 7.35(4H, m), 7.00(1H, width s), 5.09(2H, s), 4.60-4.10(3H, m), 4.02(3H, m), 3.88(2H, m), 3.53(2H, width s), 2.42-2.35(2H, m), 1.94(1H, m), 1.56(3H, s), 1.55(3H, s), 0.82(9H, width s), -0.01(6H, s). LCMS (M + H)⁺m/z 665。

Intermediate 167

(S) -N- (2- (2- ((tert-butyldimethylsilyloxy) methyl) -5-oxopyrrolidin-1-yl) -4-fluorobenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide the intermediate 27, 3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7,9-tetrahydropyrimidino- [2, 1-c][1，4]Oxazine-2-carboxylic acid and (S) -1- (2- (aminomethyl) -5-fluorophenyl) -5- ((tert-butyldimethylsilyloxy) methyl) pyrrolidin-2-one (derived from the reduction of intermediate 121, (R) -2- (2- ((tert-butyldimethylsilyloxy) methyl) -5-oxopyrrolidin-1-yl) -4-fluorobenzonitrile) the title compound was prepared.¹HNMR 400mhz (dmso) δ ppm: 8.82(1H, width s), 7.52-7.33(7H, m), 7.02(1H, width s), 5.60(2H, s), 4.60-4.20(2H, m), 4.02(3H, t, J ═ 5.0Hz), 3.89(3H, t, 5.0Hz), 3.53(2H, width s), 2.51(2H, s), 2.44-2.26(2H, m), 1.94(1H, width s), 1.57(3H, s), 1.55(3H, s), 0.82(9H, width s), -0.02(6H, s). LCMS (M + H)⁺m/z 665。

Intermediate 168

N- (4-fluoro-2- (N-methylacetamido) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide may be prepared from intermediate 27, 3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino- [2, 1-c ][1，4]Oxazine-2-carboxylic acid and N- (2- (aminomethyl) -5-fluorophenyl) -N-methylacetamide (derived from intermediate 114, reduction of N- (2-cyano-5-fluorophenyl) -N-methylacetamide) the title compound was prepared.¹HNMR 400MHz(MeOD)δppm：7.49-7.33(6H，m)，7.15-7.06(2H，m)，5.22(2H，s)，4.41(2H，d，J＝2.4Hz)，4.09(2H，t，J＝5.1Hz)，4.01(2H，t，J＝5.1Hz)，3.25(0.4H，s)，3.22(2.6H，s)，1.85(3H，s)，1.63(6H，s)。LCMS(M+H)⁺m/z 509。

Intermediate 169

N- (2-amino-4-fluorobenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide may be prepared from intermediate 27, 3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino- [2, 1-c][1，4]Oxazine-2-carboxylic acid and 2- (aminomethyl) -5-fluoroaniline the title compound was prepared.¹HNMR 400MHz(MeOD)δppm：¹HNMR 400MHz(MeOD)δppm：7.36(2H，m)，7.30(3H，m)，7.10(1H，dd，J＝8.3，6.5Hz)，6.47(1H，dd，J＝11.1，2.5Hz)，6.32(1H，ddd，(dt)，J＝8.6，2.5Hz)，5.19(2H，s)，4.40(2H，s)，4.07(2H，t，J＝5.0Hz)，3.99(2H，t，J＝5.0Hz)，1.61(6H，s)。LCMS(M+H)⁺m/z 453。

Intermediate 170

N- (2- (ethylamino) -4-fluorobenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide may be prepared from intermediate 27, 3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino- [2, 1-c][1，4]Oxazine-2-carboxylic acid and 2- (aminomethyl) -N-ethyl-5-fluoroaniline the title compound was prepared.¹HNMR 400MHz(CDCl₃)δ(ppm)：1.27(3H，t，J＝7.1Hz，CH₃)，1.63(6H，s，2xCH₃)，3.10(2H，q，J＝7.1Hz，CH₂)，4.04(4H，m，2xCH₂)，4.45(2H，d，J＝6.6Hz，NCH₂)，5.27(2H，s，OCH₂) 6.28(1H, width s, arene), 6.31(1H, m, arene), 6.98(1H, m, arene), 7.3-7.38(3H, m, arene), 7.49(2H, m, arene), 7.54(1H, width t, NH). HRMS (ESI)⁺)C₂₆H₃₀FN₄O₄[M+H⁺]The calculated value of (a): 481.2251, respectively; measurement value: 481.2254.

intermediate 171

N- (4-fluorobenzyl) -3- (benzyloxy) -N-methoxy-9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c) ][1，4]Oxazine-2-carboxamide may be prepared from intermediate 27, 3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino- [2, 1-c][1，4]Oxazine-2-carboxylic acid and (4-fluorophenyl) -N-methoxymethanamine the title compound was prepared. White crystals; mp: 141 deg.C (ethyl acetate-hexane).¹HNMR 400MHz(CDCl₃)δ(ppm)：1.66(6H，s，2xCH₃)，3.59(3H，s，OCH₃)，4.07(4H，m，2xCH₂)，4.90(2H，s，NCH₂)，5.20(2H，s，OCH₂) 6.81(2H, m, arene), 7.26-7.30(3H, m, arene), 7.36(2H, m, arene), 7.44(2H, m, arene). HRMS (ESI)⁺)C₂₅H₂₇FN₃O₅[M+H⁺]The calculated value of (a): 468.1935: measurement value: 468.1916.

intermediate 172

N- (4-fluoro-2- (1, 2, 3-thiadiazol-4-yl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide may be prepared from intermediate 27, 3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino- [2, 1-c][1，4]Oxazine-2-carboxylic acid and (4-fluoro-2- (1, 2, 3-thiadiazol-4-yl) phenyl) methylamine the title compound was prepared.¹HNMR 400MHz(CDCl₃)δ(ppm)：1.66(6H，s，2xCH₃)，4.02(4H，m，2xCH₂)，4.57(2H，d，J＝6.6Hz，NCH₂)，5.32(2H，s，OCH₂) 7.18(1H, m, arene), 7.27-7.34(4H, m, arene), 7.54(2H, m, arene), 7.74 (C1H, dd, J ═ 6.2Hz and J ═ 8.6Hz, arenes), 8.71(1H, s, CH), 8.80(1H, width t, NH). HRMS (ESI)⁺)C₂₆H₂₅FN₅O₄S[M+H⁺]The calculated value of (a): 522.1611: measurement value: 522.1601.

intermediate 173

N- (4-fluoro-2- (5-methyloxazol-2-yl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c) ][1，4]Oxazine-2-carboxamide may be prepared from intermediate 27, 3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino- [2, 1-c][1，4]Oxazine-2-carboxylic acid and (4-fluoro-2- (5-methyloxazol-2-yl) phenyl) methylamine the title compound is prepared. White crystals; mp: 186 (. degree.C. (ethyl acetate-hexane).¹HNMR 400MHz(CDCl₃)δ(ppm)：1.61(6H，s，2xCH₃)，2.43(3H，s，CH₃)，4.02(4H，m，2xCH₂)，4.80(2H，d，J＝6.3Hz，NCH₂)，5.25(2H，s，OCH₂) 6.82(1H, s, CH), 7.11(1H, m, arene), 7.29-7.34(3H, m, arene), 7.52(2H, m, arene), 7.65(1H, dd, J ═ 2.5Hz and J ═ 9.6Hz, arene), 7.69(1H, dd, J ═ 6.1Hz and J ═ 8.6Hz, arene), 9.32(1H, wide t, NH). HRMS (ESI)⁺)C₂₈H₂₈FN₄O₅[M+H⁺]The calculated value of (a): 519.2044: measurement value: 519.2024.

intermediate 174

N- (4-fluoro-2-iodobenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2Can be prepared from an intermediate 27, 3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino- [2, 1-c)][1，4]Oxazine-2-carboxylic acid and (4-fluoro-2-iodophenyl) methylamine the title compound was prepared. A white solid.¹HNMR 400MHz(CDCl₃)δppm：1.66(6H，s，2xCH₃)，4.04(4H，m，2xCH₂，)，4.57(2H，d，J＝6.6Hz，NCH₂) 7.05(1H, m, arene), 7.3-7.38(3H, m, arene), 7.42(1H, dd, J ═ 6.1Hz and J ═ 8.6Hz, arene), 7.53(2H, m, arene), 7.56(1H, dd, J ═ 2.6Hz and J ═ 8.0Hz, arene), 8.05(1H, wide t, NH). HRMS (ESI) ⁺)C₂₄H₂₄FIN₃O₄[M+H⁺]The calculated value of (a): 564.0796, respectively; measurement value: 564.0809.

intermediate 175

N- (4-fluoro-2- (2-methoxypyridin-3-yl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Intermediate 174, N- (4-fluoro-2-iodobenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ] in a mixture of acetonitrile (12 ml) and water (12 ml)][1，4]Oxazine-2-carboxamide (0.350 g, 0.62mmol) was treated with 2-methoxypyridin-3-ylboronic acid (0.190 g, 1.24mmol), sodium carbonate (0.20 g, 1.88mmol) and tetrakis (triphenylphosphine) palladium (0) (0.15 g). The reaction mixture was degassed, flushed with argon and heated at 90 ℃ for 30 minutes. The reaction mixture was then diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated. Chromatography on silica gel (gradient elution of ethyl acetate in hexanes) of the residue afforded 0.245 g (72% yield) of the title material as a white solid.¹HNMR 400MHz(CDCl₃)δppm：1.63(6H，s，2xCH₃)，3.89(3H，s，OCH₃)，4.04(4H，m，2xCH₂) 4.37(2H, Width, NCH)₂)，5.26(2H，s，OCH₂) 6.93(1H, dd, J ═ 2.5Hz and J ═ 9Hz, arenes), 7.0(1H, dd, J ═ 5Hz and J ═ 7Hz, arenes), 7.06(1H, m, arenes), 7.3-7.5(8H, m, arenes and NH), 8.24(1H, m, arenes). HRMS (ESI) ⁺)C₃₀H₃₀FN₄O₅[M+H⁺]The calculated value of (a): 545.2200, respectively; measurement value: 545.2184.

intermediate 176

N- (4-fluoro-2-phenyl-benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Intermediate 174, N- (4-fluoro-2-iodobenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ] in a mixture of acetonitrile (10 ml) and water (10 ml)][1，4]Oxazine-2-carboxamide (0.150 g, 0.266mmol) was treated with phenylboronic acid (0.042 g, 0.35mmol), sodium carbonate (0.062 g, 0.58mmol), and tetrakis (triphenylphosphine) palladium (0) (0.070 g). The reaction mixture was degassed, flushed with argon and heated at 90 ℃ for 30 minutes. The reaction mixture was then diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated. Chromatography on silica gel (gradient elution of ethyl acetate in hexanes) of the residue afforded 0.124 g (91% yield) of the title material as a light yellow solid.¹HNMR400MHz(CDCl₃)δppm：1.61(6H，s，2xCH₃)，4.03(4H，m，2xCH₂)，4.49(2H，d，J＝6.1Hz，NCH₂) 7.02(2H, m, arene), 7.29-7.51(12H, m, arene and NH). HRMS (ESI)⁺)C₃₀H₂₉FN₃O₄[M+H⁺]The calculated value of (a): 514.2142, respectively; measurement value: 514.2137.

intermediate 177

N- (4-fluoro-2- (1H-pyrazol-5-yl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c) ][1，4]Oxazine-2-carboxamide intermediate 174, N- (4-fluoro-2-iodobenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c][1，4]Oxazine-2-carboxamide (0.150 g, 0.27mmol) was reacted with 1H-pyrazol-5-ylboronic acid (0.060 g, 0.54mmol), sodium carbonate (0.085 g, 0.81mmol) and tetrakis (triphenylphosphine) palladium (0) (0.070 g) to give 0.085 g (62% yield) of the title material as a white solid (after chromatography on silica gel).¹HNMR 400MHz(CDCl₃)δ(ppm)：1.63(6H，s，2xCH₃)，4.03(4H，m，2xCH₂)，4.65(2H，d，J＝6.5Hz，NCH₂)，5.25(2H，s，OCH₂) 6.54(1H, d, J ═ 2.5Hz, CH), 7.03(1H, m, arene), 7.25(1H, dd, J ═ 2.5Hz and J ═ 9.8Hz, arene), 7.35(3H, m, arene), 7.53(2H, m, arene), 7.56(1H, d, J ═ 2.5Hz, CH), 7.60(1H, dd, J ═ 6.1Hz and J ═ 8.6Hz, arene), 8.96(1H, width t, NH). HRMS (ESI)⁺)C₂₇H₂₇FN₅O₄[M+H⁺]The calculated value of (a): 504.2047: measurement value: 504.2068.

intermediate 178

N- (4-fluoro-2- (2- (trimethylsilyl) ethynyl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Intermediate 174, N- (4-fluoro-2-iodobenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ] in a mixture of N, N-dimethylformamide (3 ml) and piperidine (1.2 ml) ][1，4]Solution of oxazine-2-carboxamide (0.277 g, 0.49mmol) inTreated with dichlorobis (triphenylphosphine) palladium (II) (0.020 g), triphenylphosphine (0.010 g), copper (l) iodide (0.010 g) and then (trimethylsilyl) acetylene (0.21 ml, 1.47mmol) under argon. The resulting mixture was sealed and heated at 50 ℃ for one hour. The reaction mixture was then diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Chromatography on silica gel (gradient elution of ethyl acetate in hexanes) of the residue afforded 0.164 g (63% yield) of the title material as a pale yellow solid.¹HNMR 400MHz(CDCl₃)δppm：0.27(9H，s，SiCH₃)，1.64(6H，s，2xCH₃)，4.04(4H，m，2xCH₂)，4.71(2H，d，J＝6.1Hz，NCH₂)，5.32(2H，s，OCH₂) 6.99(1H, m, arene), 7.19(1H, dd, J ═ 2.6Hz and J ═ 9.1Hz, arene), 7.3-7.37(4H, m, arene), 7.48-7.51(2H, m, arene), 7.75(1H, wide t, NH). HRMS (ESI)⁺)C₂₉H₃₃FN₃O₄Si[M+H⁺]The calculated value of (a): 534.2224, respectively; measurement value: 534.2229.

intermediate 179

N- (2-ethynyl-4-fluorobenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Intermediate 178, N- (4-fluoro-2- (2- (trimethylsilyl) ethynyl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ] ][1，4]A solution of oxazine-2-carboxamide (0.150 g, 0.28mmol) in methanol (5 ml) was treated with potassium carbonate (0.120 g, 0.84mmol) and the resulting mixture was stirred at 22 ℃ for one hour. The reaction mixture was then diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 0.129 g (100% yield) of the title material as a pale yellow solid.¹HNMR 400MHz(CDCl₃)δppm：1.64(6H，s，2xCH₃)，3.31(1H，s，CH)，4.04(4H，m，2xCH₂)，4.69(2H，d，J＝6.6Hz，NCH₂)，5.31(2H，s，OCH₂) 7.04(1H, m, arene), 7.21(1H, dd, J ═ 2.6Hz and J ═ 9.1Hz, arene), 7.32-7.42(3H, m, arene), 7.40(1H, dd, J ═ 6.1Hz and J ═ 8.6Hz, arene), 7.52-7.54(2H, m, arene), 8.00(1H, wide t, NH). HRMS (ESI)⁺)C₂₆H₂₅FN₃O₄[M+H]The calculated value of (a): 462.1829, respectively; measurement value: 462.1822.

intermediate 180

N- (4-fluoro-2- (3-methylisoxazol-5-yl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide intermediate 179, N- (2-ethynyl-4-fluorobenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c][1，4]A solution of oxazine-2-carboxamide (0.150 g, 0.32mmol) in dimethylsulfoxide (5 mL) was treated with nitromethane (0.14 mL, 1.92mmol), 4- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -4-methylmorpholinium chloride (DMTMM) (0.241 g, 1.0mmol) (M.Kunishima et al, Tetrahedron, 55, 1999, 13159-13170) and 4- (dimethylamino) pyridine (DMAP) (0.010 g) and the resulting mixture was stirred at 22 ℃ for 16 h. The same amounts of nitromethane, DMTMM and DMAP were then added and the mixture was stirred for an additional 24 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Chromatography on silica gel (gradient elution of ethyl acetate in dichloromethane) of the residue afforded 0.122 g (73% yield) of the title material as a white solid. ¹HNMR 400MHz(CDCl₃)δppm：1.62(6H，s，2xCH₃)，2.39(3H，s，CH₃)，4.04(4H，m，2xCH₂)，4.69(2H，d，J＝6.1Hz，NCH₂)，5.31(2H，s，OCH₂) 6.36(1H, m, CH), 7.13(1H, m, arene), 7.30-7.35(4H, m, arene), 7.50-7.53(2H, m, arene), 7.58(1H, dd, J ═ 5.5Hz and J ═ 8.6Hz, arene), 8.06(1H, width t, NH). HRMS (ESI)⁺)C₂₈H₂₈FN₄O₅[M+H⁺]The calculated value of (a): 519.2044, respectively; measurement value: 519.2059.

intermediate 181

N- (2- (3-bromoisoxazol-5-yl) -4-fluorobenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Intermediate 179, N- (2-ethynyl-4-fluorobenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ] in a mixture of ethyl acetate (10 ml) and water (2 ml)][1，4]A solution of oxazine-2-carboxamide (0.350 g, 0.76mmol) was treated with potassium bicarbonate (0.230 g, 2.3mmol) followed by dibromoformaldoxime (0.354 g, 1.75mmol) (D.M. Vyas, Y.Chiang and T.W.Doyle, Tetrahedron Letters, 1984, 25, 487-. After 1 hour, the same amounts of potassium bicarbonate and dibromoformaldoxime were added and the mixture was stirred for an additional 1.5 hours. The reaction mixture was then diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from diethyl ether to yield 0.300 g (68% yield) of the title material as a white solid. ¹HNMR 400MHz(CDCl₃)δppm：1.63(6H，s，2xCH₃)，4.04(4H，m，2xCH₂)，4.67(2H，d，J＝6.6Hz，NCH₂)，5.32(2H，s，OCH₂) 6.60(1H, s, CH), 7.17(1H, m, arene), 7.30-7.36(4H, m, arene), 7.51-7.53(2H, m, arene), 7.60(1H, dd, J ═ 5.5Hz and J ═ 8.6Hz, arene), 8.01(1H, width t, NH). HRMS (ESI)⁺)C₂₇H₂₅BrFN₄O₅[M+H⁺]The calculated value of (a): 583.0992, respectively; measurement value: 583.0986.

intermediate 182

N- (4-fluoro-2- (3-hydroxyprop-1-ynyl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide intermediate 174, N- (4-fluoro-2-iodobenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ] was prepared using the conditions described for intermediate 178][1，4]Oxazine-2-carboxamide (0.563 g, 1.00mmol) was reacted with propargyl alcohol (0.18 ml, 3.2mmol) to give 0.415 g (85% yield) of the title material as a white solid.¹HNMR 400MHz(CDCl₃)δppm：1.64(6H，s，2xCH₃)，4.04(4H，m，2xCH₂)，4.39(2H，d，J＝6.6Hz，CH₂)，4.68(2H，d，J＝6.0Hz，CH₂)，5.29(2H，s，OCH₂) 6.99(1H, m, arene), 7.13(1H, dd, J ═ 2.5Hz and J ═ 9.1Hz, arene), 7.22(1H, dd, J ═ 5.6Hz and J ═ 8.6Hz, arene), 7.33-7.37(3H, m, arene), 7.44-7.47(2H, m, arene), 7.68(1H, width t, NH). HRMS (ESI)⁺)C₂₇H₂₇FN₃O₅[M+H⁺]The calculated value of (a): 492.1935, respectively; measurement value: 492.1939.

intermediate 183

3- [2- ((3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c) ][1，4]Oxazin-2-carboxamido) methyl) -5-fluorophenyl]Prop-2-ynyl methanesulfonate intermediate 182, N- (4-fluoro-2- (3-hydroxyprop-1-ynyl) benzyl) -3- (benzyloxy) -9,9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]A solution of oxazine-2-carboxamide (0.280 g, 0.57mmol) and triethylamine (0.12 ml, 0.86mmol) in dichloromethane (5 ml) was cooled to 0 deg.C and treated dropwise with methanesulfonyl chloride (0.050ml, 0.64mmol) and stirred for 30 min. The reaction mixture was then diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Chromatography on silica gel (gradient elution of ethyl acetate in hexanes) of the residue afforded 0.245 g (75% yield) of the title material as a white solid.¹HNMR 400MHz(CDCl₃)δppm：1.65(6H，s，2xCH₃)，3.10(3H，s，SCH₃)，4.05(4H，m，2xCH₂)，4.67(2H，d，J＝6.1Hz，NCH₂)，5.03(2H，s，CH₂)，5.29(2H，s，OCH₂) 7.07(1H, m, arene), 7.18(1H, dd, J ═ 2.5Hz and J ═ 9.1Hz, arene), 7.32-7.36(3H, m, arene), 7.38(1H, dd, J ═ 5.5Hz and J ═ 8.6Hz, arene), 7.49-7.51(2H, m, arene), 7.77(1H, wide t, NH). MS (ESI)⁺)m/e 570[M+H⁺]。

Intermediate body 184

N- (2- (3- (dimethylamino) prop-1-ynyl) -4-fluorobenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide intermediate 183, 3- [2- ((3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c) ][1，4]Oxazin-2-carboxamido) methyl) -5-fluorophenyl]A solution of prop-2-ynylmethanesulfonate (0.100 g, 0.18mmol) in acetonitrile (5 ml) was treated with 0.3 ml (0.6mmol) of a 2M solution of dimethylamine in tetrahydrofuran at 22 ℃ and the resulting mixture was stirred for 30 min. The reaction mixture was then diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 0.080 g (88% yield) of the title materialA white solid.¹HNMR 400MHz(CDCl₃)δppm：1.64(6H，s，2xCH₃)，2.43(6H，s，2xNCH₃) 3.58(2H, width s, CH)₂)，4.05(4H，m，2xCH₂)，4.70(2H，d，J＝6.0Hz，NCH₂)，5.30(2H，s，OCH₂) 7.01(1H, m, arene), 7.18(1H, dd, J ═ 3Hz and J ═ 9.1Hz, arene), 7.32-7.38(4H, m, arene), 7.50-7.53(2H, m, arene), 7.79(1H, wide t, NH). HRMS (ESI)⁺)C₂₉H₃₂FN₄O₄[M+H⁺]The calculated value of (a): 519.2408, respectively; measurement value: 519.2407.

intermediate 185

N- (4-fluoro-2- (3- (methylthio) prop-1-ynyl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide intermediate 183, 3- [2- ((3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazin-2-carboxamido) methyl) -5-fluorophenyl]A solution of prop-2-ynyl methanesulfonate (0.160 g, 0.28mmol) in N, N-dimethylformamide (3 ml) was treated with sodium thiomethoxide (0.026 g, 0.37mmol) at 0 ℃ and the resulting mixture was stirred for 2 hours. The reaction mixture was then diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Chromatography on silica gel (gradient elution of ethyl acetate in hexanes) of the residue afforded 0.114 g (78% yield) of the title material as a white solid. ¹HNMR 400MHz(CDCl₃)δppm：1.64(6H，s，2xCH₃)，2.28(3H，s，SCH₃)，3.45(2H，s，SCH₂)，4.05(4H，m，2xCH₂)，4.69(2H，d，J＝6.1Hz，NCH₂)，5.31(2H，s，OCH₂) 6.98(1H, m, arene), 7.15(1H, dd, J ═ 3Hz and J ═ 9.1Hz, arene), 7.32-7.38(4H, m, arene), 7.50-7.53(2H, m, arene), 7.80(1H, broad t, NH). HRMS (ESI)⁺)C₂₈H₂₉FN₃O₄S[M+H⁺]The calculated value of (a): 522.1863, respectively; measurement value: 522.1844.

intermediate body 186

N- (4-fluoro-2- (3- (methylsulfonyl) prop-1-ynyl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Intermediate 185, N- (4-fluoro-2- (3- (methylthio) prop-1-ynyl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ] -oxazine-2-carboxamide][1，4]A solution of oxazine-2-carboxamide (0.110 g, 0.21mmol) in dichloromethane (3 ml) was treated with 3-chloroperbenzoic acid (0.120 g, 85%, 0.59mmol) at 0 deg.C and the resulting mixture was stirred for 30 min at 22 deg.C. The reaction mixture was then diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Chromatography of the residue on silica gel (gradient elution of ethyl acetate in dichloromethane) afforded 0.074 g (64% yield) of the title material as a white solid.¹HNMR 400MHz(CDCl₃)δppm：1.64(6H，s，2xCH₃)，3.03(3H，s，SCH₃)，4.03(2H，s，SCH₂)，4.05(4H，m，2xCH₂)，4.65(2H，d，J＝6.0Hz，NCH₂)，5.27(2H，s，OCH₂) 7.06(1H, m, arene), 7.17(1H, dd, J ═ 3Hz and J ═ 8.6Hz, arene), 7.31-7.38(6H, m, arene), 8.12(1H, wide t, NH). HRMS (ESI) ⁺)C₂₈H₂₉FN₃O₆S[M+H⁺]The calculated value of (a): 554.1761, respectively; measurement value: 554.1784.

intermediate 187

2- ((3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamido) methyl) -5-fluorophenylphosphonic acid diethyl ester intermediate 174, N- (4-fluoro-2-iodobenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c][1，4]A solution of oxazine-2-carboxamide (0.200 g, 0.35mmol) and triphenylphosphine (0.020 mg) in ethanol (5 ml) was flushed with argon and then treated with N, N-diisopropylethylamine (0.25 ml, 1.4mmol), palladium (II) acetate (0.020 g) and diethyl phosphite (0.15 ml, 1.16 mmol). The reaction mixture was then sealed and heated at 80 ℃ for 18 hours. The reaction mixture was then diluted with ethyl acetate, washed with 0.1N hydrochloric acid, saturated sodium bicarbonate, brine, then dried over anhydrous magnesium sulfate and concentrated. Chromatography on silica gel (gradient elution of acetonitrile in dichloromethane) of the residue afforded 0.103 g (51% yield) of the title compound as a white solid.¹HNMR 400MHz(CDCl₃)δppm：1.36(6H，t，J＝6.6Hz，2xCH₃)，1.64(6H，s，2xCH₃)，4.04(4H，m，2xCH₂)，4.08-4.22(4H，m，2xOCH₂)，4.78(2H，d，J＝6.6Hz，NCH₂)，5.29(2H，s，OCH₂) 7.21(1H, m, arene), 7.29-7.34(3H, m, arene), 7.45-7.52(3H, m, arene), 7.65-7.72(1H, m, arene), 8.67(1H, wide t, NH). HRMS (ESI) ⁺)C₂₈H₃₄FN₃O₇P[M+H⁺]The calculated value of (a): 574.2118, respectively; measurement value: 574.2126.

intermediate 188

2- ((3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazin-2-carboxamido) methyl) -5-fluoroIntermediate 187, 2- ((3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]A solution of diethyl oxazin-2-carboxamido) methyl) -5-fluorophenylphosphonate (0.115 g, 0.20mmol) in tetrahydrofuran (3 ml)/ethanol (3ml) was treated with 1N aqueous sodium hydroxide (1.0 ml, 1.0mmol) and the resulting mixture was heated at 45 ℃ for 2 h. The reaction mixture was then diluted with ethyl acetate, washed with 0.1N hydrochloric acid, brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified on a Shimadzu automated preparative HPLC system (column YMC Pack C-18, 5 μ, 20 × 250mm, acetonitrile-water elution gradient of 0.1% trifluoroacetic acid) to give 0.070 g (64% yield) of the title material as a clear oil.¹HNMR 400MHz(CDCl₃)δppm：1.37(3H，t，J＝7.1Hz，CH₃)，1.62(6H，s，2xCH₃)，4.04(4H，m，2xCH₂)，4.18(2H，m，OCH₂) 4.75(2H, Width d, J ═ 5Hz, NCH)₂)，5.32(2H，s，OCH₂) 7.21(1H, m, arene), 7.30-7.33(3H, m, arene), 7.38-7.40(2H, m, arene), 7.47-7.52(1H, m, arene), 7.56-7.63(1H, m, arene), 8.56(1H, wide t, NH). HRMS (ESI) ⁺)C₂₆H₃₀FN₃O₇P[M+H⁺]The calculated value of (a): 546.1805, respectively; measurement value: 546.1786.

intermediate 189

N- (2-acetylamino-4-fluorobenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide to intermediate 169, N- (2-amino-4-fluorobenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c][1，4]To a solution of oxazine-2-carboxamide (0.033 g, 0.073mmol) in dry tetrahydrofuran (10 ml) were added acetyl chloride (5.7. mu.L, 0.08mmol) and diisopropylethylamine (38. mu.L, 0.22 mmol). The reaction mixture was stirred at 23 ℃ for 3 hours. Then NaHCO is added₃(0.25M, 20mL), the organic material was extracted with ethyl acetate (3X25 mL). The organic extracts were combined and dried (MgSO)₄) And (4) concentrating in vacuum. The residue was purified on a Biotage system using a silica gel column with ethyl acetate: Hex (1: 2 to 2: 1) as eluent to give the title compound (0.025g, 69% yield).¹HNMR 400MHz(MeOD)δ(ppm)：7.66(1H，dd，J＝10.5，2.8Hz)，7.43-7.25(6H，m)，6.87(1H，ddd，(dt)，J＝8.8，2.6Hz)，5.19(2H，s)，4.47(2H，m)，4.08(2H，t，J＝4.9Hz)，3.99(2H，t，J＝4.9Hz)，2.19(3H，s)，1.62(6H，s)。LCMS(M+H)⁺m/z 495。

Intermediate 190

2- ((3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazin-2-carboxamido) methyl) -5-fluorobenzoic acid to intermediate 154, 2- ((3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c) ][1，4]Oxazin-2-carboxamido) methyl) -5-fluorobenzoic acid methyl ester (500 mg, 1.01mmol) in MeOH (10 ml) and CH₃CN (5 ml) suspension was added 1N NaOH (2 ml), and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo, and the residue was subjected to reverse phase column chromatography (YMC, C-18ODS, 10-25% CH)₃CN/H₂O) purification, providing 90mg (19% yield) of the title compound as an off-white powder: LC/MS M/z 482(M + H).

Intermediate 191

N- (2- ((2-aminoethyl) carbamoyl) -4-fluorobenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c][1，4]Intermediate 190, 2- ((3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazin-2-carboxamido) methyl) -5-fluorobenzoic acid (59 mg, 0.12mmol) and O- (7-azabenzotriazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate, HATU (76 mg, 0.2 mmol; aldrich) in DMF (1 ml) was stirred for 20 min. Ethanolamine (20mg, 0.3mmol) was added to the mixture and stirring was continued overnight. The mixture was concentrated in vacuo and dissolved in CH₂Cl₂In (1), washed with water and then dried (MgSO)₄) Filtered and concentrated to provide 55mg (87% yield) of the title compound: LC/MS M/z 525(M + H).

Intermediate 192

(R) -N- (4-fluoro-2- (2- (hydroxymethyl) -5-oxopyrrolidin-1-yl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide intermediate 166, (R) -N- (2- (2- ((tert-butyldimethylsilyloxy) methyl) -5-oxopyrrolidin-1-yl) -4-fluorobenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ] was added at 23 deg.C][1，4]To a stirred solution of oxazine-2-carboxamide (0.10 g, 0.150mmol) in tetrahydrofuran (5ml) was added tetrabutylammonium fluoride solution (1M in tetrahydrofuran) (180 μ L, 0.18 mmol). The reaction mixture was stirred at 23 ℃ for 3 hours. Then NaHCO is added₃(1N in H)₂O, 30mL), the organic material was extracted with ethyl acetate (2X25 mL). The combined organic extracts were dried (MgSO)₄) Filtered and concentrated in vacuo. The residue was purified on a Biotage system using a silica gel column with ethyl acetate/hexane (1: 1) to ethyl acetate 100% as eluent to give the title compound (0.060 g, 73% yield):¹HNMR 400MHz(MeOD)δ(ppm)：7.55(1H，dd，(t)，6.6Hz)，7.43(2H，m)，7.13(1H，dd，J＝9.5，2.4Hz)，7.03(1H，m)，5.26(2H，s)，4.57(1H，m)，4.32(2H，m)，4.08(2H，t，J＝5.0Hz)，7.03(2H，t，J＝5.0Hz)，3.53(2H，m)，2.69-2.56(2H，m)，2.38(1H，m)，2.22(1H，m)，1.62(6H，s)。LCMS(M+H)⁺m/z 551。

intermediate 193

(R) - (1- (2- ((3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimido [2, 1-c)][1，4]Oxazin-2-carboxamido) methyl) -5-fluorophenyl) -5-oxopyrrolidin-2-yl) methyl acetate to intermediate 192, (R) -N- (4-fluoro-2- (2- (hydroxymethyl) -5-oxopyrrolidin-1-yl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ][1，4]To a solution of oxazine-2-carboxamide (0.045 g, 0.082mmol) in tetrahydrofuran (5ml) were added acetyl chloride (12.8 μ L, 0.180mmol) and diisopropylethylamine (31.4 μ L, 0.180 mmol). The reaction mixture was stirred at 23 ℃ for 4 hours. Then NaHCO is added₃(1N in H)₂O, 30mL), the organic material was extracted with ethyl acetate (2X25 mL). The combined organic extracts were dried (MgSO)₄) Filtered and concentrated in vacuo. The residue was purified on a Biotage system using a silica gel column with ethyl acetate/hexane (1: 1) to ethyl acetate 100% as eluent to give the title compound (0.032 g, 67% yield):¹HNMR 400MHz(MeOD)δppm：7.48(3H，m)，7.33(3H，m)，7.16(1H，m)，7.03(1H，m)，5.24(2H，s)，4.60(1H，m)，4.55(1H，m)，4.22(1H，dd，J＝12.0，4.5Hz)，4.08(2H，t，J＝5.0Hz)，3.99(3H，m)，2.62(2H，m)，2.44(1H，m)，2.09-1.92(5H，m)，1.62(3H，s)，1.61(3H，s)。LCMS(M+H)⁺m/z 593。

intermediate 194

(R) - (1- (2- ((3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimido [2, 1-c)][1，4]Oxazin-2-carboxamido) methyl) -5-fluorophenyl) -5-oxopyrrolidin-2-yl) methyl methanesulfonate to intermediate 192, (R) -N- (4-fluoro-2- (2- (hydroxymethyl) -5-oxopyrrolidin-1-yl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ] at 0 deg.C][1，4]Oxazine-2-carboxamide (0.160 g, 0.291mmol) in CH₂Cl₂To the stirred solution (10 mL) was added triethylamine (81. mu.L, 0.582mmol) and methanesulfonyl chloride (27. mu.L, 0.349 mmol). The reaction mixture was stirred at 23 ℃ for 4 hours. Water (50mL) was then added, followed by CH ₂Cl₂(2X50mL) organic material was extracted. The combined organic extracts were dried (MgSO)₄) Filtered and concentrated in vacuo to give the title compound (0.178 g, 98% yield). The crude product was used without further purification in the next step: LCMS (M + H)⁺m/z 629。

Intermediate 195

(R) -N- (2- (2- (azidomethyl) -5-oxopyrrolidin-1-yl) -4-fluorobenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide to intermediate 194, (R) - (1- (2- ((3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]To a solution of oxazin-2-carboxamido) methyl) -5-fluorophenyl) -5-oxopyrrolidin-2-yl) methyl methanesulfonate (0.150 g, 0.239mmol) in DMF (10 mL) was added sodium azide (0.019 g, 0.287 mmol). The resulting mixture was stirred at 50 ℃ for 6 hours. Water (50mL) was then added and the organic material was extracted with ethyl acetate (2X50 mL). Mixing the combined organic extracts with hydrogen₂O (50mL) wash, dry (MgSO)₄) Filtered and concentrated in vacuo to give the title compound (0.125g, 91% yield). LCMS (M + H)⁺m/z 576。

Intermediate 196

N- (benzo [ b ]]Thiophene-1, 1-dione-7-ylmethyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c) ][1，4]Oxazine-2-carboxamide to intermediate 147, N- (benzo [ b ]]Thien-7-ylmethyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]To a solution of oxazine-2-carboxamide (0.100 g, 0.21mmol) in dichloroethane (10 mL) was added peracetic acid (32% in H₂O) (1.0mmol, 200. mu.L). The reaction mixture was stirred at 23 ℃ for 48 hours. Water (50mL) was added with CH₂Cl₂(2X50mL) organic material was extracted. The combined organic extracts were dried (MgSO)₄) Filtered and concentrated in vacuo to give the title compound (0.106 g, 99% yield):¹H NMR(400MHz，DMSO-d₆)δppm：9.11(1H，t，J＝6.4Hz)，7.65(1H，d，J＝6.8Hz)7.59-7.29(9H，m)，5.15(2H，s)，4.77(2H，d，J＝6.5Hz)，4.04(2H，t，J＝5.0Hz)，3.90(2H，m)，1.59(6H，s)。LCMS(M+H)⁺m/z 508。

example 1

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (4-fluorophenyl) methyl]-4, 6, 7, 9-tetrahydro-3-hydroxy-4-oxo-the intermediate 7, 3-hydroxy-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ]][1，4]Oxazine-2-carboxylic acid ethyl ester (0.036 g, 0.15mmol) and 4-fluorobenzylamine (0.11 g, 0.87mmol) in absolute ethanolThe mixture in (5 ml) and N, N-dimethylformamide (2 ml) was heated at reflux for 18 hours. The solvent was then evaporated in vacuo and the residue partitioned between ethyl acetate and 0.1N hydrochloric acid. The organic phase was washed with water, brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the resulting solid was recrystallized from ethanol to give 0.023 g (47% yield) of the title amide as white crystals; mp: 211 deg.C (ethyl acetate-hexane). ¹HNMR 400MHz(CDCl₃)δppm：4.06(4H，m，2xCH₂)，4.59(2H，d，J＝7.6Hz，NCH₂)，4.61(2H，s，OCH₂) 7.09(2H, m, arene), 7.33(2H, m, arene), 7.84(1H, width t, NH), 12.06(1H, s, OH). MS (ESI)⁺)m/z 320[M+H⁺]。

Example 2

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (4-fluoro-3-methylphenyl) methyl]4, 6, 7, 9-tetrahydro-3-hydroxy-4-oxo-the intermediate 7, 3-hydroxy-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ] is as described in preparation example 1][1，4]Oxazine-2-carboxylic acid ethyl ester (0.100 g, 0.42mmol) was reacted with 4-fluoro-3-methylbenzylamine (0.23 g, 1.66mmol) to give 0.101 g (73% yield) of the title amide as white crystals; mp: 206 ℃ and 208 ℃ (ethyl acetate).¹HNMR 400MHz(CDCl₃)δppm：2.30(3H，s，CH₃)，4.06(4H，m，2xCH₂)，4.55(2H，d，J＝6.1Hz，NCH₂)，4.60(2H，s，OCH₂) 7.01(1H, m, arene), 7.14(2H, m, arene), 7.81(1H, broad t, NH), 12.09(1H, s, OH). MS (ESI)⁺)m/z 334[M+H⁺]。

Example 3

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- [ (methylamino) carbonyl]Phenyl radical]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-4-oxo-can be synthesized from intermediate 150, N- (4-fluoro-2- (methylcarbamoyl) benzyl) -3- (benzyloxy) -4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ]][1，4]Oxazine-2-carboxamide the title compound was prepared.¹HNMR 400MHz(DMSO-d₆)δppm：2.79(3H，d，J＝4.5Hz，NCH₃)，3.83(2H，m，CH₂)，4.02(2H，m，CH₂)，4.54(2H，d，J＝6.7Hz，NCH₂)，4.58(2H，s，OCH₂) 7.31(2H, m, arene), 7.38(1H, m, arene), 8.54(1H, width q, NH), 9.21(1H, width t, NH), 12.24(1H, s, OH). HRMS (ESI) ⁺)C₁₇H₁₈FN₄O₅[M+H⁺]The calculated value of (a): 377.1261, respectively; measurement value: 377.1249.

example 4

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (4-fluorophenyl) methyl]4, 6, 7, 9-tetrahydro-3-hydroxy-9-methyl-4-oxo-as described in the preparation of example 1, intermediate 15, 3-hydroxy-9-methyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ]][1，4]Oxazine-2-carboxylic acid ethyl ester (0.050 g, 0.20mmol) was reacted with 4-fluorobenzylamine (0.11 g, 0.87mmol) to give 0.056 g (84% yield) of the title amide as white crystals; mp: 165 ℃ and 167 ℃ (ethyl acetate-hexane).¹HNMR400MHz(CDCl₃)δppm：1.62(3H，d，J＝7.0Hz，CH₃)，3.90(2H，m，CH₂)，4.15-4.32(2H，m，CH₂)，4.61(3H，m，NCH₂And OCH), 7.08(2H, m, arene), 7.34(2H, m, arene), 7.82(1H, wide t, NH), 12.06(1H, s, OH). C₁₆H₁₆FN₃O₄Analytical calculation of (a): c57.65, H4.83, N12.60. Measurement value: c57.44, H4.69, N12.37.

Example 5

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (4-fluoro-3-methylphenyl) methyl]4, 6, 7, 9-tetrahydro-3-hydroxy-9-methyl-4-oxo-as described in the preparation of example 1, intermediate 15, 3-hydroxy-9-methyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ]][1，4]Oxazine-2-carboxylic acid ethyl ester (0.090 g, 0.35mmol) was reacted with 4-fluoro-3-methylbenzylamine (0.180 g, 1.3mmol) to give 0.068 g (55% yield) of the title amide as white crystals; mp: 134 deg.C (ethyl acetate-hexane). ¹HNMR 400MHz(CDCl₃)δppm：1.62(3H，d，J＝6.6Hz，CH₃)，2.30(3H，s，CH₃)，3.90(2H，m，CH₂)，4.13-4.32(2H，m，CH₂)，4.49-4.64(3H，m，NCH₂And OCH), 7.01(1H, m, arene), 7.16(2H, m, arene), 7.79(1H, wide t, NH), 12.09(1H, s, OH). C₁₇H₁₈FN₃O₄Analytical calculation of (a): c58.78, H5.22, N12.09. Measurement value: c58.57, H5.55, N11.90.

Example 6

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (3, 4-dichlorophenyl) methyl]4, 6, 7, 9-tetrahydro-3-hydroxy-9-methyl-4-oxo-as described in the preparation of example 1, intermediate 15, 3-hydroxy-9-methyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ]][1，4]Oxazine-2-carboxylic acid ethyl ester (0.075 g, 0.29mmol) and 3, 4-dichlorobenzylamine (0.140 g, 0.8mmol) were reacted to giveTo 0.085 g (75% yield) of the title amide as white crystals; mp: 192 deg.C (ethyl acetate-hexane).¹HNMR 400MHz(CDCl₃)δppm：1.64(3H，d，J＝6.6Hz，CH₃)，3.91(2H，m，CH₂)，4.17-4.32(2H，m，CH₂)，4.50-4.68(3H，m，NCH₂And OCH), 7.20(1H, dd, J ═ 2.0Hz and J ═ 8.0Hz, arenes), 7.44(1H, d, J ═ 2.0Hz, arenes), 7.46(1H, d, J ═ 8.0Hz, arenes), 7.86(1H, wide t, NH), 11.92(1H, s, OH). MS (ESI)⁺)m/z 384[M+H⁺].C₁₆H₁₅Cl₂N₃O₄Analytical calculation of (a): c50.02, H3.94, N10.94. Measurement value: c49.40, H4.06, N10.41.

Example 7

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (3-chloro-4-fluorophenyl) methyl]4, 6, 7, 9-tetrahydro-3-hydroxy-9-methyl-4-oxo-as described in the preparation of example 1, intermediate 15, 3-hydroxy-9-methyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ] ][1，4]Oxazine-2-carboxylic acid ethyl ester (0.075 g, 0.30mmol) was reacted with 3-chloro-4-fluorobenzylamine (0.14 g, 0.88mmol) to give 0.050 g (46% yield) of the title amide as white crystals; mp: 172 ℃ (ethyl acetate-ether).¹HNMR 400MHz(CDCl₃)δppm：1.63(3H，d，J＝6.6Hz，CH₃)，3.91(2H，m，CH₂)，4.17-4.32(2H，m，CH₂)，4.50-4.67(3H，m，NCH₂And OCH), 7.16(1H, m, arene), 7.24(1H, m, arene), 7.40(1H, m, arene), 7.85(1H, width t, NH), 11.95(1H, s, OH) C₁₆H₁₅ClFN₃O₄Analytical calculation of (a): c52.25, H4.11, N11.42. Measurement value: c51.99, H4.01, N11.09.

Example 8

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (3, 4-dimethylphenyl) methyl]4, 6, 7, 9-tetrahydro-3-hydroxy-9-methyl-4-oxo-as described in the preparation of example 1, intermediate 15, 3-hydroxy-9-methyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ]][1，4]Oxazine-2-carboxylic acid ethyl ester (0.075 g, 0.30mmol) was reacted with 3, 4-dimethylbenzylamine (0.15 g, 1.1mmol) to give 0.033 g (33% yield) of the title amide as a white solid.¹HNMR 400MHz(CDCl₃)δppm：1.61(3H，d，J＝6.6Hz，CH₃)，2.28(3H，s，CH₃)，2.29(3H，s，CH₃)，3.90(2H，m，CH₂)，4.16-4.30(2H，m，CH₂)，4.50-4.65(3H，m，NCH₂And OCH), 7.08-7.17(3H, m, arene), 7.78(1H, wide t, NH), 12.17(1H, s, OH). MS (ESI)⁺)m/z 344[M+H⁺]。

Example 9

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- [ (methylamino) carbonyl]Phenyl radical]Methyl radical]Intermediate 140, N- (4-fluoro-2- (methylcarbamoyl) benzyl) -3-benzyloxy-9-methyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ] in a mixture of ethyl acetate (25 ml) and ethanol (25 ml) ][1，4]A solution of oxazine-2-carboxamide (0.268 g, 0.56mmol) was hydrogenated under 1 atmosphere of hydrogen at 25 deg.C with 10% activated palladium on carbon (0.09 g) for 2.5 h to give 0.121 g (56% yield) of the title ester as a white solid.¹HNMR 400MHz(DMSO-d₆)δppm：1.57(3H，d，J＝6.7Hz，CH₃)，2.79(3H，d，J＝4.6Hz，NCH₃)，3.70(1H，m，CH)，3.87(1H，m，CH)，3.98(1H，m，CH)，4.15(1H，m，CH)，4.55(2H，m，NCH₂) 4.62(1H, q, J ═ 6.6Hz, OCH), 7.25-7.44(3H, m, arenes), 8.59(1H, width q, NH), 9.39(1H, width NH), 12.18(1H, s, OH). HRMS (ESI)⁺)C₁₈H₂₀FN₄O₅[M+H⁺]The calculated value of (a): 391.1418, respectively; measurement value: 391.1431.

examples 10 to 14

Examples 10-14 can be prepared as described for the synthesis of example 1 from ethyl 9-ethyl-3-hydroxy-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ] [1, 4] oxazine-2-carboxylate and the indicated amine. Ethyl 9-ethyl-3-hydroxy-4-oxo-4, 6, 7, 9-tetrahydropyrimido [2, 1-c ] [1, 4] oxazine-2-carboxylate was prepared according to the procedure used for the preparation of intermediate 15.

Example 10

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, 9-ethyl-N- [ (4-fluorophenyl) methyl]4, 6, 7, 9-tetrahydro-3-hydroxy-4-oxo-the title compound can be prepared from 4-fluorobenzylamine.¹HNMR 400MHz(CDCl₃)δppm：1.02(3H，t，J＝7.3Hz，CH₃)，1.93(1H，m，CH)，2.15(1H，m，CH)，3.88(2H，m，CH₂)，4.2-4.29(2H，m，CH₂)，4.46(1H，m，CH)，4.53-4.69(2H，m，CH₂) 7.06(2H, m, arene), 7.34(2H, m, arene), 7.82(1H, broad t, NH), 12.05(1H, s, OH). HRMS (ESI)⁺)C₁₇H₁₉FN₃O₄[M+H⁺]The calculated value of (a): 348.1360, respectively; measurement value: 348.1355.

Example 11

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, 9-ethyl-N- [ (4-fluoro-3-methylphenyl) methyl]-4, 6, 7, 9-tetrahydro-3-hydroxy-4-oxo-. the title compound can be prepared from (4-fluoro-3-methylphenyl) methylamine.¹HNMR 400MHz(CDCl₃)δppm：1.01(3H，t，J＝7.4Hz，CH₃)，1.91(1H，m，CH)，2.16(1H，m，CH)，2.30(3H，s，CH₃)，3.87(2H，m，CH₂)，4.2-4.30(2H，m，CH₂)，4.46(1H，m，CH)，4.48-4.65(2H，m，CH₂) 7.01(1H, m, arene), 7.14(2H, m, arene), 7.81(1H, broad t, NH), 12.07(1H, s, OH). C₁₈H₂₀FN₃O₄Analytical calculation of (a): c59.82, H5.57, N11.62; measurement value: c59.53, H5.86, N11.42.

Example 12

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (3, 4-dichlorophenyl) methyl]-9-ethyl-4, 6, 7, 9-tetrahydro-3-hydroxy-4-oxo-. the title compound can be prepared from (3, 4-dichlorophenyl) methylamine.¹HNMR 400MHz(CDCl₃)δppm：1.00(3H，t，J＝7.3Hz，CH₃)，1.91(1H，m，CH)，2.15(1H，m，CH)，3.85(2H，m，CH₂)，4.19-4.28(2H，m，CH₂)，4.45(1H，m，CH)，4.48-4.66(2H，m，CH₂) 7.19(1H, m, arene), 7.43(2H, m, arene), 7.84(1H, broad t, NH), 11.88(1H, s, OH). C₁₇H₁₇Cl₂N₃O₄Analytical calculation of (a): c51.27, H4.30, N10.55; measurement value: c51.16, H4.21, N10.34.

Example 13

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (3, 4-dimethylphenyl) methyl]-9-ethyl-4, 6, 7, 9-tetrahydro-3-hydroxy-4-oxo-. the title compound can be prepared from (3, 4-dimethylphenyl) methylamine.¹HNMR 400MHz(CDCl₃)δppm：0.98(3H，t，J＝7.3Hz，CH₃)，1.87(1H，m，CH)，2.12(1H，m，CH)，2.26(3H，s，CH₃)，2.27(3H，s，CH₃)，3.83(2H，m，CH₂)，4.17-4.26(2H，m，CH₂)，4.41(1H，m，CH)，4.45-4.64(2H，m，CH₂) 7.05-7.24(3H, m, arene), 7.75(1H, width t, NH), 12.13(1H, s, OH) ₁₉H₂₃N₃O₄Analytical calculation of (a): c63.85, H6.49, N11.76; measurement value: c63.55, H6.48, N11.74.

Example 14

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (3-chloro-4-fluorophenyl) methyl]-9-ethyl-4, 6, 7, 9-tetrahydro-3-hydroxy-4-oxo-. the title compound can be prepared from (3-chloro-4-fluorophenyl) methylamine.¹HNMR 400MHz(CDCl₃)δppm：1.03(3H，t，J＝7.3 Hz，CH₃)，1.92(1H，m，CH)，2.17(1H，m，CH)，3.88(2H，m，CH₂)，4.1 8-4.32(2H，m，CH₂)，4.46(1H，m，CH)，4.5-4.68(2H，m，CH₂) 7.16(1H, m, arene), 7.24(1H, m, arene), 7.40(1H, m, arene), 7.84(1H, broad t, NH), 11.93(1H, s, OH). C₁₇H₁₇ClFN₃O₄Analytical calculation of (a): c53.48, H4.48, N11.00; measurement value:C 53.25，H 4.49，N 10.79。

examples 15 to 16

Examples 15-16 may be prepared from 3- (benzyloxy) -9-ethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimido [2, 1-c ] [1, 4] oxazine-2-carboxylic acid and the indicated amine according to the procedure described for the synthesis of intermediate 140 and example 9. 3- (benzyloxy) -9-ethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimido [2, 1-c ] [1, 4] oxazine-2-carboxylic acid was prepared according to the procedure used for the preparation of intermediate 16.

Example 15

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, 9-ethyl-N- [ [ 4-fluoro-2- [ (methylamino) carbonyl]Phenyl radical]Methyl radical]4, 6, 7, 9-tetrahydro-3-hydroxy-4-oxo-the title compound may be prepared from intermediate 39. ¹HNMR 400MHz(CDCl₃)δppm：1.03(3H，t，J＝7.3Hz，CH₃)，1.98(1H，m，CH)，2.28(1H，m，CH)，3.06(3H，d，J＝4.5Hz，NCH₃)，3.86(2H，m，CH₂)，4.14-4.29(2H，m，CH₂)，4.48(1H，m，CH)，4.60(2H，m，CH₂) 6.2(1H, broad, NH), 7.14-7.21(2H, m, arene), 7.54(1H, m, arene), 8.85(1H, broad, t, NH), 12.1(1H, s, OH). HRMS (ESI)⁺)C₁₉H₂₂FN₄O₅[M+H⁺]The calculated value of (a): 405.1574, respectively; measurement value: 405.1579.

example 16

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, 9-ethyl-N- [ [ 4-fluoro-2- (1H)-1, 2, 4-triazol-1-yl) phenyl]Methyl radical]4, 6, 7, 9-tetrahydro-3-hydroxy-4-oxo-according to a method analogous to that described in example 9, starting from intermediate 151, N- (4-fluoro-2- (1H-1, 2, 4-triazol-1-yl) benzyl) -3- (benzyloxy) -9-ethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ]][1，4]Oxazine-2-carboxamide the title compound was prepared.¹HNMR 400MHz(DMSO-d₆)δppm：0.94(3H，t，J＝7.5Hz，CH₃)，1.88(1H，m，CH)，2.27(1H，m，CH)，3.68(1H，m，CH)，3.87(1H，m，CH)，4.0(1H，m，CH)，4.19(1H，m，CH)，4.36-4.49(3H，m，CH₂And CH), 7.43(1H, m, arene), 7.56(2H, m, arene), 8.32(1H, m, CH), 9.05(1H, m, CH), 9.3(1H, wide t, NH), 12.04(1H, s, OH). HRMS (ESI)⁺)C₁₉H₂₀FN₆O₄[M+H⁺]The calculated value of (a): 415.1530, respectively; measurement value: 415.1515.

examples 17 to 18

Examples 17-18 can be prepared from ethyl 3-hydroxy-9-isopropyl-4-oxo-4, 6, 7, 9-tetrahydropyrimido [2, 1-c ] [1, 4] oxazine-2-carboxylate and the indicated amine according to the procedure described for the synthesis of example 1. Ethyl 3-hydroxy-9-isopropyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ] [1, 4] oxazine-2-carboxylate may be prepared according to the procedure used to prepare intermediate 15.

Example 17

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (4-fluorophenyl) methyl]-4, 6, 7, 9-tetrahydro-3-hydroxy-9- (1-methylethyl) -4-oxo-. the title compound can be prepared from 4-fluorobenzylamine.¹HNMR 400MHz(CDCl₃)δppm：0.80(3H，d，J＝6.7Hz，CH₃)，1.13(3H，d，J＝7.1Hz，CH₃)，2.54(1H，m，CH)，3.77(2H，m，CH₂)，4.3(2H，m，CH₂)，4.40(1H，d，J＝2.5Hz，CH)，4.50-4.72(2H，m，CH₂) 7.09(2H, m, arene), 7.34(2H, m, arene), 7.82(1H, broad t, NH), 12.04(1H, s, OH). C₁₈H₂₀FN₃O₄Analytical calculation of (a): c59.82, H5.57, N11.62; measurement value: c59.22, H5.81, N11.50.

Example 18

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (4-fluoro-3-methylphenyl) methyl]-4, 6, 7, 9-tetrahydro-3-hydroxy-9- (1-methylethyl) -4-oxo-. the title compound can be prepared from (4-fluoro-3-methylphenyl) methylamine.¹HNMR 400MHz(CDCl₃)δppm：0.80(3H，d，J＝6.6Hz，CH₃)，1.13(3H，d，J＝7.1Hz，CH₃)，2.30(3H，s，CH₃)，2.54(1H，m，CH)，3.77(2H，m，CH₂)，4.3(2H，m，CH₂) 4.40(1H, width s, CH), 4.46-4.68(2H, m, CH)₂) 7.02(1H, m, arene), 7.17(2H, m, arene), 7.80(1H, broad t, NH), 12.07(1H, s, OH). HRMS (ESI)⁺)C₁₉H₂₃FN₃O₄[M+H⁺]The calculated value of (a): 376.1673, respectively; measurement value: 376.1671.

example 19

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (4-fluorophenyl) methyl]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-to intermediate 25, 3-hydroxy-9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ]][1，4]Oxazine-2-carboxylic acid ethyl ester (3.0 g) 11.19mmol) in DMF (20ml) and ethanol (10 ml) was added triethylamine (1.55 ml) followed by 4-fluorobenzylamine (3.82 ml, 33.57 mmol). The mixture was stirred at 90 ℃ for 2 hours and then concentrated. The resulting oil was partitioned between ethyl acetate (50ml) and 1N aqueous HCl (35 ml). The aqueous layer was back-extracted with ethyl acetate (20mL) and the organic layers were combined and washed with H₂O (4 × 20mL) and brine, then dried (Na)₂SO₄) And (4) concentrating. The brown residue was triturated with ether, the solid filtered and washed with ether. The light brown solid was washed with 95: 5MeOH/H₂Recrystallization from O gave the title compound as colorless needle crystals (3.18g, 82% yield).¹H NMR(500MHz，CDCl₃)δppm：11.96(1H，s)，7.77(1H，brs)，7.30(2H，dd，J＝8.4，5.3Hz)，7.04(2H，t，J＝8.7Hz)，4.57(2H，d，J＝6.1Hz)，4.01(4H，s)，1.56(6H，s)。HRMS(M+H)C₁₇H₁₉FN₃O₄The calculated value of (a): 348.13597, respectively; measurement value: 348.1365.C₁₇H₁₈FN₃O₄Analytical calculation of (a): c, 58.78; h, 5.22; and N, 12.09. Measurement value: c, 58.38; h, 5.23; n, 11.80.

Example 20

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (4-fluoro-3-methylphenyl) methyl]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-intermediate 25, 3-hydroxy-9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ]][1，4]Oxazine-2-carboxylic acid ethyl ester (4 ml, 1mmol), Et₃A solution of N (0.14 mL, 1mmol) and 3-methyl-4-fluorobenzylamine (0.418 g, 3mmol) in DMF was heated at 90 ℃ for 5 hours. The reaction mixture was cooled and the product was isolated by reverse phase preparative HPLC using MeOH/H ₂O-0.1％CF₃CO₂H is used as eluent. Fractions containing the desired material were combined and concentrated to give the titled compoundCompound yellow powder (0.19g, 52% yield).¹H NMR(500MHz，CDCl₃)δppm：11.99(1H，s)，7.73(1H，s)，7.14(1H，d，J＝7.3Hz)，7.12-7.09(1H，m)，6.98(1H，t，J＝9.0Hz)，4.54(2H，d，J＝6.4Hz)，4.01(4H，s)，2.27(3H，s)，1.56(6H，s)。HRMS(M+H)C₁₈H₂₁FN₃O₄The calculated value of (a): 362.1516, respectively; measurement value: 362.1509.C₁₈H₂₀FN₃O₄+0.07H₂Analytical calculation of O: c, 59.26; h, 5.55; n, 11.48. Measurement value: c, 58.88; h, 5.36; n, 11.34.

Examples 21 to 41

Examples 21-41 can be prepared from the intermediate 25, 3-hydroxy-9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ] [1, 4] oxazine-2-carboxylic acid ethyl ester and the indicated amine following the procedures described in the syntheses of examples 1, 19 and 20.

Example 21

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- (1H-1, 2, 4-triazol-1-yl) phenyl]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-the title compound may be prepared from intermediate 69. The solid is a mixture of a solid and a liquid,¹H NMR(500MHz，DMSO-d₆)δppm：11.93(1H，s)，9.29(1H，t，J＝6.2Hz)，9.05(1H，s)，8.32(1H，s)，7.57-7.53(2H，m)，7.43(1H，td，J＝7.9，1.7Hz)，4.44(2H，d，J＝6.1Hz)，3.98(2H，t，J＝4.9Hz)，3.83(2H，t，J＝4.9Hz)，1.56(6H，s)。HRMS(M+H)C₁₉H₂₀N₆O₄calculated value of F: 415.15302, respectively; measurement value: 415.1520.C₁₉H₁₉N₆O₄Analytical calculation of F: c, 55.07; h, 4.62; n, 20.28; f, 4.58; measurement value: c, 54.95; h, 4.67; n, 20.27; f, 4.56.

Example 22

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 2-fluoro-4- (1H-1, 2, 4-triazol-1-yl) phenyl]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-the title compound can be prepared from intermediate 70. The solid is a mixture of a solid and a liquid, ¹H NMR(500MHz，DMSO-d₆)δppm：12.07(1H，s)，9.46(1H，bs)，9.33(1H，s)，8.26(1H，s)，7.81(1H，dd，J＝11.1，2.0Hz)，7.73(1H，dd，J＝8.2，1.8Hz)，7.52(1H，t，J＝8.2Hz)，4.59(2H，d，J＝6.1Hz)，3.98(2H，t，J＝5.0Hz)，3.84(2H，t，J＝5.0Hz)，1.58(6H，s)。HRMS(M+H)C₁₉H₂₀N₆O₄Calculated value of F: 415.15302, respectively; measurement value: 415.1520.C₁₉H₁₉N₆O₄F+1.25H₂Analytical calculation of O: c, 52.23; h, 4.96; n, 19.23; f, 4.35; measurement value: c, 52.29; h, 4.66; n, 19.23; f, 4.35.

Example 23

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- (4-morpholinyl) phenyl]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-the title compound can be prepared from intermediate 73. The solid is a mixture of a solid and a liquid,¹H NMR(500MHz，CDCl₃)δppm：12.09(1H，s)，7.91(1H，brs)，7.31-7.28(1H，m)，6.90(1H，dd，J＝10.4，2.4Hz)，6.84(1H，td，J＝8.1，2.4Hz)，4.66(2H，d，J＝6.4Hz)，4.02(4H，s)，3.89-3.87(4H，m)，2.94-2.92(4H，m)，1.59(6H，s)。HRMS(M-H)C₂₁H₂₄N₄O₅calculated value of F: 431.17307, respectively; measurement value: 431.1719.C₂₁H₂₅N₄O₅Analytical calculation of F: c, 58.32; h, 5.82; n, 12.95; f, 4.39; measurement value: c, 58.13; h, 5.81; n, 12.79; f, 4.33.

Example 24

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 2-fluoro-4- (4-morpholinyl) phenyl]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-the title compound may be prepared from intermediate 74.¹H NMR(500MHz，CDCl₃)δppm：12.01(1H，s)，7.80(1H，brs)，7.28-7.24(1H，m)，6.66(1H，d，J＝8.5Hz)，6.61(1H，dd，J＝13.4，1.8Hz)，4.56(2H，d，J＝6.1Hz)，4.01(4H，s)，3.85-3.84(4H，m)，3.17-3.15(4H，m)，1.60(6H，s)。HRMS(M-H)C₂₁H₂₄N₄O₅Calculated value of F: 431.17307, respectively; measurement value: 431.1729.C₂₁H₂₅N₄O₅Analytical calculation of F: c, 58.32; h, 5.82; n, 12.95; f, 4.39; measurement value: c, 58.23; h, 5.73; n, 12.82; f, 4.21.

Example 25

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [3- (3, 4-dichlorophenyl) propyl]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-the title compound can be prepared from 3- (3, 4-dichlorophenyl) propan-1-amine. ¹H NMR(500MHz，CDCl₃)δppm：12.05(1H，s)，7.46(1H，brs)，7.35(1H，d，J＝8.2Hz)，7.28(1H，d，J＝2.1Hz)，7.04(1H，dd，J＝8.2，2.1Hz)，4.02(4H，s)，3.46(2H，q，J＝6.9Hz)，2.67(2H，t，J＝7.6Hz)，1.95(2H，m)，1.59(6H，s)。HRMS(M+H)C₁₉H₂₂N₃O₄Cl₂The calculated value of (a): 426.09875, respectively; measurement value: 426.0996.C₁₉H₂₁N₃O₄Cl₂Analytical calculation of (a): c, 53.53; h, 4.96; n, 9.85; cl, 16.63; measurement value: c, 53.57; h, 4.96; n, 9.76; cl, 16.63.

Example 26

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [3- (4-fluorophenyl) propyl]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-the title compound can be prepared from 3- (4-fluorophenyl) propan-1-amine.¹H NMR(500MHz，CDCl₃)δppm：12.09(1H，s)，7.15(2H，dd，J＝8.2，5.5Hz)，6.97(2H，t，J＝8.5Hz)，4.02(4H，s)，3.44(2H，q，J＝13.9，6.9Hz)，2.68(2H，t，J＝7.6Hz)，1.98-1.92(2H，m)，1.62(6H，s)。HRMS(M+H)C₁₉H₂₃N₃O₄Calculated value of F: 376.16727, respectively; measurement value: 376.1687.C₁₉H₂₂N₃O₄Analytical calculation of F: c, 60.79; h, 5.90; n, 11.19; f, 5.06; measurement value: c, 60.70; h, 5.87; n, 11.14; f, 4.92.

Example 27

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- (tetrahydro-1, 1-dioxo-2H-1, 2-thiazin-2-yl) phenyl]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxyYl-9, 9-dimethyl-4-oxo-the title compound may be prepared from intermediate 76.¹H NMR(500MHz，CDCl₃)δppm：12.07(1H，s)，8.31(1H，d，J＝6.44Hz)，7.46(1H，dd，J＝8.5，6.4Hz)，7.19(1H，dd，J＝9.0，2.6Hz)，7.08(1H，td，J＝8.2，2.7Hz)，4.92(1H，dd，J＝14.0，8.8Hz)，4.37(1H，dd，J＝14.0，3.4Hz)，4.02-3.97(2H，m)，3.99(2H，s)，3.87-3.82(1H，m)，3.45-3.41(1H，m)，3.30-3.20(2H，m)，2.46-2.32(2H，m)，2.00-1.88(2H，m)，1.57(3H，s)，1.53(3H，s)。HRMS(M-H)C₂₁H₂₆N₄O₆Calculation of FS: 481.15572, respectively; measurement value: 481.1570.C₂₁H₂₅N₄O₆Analytical calculation of FS: c, 52.49; h, 5.24; n, 11.66; f, 3.95; s, 6.67; measurement value: c, 52.29; h, 5.37; n, 11.40; f, 3.91; and S, 6.70.

Example 28

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (3, 5-difluoro-2-pyridinyl) methyl ]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-the title compound can be prepared from intermediate 102.¹H NMR(500MHz，CDCl₃)δppm：11.86(1H，s)，8.58(1H，brs)，8.33(1H，d，J＝2.4Hz)，7.27-7.24(1H，m)，4.76(2H，d，J＝5.2Hz)，4.03(4H，s)，1.63(6H，s)。HRMS(M+H)C₁₆H₁₇F₂N₄O₄The calculated value of (a): 367.1218, respectively; measurement value: 367.1230.

example 29

N-((5-chloropyridin-2-yl) methyl) -3-hydroxy-9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c][1，4]The title compound can be prepared from intermediate 103.¹H NMR(500MHz，CDCl₃)δppm：11.80(1H，brs)，8.64(1H，brs)，8.57(1H，d，J＝2.4Hz)，7.78(1H，dd，J＝8.6，2.4Hz)，7.44(1H，d，J＝8.6Hz)，4.72(2H，d，J＝6.1Hz)，4.02(4H，s)，1.61(6H，s)。HRMS(M+H)C₁₇H₁₈ClN₄O₄The calculated value of (a): 365.1017, respectively; measurement value: 365.1028.C₁₆H₁₇ClN₄O₄·0.25H₂O·0.5CF₃CO₂Analytical calculation of H: c, 47.90; h, 4.26; n, 13.14, Cl, 8.32; measurement value: c, 47.88; h, 3.98; n, 12.94, Cl, 8.57.

Example 30

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (3-bromo-4-fluorophenyl) methyl]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-the title compound can be prepared from (3-bromo-4-fluorophenyl) methylamine as an off-white solid,¹H-NMR(500MHz，CDCl₃)δppm：11.88(1H，s)，7.76-7.84(1H，br)，7.53(1H，dd，J＝6.3，2.0Hz)，7.26-7.29(H，m)，7.07-7.14(1H，m)，4.57(2H，d，J＝6.4Hz)，4.02(4H，s)，1.58(6H，s).¹³C-NMR(126MHz，CDCl₃)δppm：168.41，157.79，151.99，146.52，134.91，132.89，128.44，128.39，125.30，117.04，116.86，77.69，75.84，58.21，43.22，41.98，28.11。HRMS[M+H]⁺ C₁₇H₁₈N₃O₄calculated values of FBr: 426.04648, respectively; measurement value: 426.0468.

example 31

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (3, 4-dimethylphenyl) methyl]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-the title compound can be prepared from (3, 4-dimethylphenyl) methylamine. An off-white solid which is,¹H-NMR(500MHz，CDCl₃)δppm：7.74(1H)，7.04-7.15(3H，m)，4.56(2H，d，J＝5.8Hz)，4.00-4.07(4H，m)，2.27(3H，s)，2.26(3H，s)，1.57(6H，s).¹³C-NMR(126MHz，CDCl₃)δppm：167.92，158.58，151.61，146.22，137.37，136.47，134.53，130.23，129.11，126.12，125.12，75.93，58.10，43.42，43.00，28.04，19.85，19.53。HRMS[M+H]⁺C₁₉H₂₄N₃O₄the calculated value of (a): 358.17669, respectively; measurement value: 358.1783.

Example 32

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (3-chloro-4-fluorophenyl) methyl]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-the title compound can be prepared from (3-chloro-4-fluorophenyl) methylamine. An off-white solid which is,¹H-NMR(500MHz，CDCl₃)δppm：11.88(1H，br s)，7.80(1H，t，J＝5.5Hz)，7.38(1H，dd，J＝6.7，2.1Hz)，7.19-7.23(1H，m)，7.13(1H，t，J＝8.5Hz)，4.57(2H，d，J＝6.4Hz)，4.02(4H，s)，1.58(6H，s).¹³C-NMR(126MHz，CDCl₃)δppm：168.41，157.82，151.99，146.52，134.54，130.02，127.58，127.52，125.32，121.61，117.18，117.01，75.84，58.21，43.23，42.08，28.11。HRMS[M+H]⁺ C₁₇H₁₈N₃O₄FCl calculated value: 382.09644, respectively; measurement value: 382.0980.

example 33

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (3, 4-difluorophenyl) methyl]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-the title compound can be prepared from (3, 4-difluorophenyl) methylamine. A light brown solid, which is,¹H-NMR(500MHz，CDCl₃)δppm：7.77(1H)，7.30-7.36(2H，m)，7.27(1H，s)，4.59(2H，d，J＝6.4Hz)，4.01-4.06(4H，m)，1.58(6H，s).¹³C-NMR(126MHz，CDCl₃)δppm：168.22，158.36，151.98，151.17，146.35，134.33，125.74，123.70，123.67，117.87，117.73，116.88，116.73，75.90，58.13，43.42，42.28，28.06。HRMS[M+H]⁺C₁₇H₁₈N₃O₄F₂the calculated value of (a): 366.12655, respectively; measurement value: 366.1269.

example 34

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (4-chlorophenyl) methyl]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-the title compound can be prepared from (4-chlorophenyl) methylamine. A light pink solid.¹H-NMR(500MHz，CDCl₃)δppm：7.77(1H，br)，7.33-7.35(2H，m)，7.25-7.28(2H，m)，4.59(2H，d，J＝6.4Hz)，4.04(4H，ddd，J＝14.0，7.9，2.7Hz)，1.58(6H，s).¹³C-NMR(126MHz，CDCl₃)δppm：168.12，158.48，151.87，146.28，135.72，133.98，129.92，129.18，129.09，125.90，75.92，58.12，43.45，42.61，28.06。HRMS[M+H]⁺C₁₇H₁₉N₃O₄Calculated Cl: 364.10642, respectively; measurement value: 364.1060.

example 35

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (2, 4-difluorophenyl) methyl]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-the title compound can be prepared from (2, 4-difluorophenyl) methylamine. An off-white solid which is,¹H-NMR(500MHz，CDCl₃)δppm：7.86(1H，t，J＝5.6Hz)，7.34-7.40(1H，m)，6.83-6.90(2H，m)，4.62(2H，d，J＝6.4Hz)，4.01-4.06(4H，m)，1.59(6H，s).¹³C-NMR(126MHz，CDCl₃)δppm：168.09，158.43，151.81，146.22，131.30，131.25，131.22，131.18，125.87，120.37，120.34，111.85，111.82，111.68，111.65，104.47，104.27，104.07，75.94，58.12，43.43，37.00，28.07。HRMS[M+H]⁺C₁₇H₁₈N₃O₄F₂the calculated value of (a): 366.12655, respectively; measurement value: 366.1281.

Example 36

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (2-chloro-4-fluorophenyl) methyl]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-the title compound can be prepared from (2-chloro-4-fluorophenyl) methylamine. An off-white solid which is,¹H-NMR(500MHz，CDCl₃)δppm：8.05(1H，br)，7.41(1H，dd，J＝8.4，6.0Hz)，7.17(1H，dd，J＝8.2，2.4Hz)，6.99(1H，td，J＝8.2，2.7Hz)，4.66(2H，d，J＝6.4Hz)，4.04(4H，s)，1.60(6H，s).¹³C-NMR(126MHz，CDCl₃)δppm：167.88，163.30，161.31，158.70，151.77，146.08，134.55，134.47，131.65，131.58，130.70，130.67，126.12，117.48，117.28，114.68，114.51，109.67，75.99，58.10，43.51，40.82，28.08。HRMS[M+H]⁺C₁₇H₁₈N₃O₄FCl calculated value: 382.09644, respectively; measurement value: 382.0987.

example 37

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (2, 4-dimethylphenyl) methyl]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-the title compound can be prepared from (2, 4-dimethylphenyl) methylamine. An off-white solid which is,¹H-NMR(500MHz，CDCl₃)δppm：12.08(1H，brs)，7.63(1H，br)，7.15(1H，d，J＝7.6Hz)，7.00-7.05(2H，m)，4.57(2H，d，J＝5.8Hz)，4.01(4H，s)，2.32(3H，s)，2.32(3H，s)，1.55(6H，s).¹³C-NMR(126MHz，CDCl₃)δppm：167.97，157.98，151.74，146.35，137.95，136.22，131.90，131.67，128.38，127.10，125.64，75.84，58.21，43.21，41.15，28.07，21.11，19.13。HRMS[M+H]⁺C₁₉H₂₄N₃O₄the calculated value of (a): 358.17669, respectively; measurement value: 358.1771.

example 38

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (3, 5-dimethylphenyl) methyl]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-the title compound can be prepared from (3, 5-dimethylphenyl) methylamine. An off-white solid which is,¹H-NMR(500MHz，CDCl₃)δppm：12.09(1H，s)，7.72-7.80(1H，br)，6.95(1H，s)，6.94(2H，s)，4.55(2H，d，J＝6.4Hz)，4.00-4.04(4H，s)，2.32(6H，s)，1.57(6H，s).¹³C-NMR(126MHz，CDCl₃)δppm：168.19，157.89，151.73，146.44，138.71，137.25，129.58，125.61，125.48，75.86，58.23，43.18，43.06，28.08，21.38。HRMS[M+H]⁺C₁₉H₂₄N₃O₄the calculated value of (a): 358.17669, respectively; measurement value: 358.1758.

example 39

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (4-fluoro-2-methylphenyl) methyl]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-. the title compound can be prepared from (4-fluoro-2-methylphenyl) methylamine. An off-white solid which is, ¹H-NMR(500MHz，CDCl₃)δppm：11.97(1H，s)，7.64(1H，br)，7.23(1H，dd，J＝8.2，5.8Hz)，6.87-6.94(2H，m)，4.57(2H，d，J＝6.1Hz)，4.02(4H，s)，2.36(3H，s)，1.56(6H，s).¹³C-NMR(126MHz，CDCl₃)δppm：168.07，163.40，161.44，157.82，151.86，146.43，138.81，138.75，130.78，130.75，129.97，129.90，125.42，117.69，117.52，113.20，113.03，75.81，58.23，43.21，40.71，28.09，19.32。HRMS[M+H]⁺C₁₈H₂₁N₃O₄Calculated value of F: 362.15162, respectively; measurement value: 362.1521.

example 40

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (4-fluoro-1-naphthyl) methyl]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-the title compound can be prepared from intermediate 37. A white solid.¹H-NMR(500MHz，CDCl₃)δppm：12.00(1H，s)，8.15-8.20(1H，m)，8.05(1H，d，J＝8.2Hz)，7.73(1H，br)，7.58-7.65(2H，m)，7.43(1H，dd，J＝7.8，5.3Hz)，7.12(1H，dd，J＝10.1，7.9Hz)，5.02(2H，d，J＝6.1Hz)，3.99(4H，ddd，J＝13.8，8.0，2.9Hz)，1.49(6H，s).¹³C-NMR(126MHz，CDCl₃)δppm：168.01，160.13，158.12，157.77，151.87，146.51，132.72，132.68，128.59，128.56，127.86，126.54，126.46，125.42，124.45，123.23，121.65，121.60，109.00，108.84，75.76，58.21，43.14，40.86，27.99。HRMS[M+H]⁺C₂₁H₂₁N₃O₄Calculated value of F: 398.15162, respectively; measurement value: 398.1536.

EXAMPLE 41

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (4-fluoro-2-methoxyphenyl) methyl]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-. the title compound can be prepared from (4-fluoro-2-methoxyphenyl) methylamine. HRMS [ M + H ]]⁺ C₁₈H₂FN₃O₅The calculated value of (a): 378.1465, respectively; measurement value: 378.1480. light yellow crystals;¹H NMR(CDCl₃，500MHz)δppm：1.58(6H.s，gem-di-Me)，3.88(3H，s，OMe)，4.00(4H，s，CH₂)，4.53(2H，d，J＝6.5Hz，CH₂)，6.61-6.64(2H，m，Ar-Hs)，7.24(1H，m，Ar-Hs)；¹³C NMR(CDCl₃，125.8Hz)δppm：28.03(CH₃)，38.79(CH₂)，43.09(CH₂)，55.72(CH₃)，58.27(CH₂)，75.78(C)，99.15，99.35(d，J＝27Hz，CH)，106.97，107.14(d，J＝21Hz，CH)，121.17，121.20(d，J＝3.8Hz，C)，125.75(C)，130.44，130.51(d，J＝9.6Hz，CH)，146.26(C)，151.50(C)，157.87(C＝O)，158.77，158.83(d，J＝9.6Hz，C)，162.63，164.48(d，J＝234Hz，CF)，167.81(C＝O)；HRMS(ESI)C₁₈H₂₁FN₃O₅calculated value of (M + H): 378.1465, measurement: 378.1480, respectively; UV (MeOH) λ max 219nm (. epsilon.1.66X 10)⁴)，245(ε9.69x10³)，305(ε7.70x10³)；C₁₈H₂₀FN₃O₅·0.2H₂Analytical calculation of O: c55.95, H5.48, N10.88; measurement value: c55.99, H5.11, N10.63.

Examples 42 to 43

Examples 42-43 may be prepared from intermediate 31, 9, 9-diethyl-3-hydroxy-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ] [1, 4] oxazine-2-carboxylic acid ethyl ester and the indicated amine according to the procedures described for examples 1, 19 and 20.

Example 42

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, 9, 9-diethyl-N- [ (4-fluorophenyl) methyl ]4, 6, 7, 9-tetrahydro-3-hydroxy-4-oxo-the title compound can be prepared from 4-fluorobenzylamine.¹HNMR(500MHz，CDCl₃)δppm：11.96(1H，br)，7.76(1H，br)，7.30(2H，m)，7.06(2H，m)，4.58(2H，d，J＝6.4Hz)，4.00，(4H，m)，1.93(2H，m)，1.86(2H，m)，0.86(6H，t，J＝7.3Hz).¹³C NMR(500MHz，CDCl₃)δppm：168.36，163.46，157.87，151.61，143.23，133.14，129.50，125.58，115.99，115.82，80.89，58.46，43.13，42.50，31.36，7.79。HRMS[M+H]⁺C₁₉H₂₃N₃O₄Calculated value of F: 376.16727, respectively; measurement value: 376.1675.

example 43

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, 9, 9-diethyl-N- [ (4-fluoro-3-methylphenyl) methyl]4, 6, 7, 9-tetrahydro-3-hydroxy-4-oxo-), the title compound can be prepared from 3-methyl, 4-fluorobenzylamine.¹H NMR(500MHz，CDCl₃)δppm：11.99(1H，br)，7.74(1H，br)，7.15-7.09(2H，m)，6.99(1H，m)，4.54(2H，d，J＝6.1Hz)，4.00，(4H，m)，2.27(1H，s)，1.93(2H，m)，1.86(2H，m)，0.84(6H，t，J＝7.3Hz).¹³C NMR(126MHz，CDCl₃)δppm：168.32，161.97，160.02，157.84，151.56，146.23，132.83，130.96，126.64，125.59，115.38，80.88，58.48，43.11，42.52，31.36，14.66，7.79。HRMS[M+H]⁺C₂₀H₂₅N₃O₄Calculated value of F: 390.18292, respectively; measurement value: 390.1835.

examples 44 to 45

The procedure described in examples 1, 19 and 20 can be followed from intermediate 36, 3-hydroxy-10, 10-dimethyl-4-oxo-6, 7, 8, 10-tetrahydro-4H-pyrimido [2, 1-c ]][1，4]OxazazemEsters of 2-carboxylic acids and the indicated amines preparation examples 44 to 45.

Example 44

6H-pyrimido [2, 1-c][1，4]Oxazazem-2-carboxamide, N- [ (4-fluorophenyl) methyl group]-4, 7, 8, 10-tetrahydro-3-hydroxy-10, 10-dimethyl-4-oxo-the title compound can be prepared from 4-fluorobenzylamine.¹H NMR(500MHz，CDCl₃)δppm：11.97(1H，s)，7.72(1H，br)，7.31(1H，d，J＝8.5Hz)，7.30(1H，d，J＝8.5Hz)，7.05(1H，t，J＝8.5Hz)，4.58(2H，d，J＝6.4Hz)，4.57(2H，br)，3.67(2H，t，J＝6.4Hz)，1.95(2H，p，J＝6.1Hz)，1.57(6H，s).¹³C NMR(126MHz，CDCl₃)δppm：168.32，163.45，161.49，158.20，153.63，147.44，133.17，129.50，129.43，124.70，115.97，115.81，82.29，60.87，42.47，38.68，27.82，27.30。HRMS[M+H]⁺C₁₈H₂₁N₃O₄Calculated value of F: 362.15162, respectively; measurement value: 362.1530.

example 45

6H-pyrimido [2, 1-c][1，4]Oxazazem-2-carboxamide, N- [ (4-fluoro-3-methylphenyl) methyl]-4, 7, 8, 10-tetrahydro-3-hydroxy-10, 10-dimethyl-4-oxo-the title compound can be prepared from 3-methyl, 4-fluorobenzylamine. ¹H NMR(500MHz，CDCl₃)δppm：12.00(1H，s)，7.70(1H，br)，7.14(1H，m)，7.1(1H，m)，6.98(1H，t，J＝8.9Hz)，4.56(2H，br)，4.54(2H，d，J＝6.4Hz)，3.68(2H，t，J＝6.4Hz)，2.27(3H，s)，1.95(2H，p，J＝6.1Hz)，1.57(6H，s).¹³C NMR(126MHz，CDCl₃)δppm：168.26，164.98，160.02，158.22，153.59，147.44，132.82，130.97，126.58，125.46，124.75，115.38，82.30，60.87，42.51，38.68，27.83，27.31，14.66。HRMS[M+H]⁺C₁₉H₂₃N₃O₄Calculated value of F: 376.16727, respectively; measurement value: 376.1686.

examples 46 to 51

Examples 46-52 can be prepared from the indicated intermediates following the procedure provided for example 46.

Example 46

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- [2- (4-morpholinyl) -2-oxoethoxy]Phenyl radical]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-intermediate 157, 3-benzyloxy-9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydro-pyrimido [2, 1-c ]][1，4]A solution of oxazine-2-carboxylic acid 4-fluoro-2- (2-morpholin-4-yl-2-oxo-ethoxy) -benzylamide (187 mg, 0.32mmol) in trifluoroacetic acid (2 ml) was stirred at room temperature for 2.5 h, after which the mixture was concentrated to dryness in vacuo. The residual oil was crystallized from 95% ethanol to give 120mg (0.25mmol, 77% yield) of the title compound as a white crystalline powder:¹H NMR(CDCl₃，500MHz)δppm：1.57(6H，s，Me)，3.51，3.64(4H，brs，NCH₂)，3.70(4H，m，OCH₂)，3.99(4H，s，NCH₂，OCH₂)，4.60(2H，d，J＝6Hz，NCH₂)，4.76(2H，s，OCH₂)，6.59(1H，dd，J＝10，2.5Hz，Ar-H)，6.63(1H，dt，J＝2.5，8Hz，Ar-H)，7.29(1H，dd，J＝6.5，8.5Hz，Ar-H)，8.25(1H，t，J＝6Hz，NH)，12.2(br，OH).¹³C NMR(CDCl₃，125.77Hz)δppm：27.93(CH₃)，38.44(NCH₂)，42.39(NCH₂)，43.14(NCH₂)，45.31(NCH₂)，58.19(OCH₂)，66.40(OCH₂)，66.59，66.86(OCH₂)，75.94(C)，100.26，100.46(d，J＝26Hz，CH)，108.19，108.36(d，J＝21Hz，CH)，122.03，122.06(d，J＝3Hz，C)，125.84(C)，131.06，131.14(d，J＝11Hz，CH)，146.37(C)，151.46(C)，157.06，157.14(d，J＝11Hz，C)，157.96(C＝O)，162.25，164.21(d，J＝248Hz，CF)，165.47(C＝O)，168.23(C＝O)；HRMSC₂₃H₂₈N₄O₇calculated value of F (M + H): 491.1942, measurement: 491.1958, respectively; UV (MeOH) λ max 249nm (. epsilon.7.84X 10)³)，290nm(ε3.06x10³)，303nm(ε2.2x10³)；C₂₃H₂₇N₄O₇F·1.7H₂Analytical calculation of O: c53.01, H5.88, N10.75; measurement value: c52.53, H5.37, N10.48.

Example 47

Benzoic acid, 5-fluoro-2- [ [ [ (4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxopyrimidino [2, 1-c ]][1，4]Oxazin-2-yl) carbonyl ]Amino group]Methyl radical]Methyl ester can be prepared from intermediate 154, 2- ((3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazin-2-carboxamido) methyl) -5-fluorobenzoic acid methyl ester the title compound was prepared. A white solid;¹H NMR(300MHz，CDCl₃)δppm：11.94(1H，br s)，8.76(1H，t，J＝6.77Hz)，7.69(1H，dd，J＝9.2，2.9Hz)，7.53(1H，dd，J＝8.4，5.5Hz)，7.15-7.22(1H，m)，4.71(2H，d，J＝7.0Hz)，3.97(4H，s)，3.89-3.94(3H，m)，1.56(6H，s)；HRMS(ESI)C₁₉H₂0FN₄O₆calculated value of (M + H): 406.1414, measurement: 406.1432.

example 48

Benzoic acid, 5-fluoro-2- [ [ [ (4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxopyrimidino [2, 1-c ]][1，4]Oxazin-2-yl) carbonyl]Amino group]Methyl radical]May be prepared from the intermediate 190, 2- ((3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazin-2-carboxamido) methyl) -5-fluorobenzoic acid the title compound was prepared. A white solid;¹H NMR(500MHz，CDCl₃)δppm：11.92(1H，br s)，8.68(1H，t，J＝6.4Hz)，7.80(1H，dd，J＝8.7，2.6Hz)，7.60(1H，dd，J＝8.5，5.5Hz)，7.30(1H，dt，J＝8.1，2.8Hz)，4.78(2H，d，J＝6.7Hz)，4.00(4H，s)，1.58(6H，s)；HRMS(ESI)C₁₈H₁₈FN₃O₆calculated value of (M + H): 392.1258, measurement: 392.1250.

example 49

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- [ (methylamino) carbonyl]Phenyl radical]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-can be synthesized from intermediate 143, N- (4-fluoro-2- (methylcarbamoyl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ]][1，4]Oxazine-2-carboxamide the title compound was prepared.¹H NMR(500MHz，DMSO-d₆)δppm：11.97(1H，br s)，9.46(1H，br s)，8.55-8.51(1H，m)，7.40-7.38(1H，m)，7.32-7.27(2H，m)，4.56(2H，d，J＝6.1Hz)，3.97(2H，t，J＝4.9Hz)，3.82(2H，t，J＝4.9Hz)，2.80(3H，d，J＝4.6Hz)，1.55(6H，s)。HRMS(M+H)C₁₉H₂₂FN₄O₅The calculated value of (a): 405.1574, respectively; measurement value: 405.1588.

Example 50

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [2- [ (cyclopropylamino) carbonyl]-4-fluorophenyl group]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-can be synthesized from intermediate 155, N- (2- (cyclopropylcarbamoyl) -4-fluorobenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ]][1，4]Oxazine-2-carboxamide the title compound was prepared. A white solid;¹H NMR(300MHz，CDCl₃)δppm：11.98(1H，br s)，8.84(1H，t，J＝7.32Hz)，7.48(1H，dd，J＝9.0，5.3Hz)，7.05-7.16(2H，m)，6.20-6.31(1H，br s)，4.56(2H，d，J＝6.6Hz)，3.92-4.02(4H，m)，2.90(1H，dt，J＝7.1，3.3Hz)，1.59(6H，s)，0.88(2H，q，J＝6.6Hz)，0.57-0.66(2H，m)；HRMS(ESI)C₂₁H₂₃FN₄O₅calculated value of (M + H): 431.1731, measurement: 431.1734.

example 51

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- [ [ (2-hydroxyethyl) amino]Carbonyl radical]Phenyl radical]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-can be prepared from intermediate 191, N- (2- ((2-aminoethyl) carbamoyl) -4-fluorobenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ] o][1，4]Oxazine-2-carboxamide the title compound was prepared.¹HNMR(500MHz，CDCl₃)δppm：11.98(1H，br s)，8.88(1H，t，J＝6.0Hz)，7.51(1H，dd，J＝8.2，5.5Hz)，7.21(1H，dd，J＝8.5，2.8Hz)，7.14(1H，dt，J＝8.3，2.6Hz)，6.57-6.63(1H，m)，4.58(2H，d，J＝6.7Hz)，4.00(4H，s)，3.87(2H，t，J＝5.1Hz)，3.63-3.68(2H，m)，1.60(6H，s)；HRMS(ESI)C₂₀H₂₃FN₄O₆Calculated value of (M + H): 435.1680, measurement: 435.1700.

example 52

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- (4-morpholinylcarbonyl) phenyl]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-can be synthesized from intermediate 156, N- (4-fluoro-2- (morpholine-4-carbonyl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c) ][1，4]Oxazine-2-carboxamide the title compound was prepared. A white solid;¹HNMR(500MHz，CDCl₃)δppm：11.94(1H，s)，8.46(1H，t，J＝5.5Hz)，7.47(1H，dd，J＝8.5，5.5Hz)，7.10(1H，dt，J＝8.4，2.4Hz)，6.94(1H，dd，J＝8.2，2.4Hz)，4.00(4H，s)，3.79-3.88(2H，br)，3.78(2H，br)，3.61(2H，br)，3.31-3.40(2H，br)，1.61(6H，s)；HRMS(ESI)C₂₂H₂₅FN₄O₆calculated value of (M + H): 461.1836, measurement: 461.1852.

examples 53 to 60

Examples 53-60 can be prepared from the intermediate 25, 3-hydroxy-9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ] [1, 4] oxazine-2-carboxylic acid ethyl ester and the indicated amine following the procedures described in the syntheses of examples 1, 19 and 20.

Example 53

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- (1H-imidazol-1-yl) phenyl]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-the titled compound can be prepared from intermediate 89A compound (I) is provided.¹H-NMR(500MHz，CDCl₃)δppm：11.66(1H，bs)，8.07(1H，s)，7.74(1H，t，J＝5.5Hz)，7.57(1H，dd，J＝8.7，5.9Hz)，7.35(1H，s)，7.25-7.21(2H，m)，7.08(1H，dd，J＝8.2，2.4Hz)，4.42(2H，d，J＝6.4Hz)，4.01(4H，s)，1.59(6H，s)。HRMS[M+H]⁺C₂₀H₂₁N₅O₄Calculated value of F: 414.15777, respectively; measurement value: 414.1563.C₂₀H₂₀N₅O₄F·0.25H₂Analytical calculation of O: c, 57.48; h, 4.94; n, 16.76; f, 4.55; measurement value: c, 57.77; h, 4.89; n, 16.29; f, 4.48.

Example 54

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 5-fluoro-2- (1H-1, 2, 4-triazol-1-yl) phenyl]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-e the title compound can be prepared from intermediate 97.¹H NMR(500MHz，CDCl₃)δppm：11.82(1H，s)，8.70(1H，t，J＝6.5Hz)，8.39(1H，s)，8.17(1H，s)，7.40(1H，dd，J＝8.6，2.7Hz)，7.34(1H，dd，J＝8.9，4.9Hz)，7.17-7.13(1H，m)，4.44(2H，d，J＝6.7Hz)，4.01(4H，s)，1.62(6H，s)。HRMS(M+H)C₁₉H₂₀FN₆O₄The calculated value of (a): 415.1530, respectively; measurement value: 415.1544.C₁₉H₁₉FN₆O₄Analytical calculation of (a): c, 55.07; h, 4.62; n, 20.28, F, 4.58; measurement value: c, 54.83; h, 4.51; n, 19.89, F, 4.56.

Example 55

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 3-fluoro-2- (tetrahydro-1, 1-dioxo-2H-1, 2-thiazin-2-yl) phenyl]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-the title compound can be prepared from intermediate 93. A white solid. 36% yield.¹H-NMR(500MHz，CDCl₃)δppm：11.96(1H，s)，8.42-8.39(2H，m)，7.14-7.11(1H，m)，4.97(1H，dd J＝14.3，8.8Hz)，4.37(1H，dd，J＝14.3，4.0Hz)，4.00(4H，s)，3.86-3.80(1H，m)，3.75-3.70(1H，m)，3.34-3.24(2H，m)，2.44-2.39(2H，m)，2.08-2.00(1H，m)，1.83-1.77(1H，m)，1.60(3H，s)，1.57(3H，s)。HRMS[M+H]⁺C₂₁H₂₆N₄O₆Calculation of FS: 481.15572, respectively; measurement value: 481.1559.C₂₁H₂₅N₄O₆Analytical calculation of FS: c, 52.49; h, 5.24; n, 11.66; s, 6.67; f, 3.95; measurement value: c, 52.43; h, 5.21; n, 11.61; s, 6.56; f, 4.16.

Example 56

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 3-fluoro-2- (1H-1, 2, 4-triazol-1-yl) phenyl]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-the title compound can be prepared from intermediate 95. A white solid.¹H-NMR(500MHz，CDCl₃)δppm：11.86(1H，s)，8.76(1H，brs)，8.46(1H，d，J＝3.0Hz)，8.22(1H，s)，7.48-7.47(2H，m)，7.29-7.26(1H，m)，4.44(2H，d，J＝6.7Hz)，4.01(4H，s)，1.63(6H，s)。HRMS[M+H]⁺C₁₉H₂₀N₆O₄Calculated value of F: 415.15302, respectively; measurement value: 415.1541.C₁₉H₁₉N₆O₄Analytical calculation of F: c, 55.07; h, 4.62; n, 20.28; f, 4.58; measurement value: c, 55.18; h, 4.42; n, 20.17;F，4.51。

example 57

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- (2H-1, 2, 3-triazol-2-yl) phenyl]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-the title compound can be prepared from intermediate 77. Light orange solid. ¹H-NMR(300MHz，CDCl₃)δppm：11.99(1H，s)，8.99(1H，t，J＝6.4Hz)，7.91(2H，s)，7.65-7.58(2H，m)，7.10(1H，td，J＝8.1，2.6Hz)，4.61(2H，d，J＝7.0Hz)，3.97(4H，s)，1.55(6H，s)。HRMS[M-H]^-C₁₉H₁₈N₆O₄Calculated value of F: 413.13736, respectively; measurement value: 413.1354.C₁₉H₁₇N₆O₄Analytical calculation of F: c, 55.07; h, 4.62; n, 20.28; f, 4.58; measurement value: c, 54.94; h, 4.78; n, 20.32; f, 4.53.

Example 58

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 2-fluoro-4- (2H-1, 2, 3-triazol-2-yl) phenyl]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-the title compound can be prepared from intermediate 77. Light brown solid.¹H-NMR(300MHz，CDCl₃)δppm：11.85(1H，s)，7.88-7.82(3H，m)，7.79(2H，s)，7.47(1H，t，J＝8.3Hz)，4.67(2H，d，J＝6.2Hz)，3.99(4H，s)，1.56(6H，s)。HRMS[M+H]⁺C₁₉H₂₀N₆O₄Calculated value of F: 415.15302, respectively; measurement value: 415.1513.C₁₉H₁₉N₆O₄Analytical calculation of F: c, 55.07; h, 4.62; n, 20.28; f, 4.58; measurement value: c, 54.94; h, 4.76; n, 19.94; f, 4.26.

Example 59

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (2-bromo-4-fluorophenyl) methyl]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-the title compound can be prepared from (2-bromo-4-fluorophenyl) methylamine. White needle-shaped crystals.¹H-NMR(300MHz，CDCl₃)δppm：11.78(1H，s)，8.08(1H，t，J＝6.0Hz)，7.39(1H，dd，J＝8.8，5.8Hz)，7.31(1H，dd，J＝8.0，2,6Hz)，7.01(1H，dt，J＝8.2，2.6Hz)，4.61(2H，d，J＝6.6Hz)，3.99(4H，s)，1.56(6H，s)。HRMS[M+H]⁺ C₁₇H₁₈N₃O₄Calculated values of FBr: 426.04648, respectively; measurement value: 426.0465.

example 60

1H-1, 2, 4-triazole-3-carboxylic acid, 1- [ 5-fluoro-2- [ [ [ (4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxopyrimidino [2, 1-c ]][1，4]Oxazin-2-yl) carbonyl]Amino group]Methyl radical]Phenyl radical]The title compound may be prepared from intermediate 91. A white solid. ¹H-NMR(300MHz，CDCl₃)δppm：11.90(1H，s)，8.49(1H，s)，8.36(1H，t，J＝6.2Hz)，7.72(1H，dd，J＝8.8，5.9Hz)，7.26-7.20(1H，m)，7.14(1H，dd，J＝8.4，2,6Hz)，4.49(2H，d，J＝6.6Hz)，4.01(3H，s)，3.98(4H，s)，1.58(6H，s)。HRMS[M+H]⁺C₂₁H₂₂N₆O₆Calculated value of F:473.1585, respectively; measurement value: 473.1563.C₂₁H₂₁N₆O₆F·0.5H₂Analytical calculation of O: c, 52.39; h, 4.61; n, 17.46; f, 3.95; measurement value: c, 52.14; h, 4.70; n, 17.41; f, 4.12.

Example 61

1H-1, 2, 4-triazole-3-carboxylic acid, 1- [ 5-fluoro-2- [ [ [ (4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxopyrimidino [2, 1-c ]][1，4]Oxazin-2-yl) carbonyl]Amino group]Methyl radical]Phenyl radical]To example 60, 1H-1, 2, 4-triazole-3-carboxylic acid, 1- [ 5-fluoro-2- [ [ [ (4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxopyrimidino [2, 1-c ] at 0 deg.C][1，4]Oxazin-2-yl) carbonyl]Amino group]Methyl radical]Phenyl radical]To a solution of methyl ester (2.156g, 4.6mmol) in tetrahydrofuran (200 ml) and water (50 ml) was added lithium hydroxide monohydrate (0.58 g, 13.8 mmol). The mixture was stirred at 0 ℃ for 2 hours and at room temperature for 1 hour. The resulting solution was partitioned between ethyl acetate and water. The aqueous phase was acidified with 1N HCl and acidified with ethyl acetate and CH₂Cl₂And (4) extracting. Mixing the organic extracts, and drying (Na)₂SO₄) And concentrated to give the title compound as a white solid (2.05g, 97% yield).¹H-NMR(300MHz，CDCl₃)δppm：11.91(1H，bs)，8.55(1H，s)，8.43(1H，t，J＝6.6Hz)，7.77(1H，dd，J＝8.8，5.9Hz)，7.28-7.23(1H，m)，7.16(1H，dd，J＝8.0，2.6Hz)，4.47(2H，d，J＝6.9Hz)，3.98(4H，s)，1.59(6H，s)。HRMS[M+H]⁺C₂₀H₂₀N₆O₆Calculated value of F: 459.14285, respectively; measurement value: 459.1442.

examples 62 to 72

Examples 62-72 may be prepared from intermediate 61, 1H-1, 2, 4-triazole-3-carboxylic acid, 1- [ 5-fluoro-2- [ [ [ (4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxopyrimidino [2, 1-c ] [1, 4] oxazin-2-yl) carbonyl ] amino ] methyl ] phenyl ] -according to the procedure described for the synthesis of example 62.

Example 62

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- [3- (4-morpholinylcarbonyl) -1H-1, 2, 4-triazol-1-yl]Phenyl radical]Methyl radical]To example 61, 1H-1, 2, 4-triazole-3-carboxylic acid, 1- [ 5-fluoro-2- [ [ [ (4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxopyrimidino [2, 1-c ] at 0 deg.C][1，4]Oxazin-2-yl) carbonyl]Amino group]Methyl radical]Phenyl radical]To a solution of O- (7-azabenzotriazol-1-yl) -N, N, N1, N1-tetramethyluronium hexafluorophosphate (0.044 g, 0.115mmol) in DMF (2ml) (0.0259 g, 0.057mmol) was added. The solution was stirred at 0 ℃ for 10 minutes, then morpholine (0.025mL, 0.285mmol) was added, and then it was stirred at room temperature for 2 hours. Chromatography by preparative HPLC on reversed phase (YMCCombiprep ODS-A, 30mmx50mm, MeOH/H)₂O/0.1％CF₃CO₂H) Purification gave the title compound as a white solid (0.015g, 50% yield).¹H-NMR(500MHz，CDCl₃)δppm：8.50(1H，t，J＝6.9Hz)，8.45(1H，s)，7.69(1H，dd，J＝8.7，5.9Hz)，7.22(1H，td，J＝8.2，2,3Hz)，7.13(1H，dd，J＝8.2，2.4Hz)，4.49(2H，s)，3.98(4H，s)，3.88-3.72(8H，m)，1.57(6H，s)。HRMS[M+H]⁺C₂₄H₂₇N₇O₆Calculated value of F: 528.20069, respectively; measurement value: 528.2025.

example 63

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [2- [3- [ (dimethylamino) carbonyl ] amino]-1H-1, 2, 4-triazol-1-yl]-4-fluorophenyl group]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-. light purple solid. ¹H-NMR(300MHz，CDCl₃)δppm：8.51-8.45(2H，m)，7.70(1H，dd，J＝8.4，5.9Hz)，7.24-7.18(1H，m)，7.12(1H，dd，J＝8.2，2.4Hz)，4.47(2H，d，J＝6.9Hz)，3.97(4H，s)，3.24(3H，s)，3.15(3H，s)，1.54(6H，s)。HRMS[M+H]⁺C₂₂H₂₅N₇O₅Calculated value of F: 486.19013, respectively; measurement value: 486.1887.

example 64

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- [3- [ [ (methylsulfonyl) amino group]Carbonyl radical]-1H-1, 2, 4-triazol-1-yl]Phenyl radical]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-. white solid.¹H-NMR(300MHz，CDCl₃)δppm：8.52(1H，s)，8.36(1H，t，J＝6.8Hz)，7.70(1H，dd，J＝8.6，5.7Hz)，7.26-7.19(1H，m)，7.13(1H，dd，J＝8.4，2.6Hz)，4.46(2H，d，J＝7.0Hz)，3.95(4H，s)，3.39(4H，s)，1.57(6H，s)。HRMS[M+H]⁺C₂₁H₂₃N₇O₇Calculation of FS: 536.1364, respectively; measurement value: 536.1376.C₂₁H₂₂N₇O₇FS·0.07CF₃CO₂Analytical calculation of H: c, 46.72; h, 4.09; n, 18.04; f, 4.23; measurement value: c, 46.42; h, 3.91; n, 17.70; f, 4.17.

Example 65

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, 4, 6, 7, 9-tetrahydro-3-hydroxy-N- [ (1R) -2-hydroxy-1-phenylethyl]-9, 9-dimethyl-4-oxo-. white solid.¹H-NMR(300MHz，CDCl₃)δppm：8.43(1H，s)，8.20(1H，t，J＝6.0Hz)，7.64(1H，dd，J＝8.8，5.9Hz)，7.42-7.40(1H，m)，7.26-7.19(1H，m)，7.11(1H，dd，J＝8.0，2.6Hz)，4.53(2H，d，J＝6.6Hz)，3.99(4H，s)，3.06(3H，d，J＝4.7Hz)，1.56(6H，s)。HRMS[M+H]⁺C₂₁H₂₃N₇O₅Calculated value of F: 472.1745, respectively; measurement value: 472.1741.C₂₁H₂₂N₇O₅Analytical calculation of F: c, 53.50; h, 4.70; n, 20.79; f, 4.03; measurement value: c, 53.22; h, 4.51; n, 20.70; f, 4.01.

Example 66

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [2- [3- [ (4-acetyl-1-piperazinyl) carbonyl ] carbonyl]-1H-1, 2, 4-triazol-1-yl]-4-fluorophenyl group]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-. white solid.¹H-NMR(300MHz，CDCl₃)δppm：8.46(1H，s)，8.36(1H，t，J＝5.7Hz)，7.68(1H，dd，J＝8.6，5.7Hz)，7.27-7.21(1H，m)，7.14(1H，dd，J＝8.2，2.7Hz)，4.48(2H，d，J＝6.6Hz)，3.98(4H，s)，3.94-3.61(8H，m)，2.13(3H，s)，1.55(6H，s)。HRMS[M+H]⁺C₂₆H₃₀N₈O₆Calculated value of F: 569.2272, respectively; measurement value: 569.2269.C ₂₆H₂₉N₈O₆F·0.8H₂Analytical calculation of O: c, 53.57; h, 5.29; n, 19.22; f, 3.26; measurement value: c, 53.48; h, 4.95; n, 19.21; f, 3.21.

Example 67

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- [3- [ [ (2-hydroxyethyl) methylamino]Carbonyl radical]-1H-1, 2, 4-triazol-1-yl]Phenyl radical]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-. white solid.¹H-NMR(300MHz，CDCl₃)δppm：8.54(1H，t，J＝7.3Hz)，8.44(1H，s)，7.66(1H，dd，J＝8.8，5.8Hz)，7.21-7.09(2H，m)，4.44(2H，d，J＝4.4Hz)，3.93(4H，s)，3.86-3.78(2H，m)，3.70-3.65(2H，m)，3.13(3H，s)，1.94(1H，bs)，1.55(6H，s)。HRMS[M+H]⁺C₂₃H₂₇N₇O₆Calculated value of F: 516.2007, respectively; measurement value: 516.2011.C₂₃H₂₆N₇O₆Analytical calculation of F: c, 53.59; h, 5.08; n, 19.02; f, 3.68; measurement value: c, 53.31; h, 5.06; n, 18.80; f, 3.60.

Example 68

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- [3- [ [ [ (4-fluorophenyl) sulfonyl ] sulfonyl]Amino group]Carbonyl radical]-1H-1, 2, 4-triazol-1-yl]Phenyl radical]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-. white solid.¹H-NMR(300MHz，CDCl₃)δppm：8.47(1H，s)，8.18-8.13(2H，m)，7.68(1H，dd，J＝8.8，5.9Hz)，7.24-7.16(3H，m)，7.08(1H，dd，J＝8.0，2.6Hz)，4.39(2H，s)，3.96(4H，s)，1.55(6H，s)。HRMS[M+H]⁺C₂₆H₂₄N₇O₇F₂Calculated value of S: 616.1426, respectively; measurement value: 616.1426.C₂₆H₂₃N₇O₇F₂Analytical calculation of S: c, 50.73; h, 3.76; n, 15.92; f, 6.17; measurement value: c, 50.49; h, 3.66; n, 15.98; f, 6.12.

Example 69

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- [3- [ (4-methyl-1-piperazinyl) carbonyl]-1H-1, 2, 4-triazol-1-yl ]Phenyl radical]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-. light brown foam.¹H-NMR(300MHz，CDCl₃)δppm：8.43(1H，s)，8.29(1H，t，J＝6.8Hz)，7.63(1H，dd，J＝8.4，5.9Hz)，7.25-7.19(1H，m)，7.11(1H，dd，J＝8.0，2.6Hz)，4.46(2H，d，J＝6.6Hz)，3.95(4H，s)，3.30(4H，bs)，2.86(3H，s)，1.91(4H，bs)，1.53(6H，s)。HRMS[M+H]⁺C₂₅H₃₀N₈O₅Calculated value of F: 541.2323, respectively; measurement value: 541.2341.C₂₅H₂₉N₈O₅F·0.5CF₃CO₂H·0.5H₂Analytical calculation of O: c, 46.67; h, 4.41; n, 15.55; f, 14.50; measurement value: c, 46.86; h, 4.44; n, 15.67; f, 14.48.

Example 70

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [2- [3- [ [ [2- (dimethylamino) ethyl ] ethyl]Amino group]Carbonyl radical]-1H-1, 2, 4-triazol-1-yl]-4-fluorophenyl group]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-. light brown foam.¹H-NMR(300MHz，CDCl₃)δppm：8.39(1H，s)，7.58(1H，dd，J＝8.6，5.7Hz)，7.23-7.14(1H，m)，7.09(1H，dd，J＝8.4，2.6Hz)，4.50(2H，s)，3.95(4H，s)，3.84(2H，t，J＝5.5Hz)，3.34(2H，t，J＝6.0Hz)，2.89(6H，s)，1.55(6H，s)。HRMS[M+H]⁺C₂₄H₃₀N₈O₅Calculated value of F: 529.2323, respectively; measurement value: 529.2315.

example 71

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [2- [3- [ [ [2- (dimethylamino) ethyl ] ethyl]Methylamino radical]Carbonyl radical]-1H-1, 2, 4-triazol-1-yl]-4-fluorophenyl group]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-. light brown foam.¹H-NMR(300MHz，CDCl₃)δppm：8.44(1H，s)，8.21(1H，t，J＝6.5Hz)，7.67-7.58(1H，m)，7.24-7.09(2H，m)，4.48-4.45(2H，m)，3.95(4H，s)，3.94-3.89(2H，m)，3.37-3.33(2H，m)，2.91(6H，s)，2.88(3H，s)，1.56(6H，s)。HRMS[M+H]⁺C₂₅H₃₂N₈O₅Calculated value of F: 543.2480, respectively; measurement value: 543.2491. c₂₅H₃₁N₈O₅F·CF₃CO₂Analytical calculation of H: c, 45.20; h, 4.32; n, 14.54; f, 17.26; measurement value: c, 45.13; h, 4.14; n, 14.74; f, 17.01.

Example 72

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- [3- [ [ (2-hydroxyethyl) amino group ]Carbonyl radical]-1H-1, 2, 4-triazol-1-yl]Phenyl radical]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-. white solid.¹H-NMR(300MHz，CDCl₃)δppm：8.41(1H，s)，8.32(1H，t，J＝6.2Hz)，7.63(1H，dd，J＝8.4，5.9Hz)，7.20(1H，dt，J＝8.4，2.6Hz)，7.11(1H，dd，J＝8.4，2.6Hz)，4.52-4.50(2H，m)，3.95(4H，s)，3.78(2H，t，J＝5.1Hz)，3.59(2H，t，J＝5.1Hz)，1.56(6H，s)。HRMS[M+H]⁺C₂₂H₂₅N₇O₆Calculated value of F: 502.1850, respectively; measurement value: 502.1850.

example 73

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (4-fluoro-2-iodophenyl) methyl]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-can be synthesized from intermediate 174, N- (4-fluoro-2-iodobenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ]][1，4]Oxazine-2-carboxamide the title compound was prepared.¹HNMR 400MHz(CDCl₃)δppm：1.63(6H，s，2xCH₃)，4.05(4H，s，2xCH₂)，4.63(2H，d，J＝7.1Hz，NCH₂) 7.11(1H, m, arene), 7.42(1H, dd, J ═ 5.6Hz and J ═ 8.6Hz, arene), 7.62(1H, dd, J ═ 2.5Hz and J ═ 8.1Hz, arene), 8.20(1H, wide t, NH), 11.82(1H, s, OH). HRMS (ESI)⁺)C₁₇H₁₈FIN₃O₄[M+H⁺]The calculated value of (a): 474.0326, respectively; measurement value: 474.0328.

examples 74 to 77

Examples 74-77 can be prepared from the indicated intermediates by hydrogenolysis or trifluoroacetic acid mediated hydrolysis.

Example 74

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (5-fluoro [1, 1' -biphenyl)]-2-yl) methyl]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-can be synthesized from intermediate 176, N- (4-fluoro-2-phenyl-benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ] ][1，4]Oxazine-2-carboxamide the title compound was prepared.¹HNMR 400MHz(CDCl₃)δppm：1.56(6H，s，2xCH₃)，4.03(4H，s，2xCH₂)，4.56(2H，d，J＝6.0Hz，NCH₂) 7.03(1H, dd, J2.5 Hz and J9.3 Hz, aromatics), 7.09(1H, m, aromatics), 7.36(2H, m, aromatics), 7.42-7.51(5H, m, aromatics and NH), 11.96(1H, s, OH). HRMS (ESI)⁺)C₂₃H₂₃FN₃O₄[M+H⁺]The calculated value of (a): 424.1673, respectively; measurement value: 424.1675.

example 75

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- (3-pyridinyl) phenyl]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-.¹HNMR 400MHz(CDCl₃)δppm：1.57(6H，s，2xCH₃)，4.04(4H，s，2xCH₂)，4.55(2H，d，J＝6.1Hz，NCH₂) 7.04(1H, dd, J2.5 Hz and J9.1 Hz, aromatics), 7.16(1H, m, aromatics), 7.43(1H, m, aromatics), 7.49(1H, dd, J5.6 Hz and J8.6 Hz, aromatics), 7.52(1H, width t, NH), 7.71(1H, m, aromatics), 8.63(1H, m, aromatics), 8.70(1H, m, aromatics), 11.84(1H, s, OH). HRMS (ESI)⁺)C₂₂H₂₂FN₄O₄[M+H⁺]The calculated value of (a): 425.1625, respectively; measurement value: 425.1616.

example 76

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- (2-methoxy-3-pyridinyl) phenyl]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-intermediate 175, N- (4-fluoro-2- (2-methoxypyridin-3-yl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ] o ][1，4]Hydrogenolysis of oxazine-2-carboxamide to give the title material as a white solid; melting point 227 ℃.¹HNMR 400MHz(CDCl₃)δppm：1.58(6H，s，2xCH₃)，3.99(3H，s，OCH₃)，4.04(4H，s，2xCH₂) 4.43(2H, broad, NCH)₂) 6.97(1H, dd, J ═ 2.5Hz and J ═ 8.5Hz, aromatics), 7.03(1H, dd, J ═ 5.0Hz and J ═ 8.5Hz, aromatics), 7.12(1H, m, aromatics), 7.45(1H, dd, J ═ 4.5Hz and J ═ 8.6Hz, aromatics), 7.53(1H, dd, J ═ 2.0Hz and J ═ 7.1Hz, aromatics), 7.57(1H, wide t, NH), 8.28(1H, dd, J ═ 2.5Hz and J ═ 5.0Hz, aromatics), 12.03(1H, s, OH). HRMS (ESI)⁺)C₂₃H₂₄FN₄O₅[M+H⁺]The calculated value of (a): 455.1731, respectively; measurement value: 455.1737.

example 77

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- (6-methoxy-3-pyridinyl) phenyl]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo.¹HNMR 400MHz(CDCl₃)δppm：1.58(6H，s，2xCH₃)，4.02(3H，s，OCH₃)，4.04(4H，s，2xCH₂)，4.55(2H，d，J＝6.1Hz，NCH₂) 6.87(1H, d, J ═ 9.0Hz, arenes), 7.01(1H, dd, J ═ 2.0Hz, and J ═ 9.0Hz, aromatics), 7.12(1H, m, aromatics), 7.46(1H, dd, J ═ 5.5Hz and J ═ 8.6Hz, aromatics), 7.55(1H, wide t, NH), 7.60(1H, dd, J ═ 2.0Hz and J ═ 8.6Hz, aromatics), 8.17(1H, d, J ═ 2.0Hz, aromatics), 11.89(1H, s, OH). HRMS (ESI)⁺)C₂₃H₂₄FN₄O₅[M+H⁺]The calculated value of (a): 455.1731, respectively; measurement value: 455.1717.

examples 78 to 80

Examples 78-80 can be prepared from the indicated intermediates following the procedure described for example 78.

Example 78

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [2- (1, 2-dihydro-2-oxo-3-pyridinyl) -4-fluorophenyl]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-intermediate 175, N- (4-fluoro-2- (2-methoxypyridin-3-yl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]A solution of oxazine-2-carboxamide (0.125 g, 0.23mmol) in acetonitrile (5 ml) was treated with sodium iodide (0.090 g, 0.6mmol) and chlorotrimethylsilane (0.45 ml, 3.5mmol), sealed in a pressure resistant vessel, and heated at 80 ℃ for 1.5 hours. The mixture was diluted with ethyl acetate, washed with water and brine, and then dried over anhydrous magnesium sulfate. Filtration and removal of the solvent afforded the title compound.¹HNMR 400MHz(CDCl₃)δppm：1.60(6H，s，2xCH₃)，4.03(4H，s，2xCH₂) 4.5(2H, broad, NCH)₂) 6.47(1H, m, arene), 6.95(1H, dd, J2 Hz and J9 Hz, arene), 7.12(1H, m, arene), 7.45(1H, dd, J2 Hz and J7 Hz, arene), 7.50(1H, dd, J6 Hz and J9 Hz, arene), 7.53(1H, dd, J2 Hz and J7 Hz, arene), 8.64(1H, wide t, NH). HRMS (ESI)⁺)C₂₂H₂₂FN₄O₅[M+H⁺]The calculated value of (a): 441.1574, respectively; measurement value: 441.1585.

example 79

Pyrimido [2, 1-c ] s ][1，4]Oxazine-2-carboxamide, N- [ [2- (1, 6-dihydro-6-oxo-3-pyridinyl) -4-fluorophenyl]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-the title compound can be prepared from example 77.¹HNMR 400MHz(CDCl₃)δppm：1.59(6H，s，2xCH₃)，4.02(3H，s，OCH₃)，4.05(4H，s，2xCH₂)，4.55(2H，d，J＝6.6Hz，NCH₂) 6.95(1H, d, J ═ 9.0Hz, aromatics), 7.00(1H, dd, J ═ 2.6Hz and J ═ 9.0Hz, aromatics), 7.17(1H, m, aromatics), 7.46(1H, dd, J ═ 5.5Hz and J ═ 8.6Hz, aromatics), 7.63(1H, d, J ═ 2.6Hz, aromatics), 7.71(1H, wide t, NH), 7.79(1H, dd, J ═ 2.6Hz and J ═ 9.1Hz, aromatics). HRMS (ESI)⁺)C₂₂H₂₂FN₄O₅[M+H⁺]The calculated value of (a): 441.1574, respectively; measurement value: 441.1570.

example 80

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [2- (1, 6-dihydro-6-oxo-2-pyridinyl) -4-fluorophenyl]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-, can be prepared from N- (4-fluoro-2- (6-methoxypyridin-2-yl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ] o][1，4]Oxazine-2-carboxamide the title compound was prepared according to the procedure described for the synthesis of intermediate 175.¹HNMR 400MHz(CDCl₃)δ(ppm)：1.62(6H，s，2xCH₃)，4.04(4H，s，2xCH₂)，4.60(2H，d，J＝7.0Hz，NCH₂) 6.38(1H, d, J ═ 7.0Hz, arenes), 6.68(1H, d, J ═ 9.0Hz, arenes), 7.14(1H, dd, J ═ 2.5Hz and J ═ 9.1Hz, arenes), 7.23(1H, m, arenes), 7.50(1H, dd, J ═ 5.6Hz and J ═ 8.6Hz, arenes), 7.58(1H, dd, J ═ 7.0Hz and J ═ 9.0Hz, arenes), 8.15(1H, t, NH).

Examples 81 to 93

Examples 81-93 can be prepared from the indicated intermediates by hydrogenolysis or trifluoroacetic acid mediated hydrolysis.

Example 81

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-can be synthesized from intermediate 152, N- (4-fluoro-2- (3-methyl-1H-1, 2, 4-triazol-1-yl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide the title compound was prepared.¹HNMR 400MHz(CDCl₃)δppm：1.64(6H，s，2xCH₃)，2.59(3H，s，CH₃)，4.04(4H，s，2xCH₂)，4.50(2H，d，J＝7.1Hz，NCH₂) 7.1(1H, dd, J2.5 Hz and J8.6 Hz, aromatics), 7.20(1H, m, aromatics), 7.72(1H, dd, J6.0 Hz and J8.6 Hz, aromatics), 8.34(1H, s, CH), 8.80(1H, width t, NH), 12.11(1H, s, OH). HRMS (ESI)⁺)C₂₀H₂₂FN₆O₄[M+H⁺]The calculated value of (a): 429.1687, respectively; measurement value: 429.1675.

example 82

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- (5-methyl-1H-1, 2, 4-triazol-1-yl) phenyl]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-.¹HNMR 400MHz(CDCl₃)δppm：1.66(6H，s，2xCH₃)，2.50(3H，s，CH₃)，4.04(4H，s，2xCH₂)，4.32(2H，d，J＝7.0Hz，NCH₂) 7.05(1H, dd, J2.5 Hz and J8.1 Hz, aromatics), 7.27(1H, m, aromatics), 7.70(1H, dd, J6.1 Hz and J8.6 Hz, aromatics), 8.04(1H, s, CH), 8.61(1H, width t, NH), 11.90(1H, s, OH). HRMS (ESI) ⁺)C₂₀H₂₂FN₆O₄[M+H⁺]The calculated value of (a): 429.1687, respectively; measurement value: 429.1688.

example 83

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 2-fluoro-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-can be synthesized from intermediate 153, N- (2-fluoro-4- (3-methyl-1H-1, 2, 4-triazol-1-yl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide the title compound was prepared.¹HNMR 400MHz(CDCl₃)δppm：1.61(6H，s，2xCH₃)，2.51(3H，s，CH₃)，4.05(4H，s，2xCH₂)，4.72(2H，d，J＝6.6Hz，NCH₂) 7.44-7.55(3H, m, arene), 7.94(1H, width t, NH), 8.46(1H, s, CH), 11.86(1H, s, OH). HRMS (ESI)⁺)C₂₀H₂₂FN₆O₄[M+H⁺]The calculated value of (a): 429.1687, respectively; measurement value: 429.1695。

Example 84

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- (1, 2, 3-thiadiazol-4-yl) phenyl]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-can be prepared from intermediate 172, N- (4-fluoro-2- (1, 2, 3-thiadiazol-4-yl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ] o][1，4]Oxazine-2-carboxamide the title compound was prepared.¹HNMR400MHz(DMSO-d₆)δppm：1.54(6H，s，2xCH₃) 3.83(2H, width t, CH)₂) 3.96(2H, width t, CH)₂)，4.61(2H，d，J＝6.7Hz，NCH₂) 7.39(1H, m, arene), 7.55(1H, m, arene), 7.62(1H, m, arene), 9.41(1H, broad t, NH), 9.63(1H, s, CH), 12.0(1H, s, OH). HRMS (ESI) ⁺)C₁₉H₁₉FN₅O₄S[M+H⁺]The calculated value of (a): 432.1142, respectively; measurement value: 432.1124.

example 85

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- (1H-pyrazol-5-yl) phenyl]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-can be synthesized from intermediate 177, N- (4-fluoro-2- (1H-pyrazol-5-yl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide the title compound was prepared.¹HNMR 400MHz(CDCl₃)δppm：1.59(6H，s，2xCH₃)，4.03(4H，s，2xCH₂)，4.67(2H，d，J＝6.6Hz，NCH₂)，6.65(1H, d, J ═ 2.5Hz, CH), 7.07(1H, m, arene), 7.31(1H, dd, J ═ 2.5Hz and J ═ 9.8Hz, arene), 7.56(1H, dd, J ═ 5.8Hz and J ═ 8.3Hz, arene), 7.75(1H, d, J ═ 2.5Hz, CH), 9.22(1H, broad t, NH), 10.33(1H, broad peak, NH), 12.2(1H, s, OH). HRMS (ESI)⁺)C₂₀H₂₁FN₅O₄[M+H⁺]The calculated value of (a): 414.1578, respectively; measurement value: 414.1560.

example 86

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- (5-methyl-2-oxazolyl) phenyl]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-can be synthesized from intermediate 173, N- (4-fluoro-2- (5-methyloxazol-2-yl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide the title compound was prepared. ¹HNMR400MHz(CDCl₃)δppm：1.58(6H，s，2xCH₃)，2.48(3H，s，CH₃)，4.01(4H，s，2xCH₂)，4.77(2H，d，J＝7.0Hz，NCH₂) 6.96(1H, s, CH), 7.13(1H, m, arene), 7.61(1H, dd, J ═ 5.8Hz and J ═ 8.3Hz, arene), 7.70(1H, dd, J ═ 3.2Hz and J ═ 9.6Hz, arene), 9.76(1H, width t, NH), 12.15(1H, s, OH). HRMS (ESI)⁺)C₂₁H₂₂FN₄O₅[M+H⁺]The calculated value of (a): 429.1574, respectively; measurement value: 429.1564.

example 87

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [2- (ethylamino) -4-fluoroPhenyl radical]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-can be prepared from intermediate 170, N- (2- (ethylamino) -4-fluorobenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ]][1，4]Oxazine-2-carboxamide the title compound was prepared.¹HNMR 400MHz(CDCl₃)δppm：1.30(3H，t，J＝7.3Hz，CH₃)，1.59(6H，s，2xCH₃)，3.12(2H，m，CH₂)，4.04(4H，s，2xCH₂)，4.52(2H，d，J＝6.6Hz，NCH₂) 5.09(1H, broad, NH), 6.3-6.37(2H, m, arene), 7.10(1H, dd, J ═ 6.6Hz and J ═ 8.1Hz, arene), 7.67(1H, broad, NH), 11.93(1H, s, OH). HRMS (ESI)⁺)C₁₉H₂₄FN₄O₄[M+H⁺]The calculated value of (a): 391.1782, respectively; measurement value: 391.1774.

example 88

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (2-ethynyl-4-fluorophenyl) methyl]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-can be synthesized from intermediate 179, N- (2-ethynyl-4-fluorobenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c) ][1，4]Oxazine-2-carboxamide the title compound was prepared.¹HNMR 400MHz(CDCl₃)δppm：1.61(6H，s，2xCH₃)，3.46(1H，s，CH)，4.04(4H，s，2xCH₂)，4.73(2H，d，J＝6.5Hz，NCH₂) 7.1(1H, m, arene), 7.26(1H, dd, J ═ 2.5Hz and J ═ 8.5Hz, arene), 7.40(1H, dd, J ═ 5.6Hz and J ═ 8.6Hz, arene), 8.18(1H, wide t, NH), 11.92(1H, s, OH). HRMS (ESI)⁺)C₁₉H₁₉FN₃O₄[M+H⁺]The calculated value of (a): 372.1360, respectively; measurement value: 372.1345.

example 89

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- (3-hydroxy-1-propynyl) phenyl]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-can be prepared from intermediate 182, N- (4-fluoro-2- (3-hydroxyprop-1-ynyl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ]][1，4]Oxazine-2-carboxamide the title compound was prepared.¹HNMR400MHz(CDCl₃)δppm：1.60(6H，s，2xCH₃)，4.04(4H，s，2xCH₂) 4.55(2H, width d, CH)₂)，4.73(2H，d，J＝6.6Hz，NCH₂) 7.07(1H, m, arene), 7.20(1H, dd, J ═ 2.5Hz and J ═ 9.1Hz, arene), 7.38(1H, dd, J ═ 5.3Hz and J ═ 8.3Hz, arene), 7.95(1H, wide t, NH), 11.90(1H, s, OH). HRMS (ESI)⁺)C₂₀H₂₁FN₃O₅[M+H⁺]The calculated value of (a): 402.1465, respectively; measurement value: 402.1463.

example 90

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- [3- [ (methylsulfonyl) oxy ] carbonyl]-1-propynyl]Phenyl radical]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-can be prepared from intermediate 183, 3- [2- ((3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ] ][1，4]Oxazin-2-carboxamido) methyl) -5-fluorophenyl]Prop-2-ynyl methanesulfonate gave the title compound.¹HNMR 400MHz(CDCl₃)δppm：1.62(6H，s，2xCH₃)，3.16(3H，s，CH₃)，4.05(4H，s，2xCH₂)，4.72(2H，d，J＝6.0Hz，NCH₂)，5.12(2H，s，OCH₂) 7.12(1H, m, arene), 7.21(1H, dd, J ═ 2.6Hz and J ═ 8.6Hz, arene), 7.45(1H, dd, J ═ 5.1Hz and J ═ 8.6Hz, arene), 8.03(1H, wide t, NH).

Example 91

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [2- [3- (dimethylamino) -1-propynyl group]-4-fluorophenyl group]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-can be synthesized from intermediate 184, N- (2- (3- (dimethylamino) prop-1-ynyl) -4-fluorobenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c- ] -][1，4]Oxazine-2-carboxamide the title compound was prepared. The title compound was isolated as the trifluoroacetate salt.¹HNMR 400MHz(CDCl₃)δppm：1.62(6H，s，2xCH₃)，3.03(6H，s，2xCH₃)，4.06(4H，s，2xCH₂)，4.23(2H，s，NCH₂)，4.75(2H，d，J＝6.0Hz，NCH₂) 7.16(1H, m, arene), 7.24(1H, dd, J ═ 2.5Hz and J ═ 8.6Hz, arene), 7.42(1H, dd, J ═ 5.6Hz and J ═ 8.6Hz, arene), 8.04(1H, wide t, NH). HRMS (ESI)⁺)C₂₂H₂₆FN₄O₄[M+H⁺]The calculated value of (a): 429.1938, respectively; measurement value: 429.1917.

example 92

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- [3- (methylsulfonyl) -1-propynyl]Phenyl radical]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-can be synthesized from intermediate 186, N- (4-fluoro-2- (3- (methylsulfonyl) prop-1-ynyl) benzyl ) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c][1，4]Oxazine-2-carboxamide the title compound was prepared.¹HNMR 400MHz(CDCl₃)δppm：1.63(6H，s，2xCH₃)，3.16(3H，s，SCH₃)，4.04(4H，s，2xCH₂)，4.17(2H，s，SCH₂)，4.70(2H，d，J＝6.0Hz，NCH₂) 7.12(1H, m, arene), 7.21(1H, dd, J ═ 2.5Hz and J ═ 8.6Hz, arene), 7.49(1H, dd, J ═ 5.6Hz and J ═ 8.6Hz, arene), 8.16(1H, wide t, NH), 11.99(1H, s, OH). HRMS (ESI)⁺)C₂₁H₂₃FN₃O₆S[M+H⁺]The calculated value of (a): 464.1292, respectively; measurement value: 464.1271.

example 93

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- [3- (tetrahydro-1, 1-dioxido-2H-1, 2-thiazin-2-yl) -1-propynyl]Phenyl radical]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-.¹HNMR 400MHz(CDCl₃)δppm：1.63(6H，s，2xCH₃)，1.86(2H，m，CH₂)，2.28(2H，m，CH₂)，3.11(2H，m，CH₂)，3.53(2H，m，CH₂)，4.05(4H，s，2xCH₂)，4.27(2H，s，NCH₂)，4.73(2H，d，J＝6.0Hz，NCH₂) 7.07(1H, m, arene), 7.17(1H, dd, J ═ 2.5Hz and J ═ 8.6Hz, arene), 7.47(1H, dd, J ═ 5.6Hz and J ═ 8.6Hz, arene), 8.12(1H, wide t, NH).

Example 94

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, 4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-N- [2- (phenylsulfonyl) ethyl]The procedure described in examples 1, 19 and 20 can be followed from intermediate 25, 3-hydroxy-9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxylic acid ethyl ester and 7- (aminomethyl) indolin-2-one the title compound was prepared. ¹HNMR(500MHz，DMSO-d₆) δ ppm: 1.58(s, 6), 3.50(s, 2), 3.83(m, 2), 3.97(m, 2), 4.42(d, 2), 6.9-7.13 (overlap m, 3). C₁₉H₂₀N₄O₅Analytical calculation of (a): c, 59.36; h, 5.24; n, 14.57. Measurement value: c, 59.61; h, 5.43; n, 14.46.

Example 95

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (4-fluoro-2-hydroxyphenyl) methyl]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-intermediate 144, N- (4-fluoro-2-hydroxybenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]A solution of oxazine-2-carboxamide (0.070 g, 0.154mmol) in dichloromethane (3 ml) and trifluoroacetic acid (3 ml) was stirred for 2 hours. The solvent was then removed in vacuo and the resulting residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with 1.0N HCl (10mL), dried over sodium sulfate, and filtered. The solvent was removed by rotary evaporator and the crude product was subjected to preparative reverse phase HPLC (C18, 30% -40% CH)₃CN/H₂O-0.1％CF₃CO₂H) And (5) purifying. The product-containing fractions were concentrated by rotary evaporator and the resulting aqueous suspension was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried (sodium sulfate), filtered and concentrated to dryness on a rotary evaporator. The residue was triturated with ether and dried in vacuo to give the title compound as a white solid. ¹HNMR(500MHz，d₆-acetone) δ ppm: 11.96(2H，s)，9.25(2H，s)，8.98(1H，br s)，7.23(1H，t，J＝7.6Hz)，6.63(1H，dd，J＝8.2，2.4Hz)，6.57(1H，dt，J＝8.4，2.4Hz)，4.53(2H，d，J＝6.7Hz)，4.05(2H，d，J＝5.2Hz)，3.90(2H，t，J＝5.2Hz)，1.55(6H，s)；HRMS[M+H]⁺C₁₇H₁₉N₃O₅Calculated value of F: 364.13088, respectively; measurement value: 364.1302.

example 96

Carbamic acid, dimethyl-, 5-fluoro-2- [ [ [ (4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxopyrimidino [2, 1-c)][1，4]Oxazin-2-yl) carbonyl]Amino group]Methyl radical]Phenyl ester according to the procedure described in example 95, dimethyl-carbamic acid 2- { [ (3-benzyloxy-9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydro-pyrimido [2, 1-c ] can be synthesized from intermediate 158][1，4]Oxazine-2-carbonyl) -amino]-methyl } -5-fluoro-phenyl ester the title compound was prepared. White crystalline powder;¹H NMR(CDCl₃，500MHz)δppm：1.56(6H，s，Me)，2.96，3.11(2s，NMe)，3.99(4H，s，CH₂)，4.51(2H，d，J＝6Hz，NCH₂)，6.85(1H，dd，J＝2.5Hz，9Hz，CH)，6.94(1H，dt，J＝2.5Hz，8.3Hz，Ar-H)，7.37(1H，dd，J＝6.5Hz，8.5Hz，Ar-H)，8.05(1H，brt，J＝5Hz，NH)，12.0(1H，s，OH)；¹³C NMR(CDCl₃，125.77Hz)δppm：27.90(CH₃)，36.68，36.92(2s，NCH₃)，37.80(NCH₂)，43.14(NCH₂)，58.20(OCH₂)，75.99(OC)，110.88，110.07(d，J＝24Hz，CH)，113.41，113.57(d，J＝21Hz，CH)，125.71(C)，125.91，125.94(d，J＝3.6Hz，C)，131.57，131.64(d，J＝9.6Hz，CH)，146.22(C)，150.83，150.92(d，J＝11Hz，C)，151.66(C)，154.68(C＝O)，157.92(C＝O)，161.70，163.68(d，J＝249Hz，CF)，167.86(C＝O)；HRMSC₂₀H₂₄N₄O₆calculated value of F (M + H): 435.1680, measurement: 435.1695 (delta +3.5 ppm). Uv (meoh): λ max 245nm (. epsilon.1.05X 10)⁴)，306nm(ε8.00x10³)；C₂₀H₂₃N₄O₆Analytical calculation of F: c55.30, H5.34, N12.90; measurement value: c55.32, H5.38, N12.77.

Example 97

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- [2- (methylamino) -2-oxoethoxy ] ethyl]Phenyl radical]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-intermediate 144, N- (4-fluoro-2-hydroxybenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ] under nitrogen atmosphere][1，4]A solution of oxazine-2-carboxamide (0.150 g, 0.331mmol) and sodium hydride (0.015 g, 0.37mmol, 60% oil dispersion) in anhydrous dimethylformamide (4 ml) was stirred for 5 minutes. The reaction mixture was treated with 2-chloro-N-methylacetamide (0.054g, 0.50mmol) and stirred for an additional 16 hours. The solvent was removed using a rotary evaporator and the resulting residue was purified by short path flash silica gel chromatography (ethyl acetate). The product containing fractions were combined and concentrated to dryness. The residue was dissolved in dichloromethane (5mL) and trifluoroacetic acid (5mL) and stirred for 1 hour. The solvent was removed by rotary evaporator and the crude product was triturated with a minimum volume of 95% ethanol. The resulting solid was collected by filtration and dried in vacuo to yield 93mg (0.21mmol, 65% yield) of the title compound as a white powder: ¹H NMR(500MHz，CDCl₃)δppm：11.92(1H，s)，7.67(1H，t，J＝6.3Hz)，7.57(1H，br)，7.30(1H，dd，J＝8.2，6.4Hz)，6.74(1H，dt，J＝8.2，2.3Hz)，6.60(1H，dd，J＝10.4，2.4Hz)，4.68(2H，d，J＝6.7Hz)，4.45(2H，s)，4.00(4H，s)，2.93(3H，d，J＝4.9Hz)，1.55(6H，s).¹³C NMR(125.77MHz，CDCl₃)δppm：168.05，167.44，164.79，162.82，157.71，156.57，156.50，152.14，146.60，131.94，131.86，125.23，120.71，120.68，108.37，108.20，100.76，100.55，75.81，67.46，58.15，43.24，38.19，28.08，25.83。HRMS[M+H]⁺C₂₀H₂₄N₄O₆Calculated value of F: 435.1680, respectively; measurement value: 435.1668.

example 98

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [2- [2- (dimethylamino) -2-oxoethoxy group]-4-fluorophenyl group]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-following the procedure described in example 97, starting from intermediate 144, N- (4-fluoro-2-hydroxybenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide the title compound was prepared. A white powder;¹H NMR(500MHz，CDCl₃)δppm：12.25(1H，br s)，8.36(1H，t，J＝5.65Hz)，7.31(1H，dd，J＝8.39，6.56Hz)，6.67(1H，dt，J＝8.32，2.29Hz)，6.57(1H，dd，J＝10.38，2.14Hz)，4.76(2H，s)，4.62(2H，d，J＝6.10Hz)，4.00(4H，s)，3.06(3H，s)，3.01(3H，s)，1.58(6H，s).¹³C NMR(125.77MHz，CDCl₃)δppm：168.25，166.62，164.23，162.27，158.02，157.39，151.36，146.39，131.25，131.18，125.95，122.23，122.20，108.25，108.08，100.47，100.27，76.03，66.24，58.22，43.15，38.59，36.07，35.77，27.94。HRMS[M+H]⁺ C₂₁H₂₆N₄O₆calculated value of F: 449.18365, respectively; measurement value: 449.1837.

example 99

4-morpholinecarboxylic acid, 5-fluoro-2- [ [ [ (4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxopyrimidino [2, 1-c)][1，4]Oxazin-2-yl) carbonyl]Amino group]Methyl radical]Phenyl ester according to the procedure described in example 97, starting from intermediate 144, N- (4-fluoro-2-hydroxybenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide the title compound was prepared. A white powder;¹H NMR(500MHz，CDCl₃)δppm：12.01(1H，br s)，7.96(1H，t，J＝5.34Hz)，7.38(1H，dd，J＝8.39，6.26Hz)，6.97(1H，dt，J＝8.24，2.44Hz)，6.87(1H，dd，J＝8.85，2.44Hz)，4.51(2H，d，J＝6.10Hz)，4.00(4H，s)，3.70-3.76(4H，m)，3.65-3.70(2H，m)，3.49-3.54(2H，m)，1.55(6H，s).¹³C NMR(125.77MHz，CDCl₃)δppm：167.91，163.68，157.86，153.48，151.71，150.51，150.42，146.31，131.58，131.50，125.83，125.59，113.84，113.67，111.03，110.84，75.93，66.59，66.52，58.22，45.17，44.41，43.16，37.70，27.95。HRMS[M+H]⁺ C₂₂H₂₆N₄O₇calculated value of F: 477.17856, respectively; measurement value: 477.1788.

example 100

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- (methylthio) phenyl]Methyl radical]4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-following the procedures described in the syntheses of examples 1, 19 and 20, one may proceed from intermediate 25, 3-hydroxy-9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ] ][1，4]The title compound was prepared from oxazine-2-carboxylic acid ethyl ester and (4-fluoro-2- (methylthio) phenyl) methylamine. A white solid.¹H NMR(300MHz，CDCl₃)δppm：11.88(1H，br)，8.03(1H，t，J＝6.04Hz)，7.28(1H，dd，J＝8.42，5.85Hz)，6.93(1H，dd，J＝9.51，2.20Hz)，6.81(1H，dt，J＝8.23，2.56Hz)，4.58(2H，d，J＝6.22Hz)，3.98(4H，s)，2.49(3H，s)，1.55(6H，s)；HRMS(ESI)C₁₈H₂₁FN₃O₄Calculated value of S (M + H): 394.1237, measurement: 394.1218.

example 101

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- (methylsulfonyl) phenyl]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-to example 100 pyrimido [2, 1-c][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- (methylthio) phenyl]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo- (158 mg, 0.4mmol) of CH₂Cl₂To the solution (4 ml) was added 3-chloroperbenzoic acid (132 mg, 0.6 mmol; 77%, Aldrich) and the mixture was stirred at room temperature for 2 hours. After removal of the solvent in vacuo, the residue was triturated with ether. Subjecting the crude powder to reverse phase column chromatography (YMC, ODS, 8% CH)₃CN/H₂O-0.1％CF₃CO₂H) Purification afforded 32mg (0.075mmol, 19% yield) of the title compound as a white powder which, after trituration with ether, afforded 35mg (0.086mmol, 21% yield) of the corresponding sulfoxide.¹H NMR(300MHz，CDCl₃)δppm：11.71(1H，s)，8.58(1H，t，J＝6.04Hz)，7.73(1H，dd，J＝8.23，2.74Hz)，7.68(1H，dd，J＝8.42，5.12Hz)，7.32(1H，dt，J＝8.05，2.93Hz)，4.79(2H，d，J＝6.95Hz)，3.97(4H，s)，3.15(3H，s)，1.56(6H，s)；HRMS(ESI)C₁₈H₁₉FN₃O₆Calculated value of S (M-H): 424.0979, measurement: 424.0973.

example 102

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- (methylsulfinyl) phenyl ]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo formed in the reaction described in example 101.¹H NMR(300MHz，CDCl₃)δppm：11.73(1H，s)，8.19(1H，t，J＝6.59Hz)，7.54(1H，dd，J＝8.05，2.93Hz)，7.47(1H，dd，J＝8.42，5.12Hz)，7.16(1H，dt，J＝8.14，2.74Hz)，4.57-4.81(2H，m)，3.99(4H，s)，2.80(3H，s)，1.56(6H，s)；HRMS(ESI)C₁₈H₂₁FN₃O₅Calculated value of S (M-H): 410.1196, measurement: 410.1194.

example 103

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- (S-methylsulfimidoyl) phenyl]Methyl radical]4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-Example 100, pyrimido [2, 1-c][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- (methylthio) phenyl]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo- (245 mg, 0.75mmol) of CH₂Cl₂(3 ml) to the solution was added tert-butyl azidoformate (115 mg, 0.8 mmol; prepared as described in Organic Synthesis 1979, 50, 9-12) and ferrous chloride (FeCl)₂50 mg) was added to the reaction solution, and the resulting mixture was stirred for 18 hours. The mixture was diluted with dichloromethane, washed with water and dried (MgSO)₄) Filtered and concentrated to give 450 mg of 3-hydroxy-9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydro-pyrimido [2, 1-c ]][1，4]Oxazine-2-carboxylic acid 4-fluoro-2- (N-tert-butoxycarbonyl-S-methyl) sulfilimininel benzylamide black colored gum; LC/MS M/z 509(M + H).

The substance (100mg) was purified from CF₃CO₂The H (1mL) solution was stirred for 20 minutes and then concentrated. By C-18 reverse phase HPLC (YMC ODS, 5-10% CH)₃CN/H₂O-0.1％CF₃CO₂H) The residue was purified to give 15mg (0.037mmol, 21% yield) of the corresponding trifluoroacetate salt of the title compound.¹H NMR(300MHz，DMSO-D6)δppm：11.62(1H，s)，9.57(1H，t，J＝6.0Hz)，8.11(1H，dd，J＝8.8，1.8Hz)，7.62-7.71(2H，m)，4.58-4.82(2H，m)，3.97(2H，t，J＝4.8Hz)，3.82(2H，t，J＝4.8Hz)，3.37(3H，s)，1.57(6H，s)；HRMS(ESI)C₁₈H₂₂FN₄O₄Calculated value of S (M + H): 409.1346, measurement: 409.1333.

example 104

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, 4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-N- [ [3- [3- (trifluoromethyl) -3-diazepanyl ] propan-3]Phenyl radical]Methyl radical]The procedure described in the syntheses of examples 1, 19 and 20 may be followed from intermediate 25, 3-hydroxy-9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ]][1，4]The title compound was prepared from oxazine-2-carboxylic acid ethyl ester and (4- (diaziridin-3-yl) phenyl) methylamine (formed in the preparation of intermediate 66). A white solid;¹H NMR(300MHz，CDCl₃)δppm：11.89(1H，s)，7.81(1H，t，J＝6.0Hz)，7.52-7.59(2H，m)，7.38-7.44(2H，m)，4.63(2H，d，J＝6.2Hz)，4.00(4H，s)，2.78(1H，d，J＝7.3Hz)，2.21(1H，d，J＝8.1Hz)，1.51-1.57(6H，m)；HRMS(ESI)C₁₉H₂₁F₃N₅O₄calculated value of (M + H): 440.1546, measurement: 440.1537.

example 105

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, 4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-N- [ [3- [3- (trifluoromethyl) -3H-diazepan-3-yl]Phenyl radical]Methyl radical]The procedure described in the syntheses of examples 1, 19 and 20 may be followed from intermediate 25, 3-hydroxy-9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ] ][1，4]Oxazine-2-carboxylic acid ethyl ester and intermediate 66, (3- (3- (trifluoromethyl) diaziridin-3-yl) phenyl) methylamine the title compound was prepared. A white solid;¹H NMR(300MHz，CDCl₃)δppm：11.86(1H，s)，7.73-7.84(1H，m)，7.35-7.40(2H，m)，7.11-7.17(1H，m，J＝2.9Hz)，7.08-7.11(1H，m)，4.60(2H，d，J＝6.2Hz)，4.00(4H，s)，1.55(6H，s)；HRMS(ESI)C₁₉H₁₉F₃N₅O₄calculated value of (M + H): 438.1389, measurement: 438.1371.

example 106

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- (2-methyl-2H-tetrazol-5-yl) phenyl]Methyl radical]4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-following the procedures described in the syntheses of examples 1, 19 and 20, one may proceed from intermediate 25, 3-hydroxy-9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ]][1，4]Oxazine-2-carboxylic acid ethyl ester and intermediate 59, (4-fluoro-2- (2-methyl-2H-tetrazol-5-yl) phenyl) methylamine hydrochloride the title compound was prepared. (white solid);¹H NMR(300MHz，CDCl₃)δppm：12.01(1H，s)，9.24(1H，t，J＝6.8Hz)，7.75(1H，dd，J＝9.5，2.6Hz)，7.63(1H，dd，J＝8.4，5.5Hz)，7.15(1H，dt，J＝8.2，2.6Hz)，4.70(2H，d，J＝7.0Hz)，4.45(3H，s)，3.96(4H，s)，1.53(6H，s)；HRMS(ESI)C₁₉H₂₁FN₇O₄calculated value of (M + H): 430.1639, measurement: 430.1649.

example 107

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- (1-methyl-1H-tetrazol-5-yl) phenyl]Methyl radical]4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-following the procedures described in the syntheses of examples 1, 19 and 20, one may proceed from intermediate 25, 3-hydroxy-9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ]][1，4]Oxazine-2-carboxylic acid ethyl ester and intermediate 62, (4-fluoro-2- (1-methyl-2H-tetrazol-5-yl) phenyl) methylamine hydrochloride the title compound was prepared. An off-white solid; ¹H NMR(500MHz，CDCl₃)δppm：11.83(1H，s)，9.17(1H，t，J＝5.8Hz)，7.75(1H，dd，J＝8.4，5.7Hz)，7.30(1H，t，J＝8.2Hz)，7.14(1H，d，J＝7.9Hz)，4.43(2H，d，J＝6.7Hz)，4.14-4.16(3H，m)，4.00(4H，s)，1.67(6H，s)；HRMS(ESI)C₁₉H₂₁FN₇O₄Calculated value of (M + H): 430.1639, measurement: 430.1619.

example 108-

Example 108-112 can be prepared from the intermediate 25, 3-hydroxy-9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ] [1, 4] oxazine-2-carboxylic acid ethyl ester and the indicated amine following the procedures described for the syntheses of examples 1, 19 and 20.

Example 108

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [2- [ (dimethylamino) sulfonyl ] carbonyl]-4-fluorophenyl group]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-the title compound can be prepared from intermediate 48, 2- (aminomethyl) -5-fluoro-N, N-dimethylbenzenesulfonamide. A white solid;¹H NMR(500MHz，CDCl₃)δppm：11.83(1H，s)，8.64(1H，t，J＝6.6Hz)，7.68(1H，dd，J＝8.6，5.5Hz)，7.50(1H，dd，J＝8.2，2.8Hz)，7.26-7.30(1H，m)，4.80(2H，d，J＝7.0Hz)，3.99(4H，s)，2.91(6H，s)，1.58(6H，s)；HRMS(ESI)C₁₉H₂₄FN₄O₆calculated value of S (M + H): 455.1401, measurement: 455.1402.

example 109

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- [ (methylamino) sulfonyl ] carbonyl]Phenyl radical]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-the title compound can be prepared from intermediate 52, 2- (aminomethyl) -5-fluoro-N-methylbenzenesulfonamide hydrochloride. An off-white solid;¹H NMR(300MHz，CDCl₃)δppm：11.69(1H，s)，8.55(1H，br)，7.58-7.67(2H，m)，7.24-7.29(1H，m)，4.87-4.97(1H，br)，4.82(2H，d，J＝6.2Hz)，3.97(4H，s)，2.71(3H，d，J＝4.4Hz)，1.56(6H，s)；HRMS(ESI)C₁₈H₂₂FN₄O₆calculated value of S (M + H): 441.1244, measurement: 441.1237.

example 110

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [2- (aminosulfonyl) -4-fluorophenyl ]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-the title compound can be prepared from intermediate 56, 2- (aminomethyl) -5-fluorobenzenesulphonamide hydrochloride. An off-white solid;¹H NMR(300MHz，DMSO-D6)δppm：11.92(1H，s)，9.33(1H，t，J＝6.4Hz)，7.66(1H，dd，J＝8.8，2.2Hz)，7.41-7.52(2H，m)，4.89(2H，d，J＝6.2Hz)，3.98(2H，t，J＝4.9Hz)，3.83(2H，t，J＝4.9Hz)，3.37(2H，br)，1.55(6H，s)；HRMS(ESI)C₁₇H₂₀FN₄O₆calculated value of S (M + H): 427.1088, measurement: 427.1082.

example 111

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [2- (1-azetidinylsulfonyl) -4-fluorophenyl]Methyl radical]The title compound may be prepared from (2- (azetidin-1-ylsulfonyl) -4-fluorophenyl) methylamine, which is synthesized according to the procedure used to prepare intermediate 48. A white solid, a solid which is,¹H NMR(500MHz，CDCl₃)δppm 11.86(1H，s)，8.57(1H，t，J＝6.3Hz)，7.65-7.72(2H，m)，7.26-7.31(1H，m)，4.82(2H，d，J＝6.7Hz)，3.99(4H，s)，3.96(4H，t，J＝7.8Hz)，2.23-2.32(2H，m)，1.58(6H，s)；HRMS(ESI)C₂₀H₂₄FN₄O₆calculated value of S (M + H): 467.1401, measurement: 467.1398.

example 112

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, 4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-N- [ [2- (methylthio) phenyl ] methyl ester]Methyl radical]Prepared as described in the synthesis of example 100. A white solid, a solid which is,¹H NMR(300MHz，CDCl₃)δppm：1.55(6H，s)，2.50(3H，s)，3.98(4H，s)，4.65(2H，d，J＝6.6Hz)，7.1-7.4(3H，m)，8.11(1H，t，J＝5.9Hz)，11.94(1H，s)；LC/MS m/z 376(M+H)。

example 113

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, 4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-N- [ [2- (methylsulfinyl) phenyl]Methyl radical]EXAMPLE 112, pyrimido [2, 1-c][1，4]Oxazine-2-carboxamide, 4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-N- [ [2- (methylthio) phenyl ] methyl ester ]Methyl radical]-4-oxo- (112 mg, 0.3mmol) of CH₂Cl₂To the solution (5 ml) was added 3-chloroperbenzoic acid (69 mg, 0.3 mmol; 77%, Aldrich) and the mixture was stirred for 5 minutes. After removal of the solvent in vacuo, the residue was purified by preparative reverse phase HPLC (YMC, ODS, 8-15% CH)₃CN/H₂O-0.1％CF₃CO₂H) Purification, after trituration with ether, afforded 58mg (0.16mmol, 53% yield) of the title compound as a white powder.¹H NMR(300MHz，CDCl₃)δppm：1.56(6H，s)，2.80(3H，s)，3.98(4H，s)，4.60-4.94(2H，m)，7.38-7.61(3H，m)，7.65-7.89(1H，m)，8.34(1H，t，J＝6.4Hz)，11.82(1H，s)。HRMS(ESI)C₁₈H₂₂N₃O₅Calculated value of S (M + H): 392.1280, measurement: 392.1281.

example 114

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, 4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-N- [ [2- (methylsulfonyl) phenyl ] methyl ester]Methyl radical]EXAMPLE 112, pyrimido [2, 1-c][1，4]Oxazine-2-carboxamide, 4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-N- [ [2- (methylthio) phenyl ] methyl ester]Methyl radical]-4-oxo- (112 mg, 0.3mmol) of CH₂Cl₂To the solution (5 ml) was added 3-chloroperbenzoic acid (140 mg, 0.62 mmol; 77%, Aldrich) and the mixture was stirred for 20 hours. After removal of the solvent in vacuo, the residue was purified by preparative reverse phase HPLC (YMC, ODS, 15% CH)₃CN/H₂O-0.1％CF₃CO₂H) After purification and trituration with ether, 61mg (0.15mmol, 50% yield) of the title compound are provided as a white powder.¹H NMR(300MHz，CDCl₃)δppm：1.56(6H，s)，3.14(3H，s)，3.96(4H，s)，4.83(2H，d，J＝7.0Hz)，7.39-7.57(1H，m)，7.60-7.68(2H，m)，8.02(1H，d，J＝8.4Hz)，8.65(1H，t，J＝7.0Hz)，11.78(1H，brs)。HRMS(ESI)C₁₈H₂₂N₃O₆Calculated value of S (M + H): 408.1229, measurement: 408.1217.

Example 115-

Example 115-116 can be prepared from the indicated intermediates by hydrogenolysis or trifluoroacetic acid mediated hydrolysis.

Example 115

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- (2-thiazolylamino) phenyl]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-can be synthesized from intermediate 163, N- (4-fluoro-2- (thiazol-2-ylamino) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7,9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide the title compound was prepared.¹H NMR(400MHz，DMSO-d6)δppm：11.97(1H，brs)，9.72(1H，brs)，9.39(1H，t，J＝6.3Hz)，8.14(1H，dd，J＝2.5，12.0Hz)，7.31-7.28(2H，m)，6.99(1H，d，J＝3.8Hz)，6.84(1H，ddd(dt)，J＝2.5，8.3Hz)，4.52(2H，d，J＝6.3Hz)，3.96-3.94(2H，m)，3.82-3.79(2H，m)，1.54(6H，s)LCMS(⁺ESI，M+H⁺)m/z 446。HRMS(ESI⁺)C₂₀H₂₁FN₅O₄S[M+H⁺]The calculated value of (a): 446.1298, respectively; measurement value: 446.1292.

example 116

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) amino]Phenyl radical]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-can be prepared from intermediate 164, N- (4-fluoro-2- (5-methyl-1, 3, 4-thiadiazol-2-ylamino) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ]][1，4]Oxazine-2-carboxamide the title compound was prepared.¹H NMR(400MHz，DMSO-d6)δppm：11.97(1H，brs)，9.66(1H，brs)，9.37(1H，brt，J＝6.1Hz)，7.99(1H，brd)，7.29(1H，brt，J＝7.1Hz)，6.88(1H，ddd(dt)，J＝2.5，8.0Hz)，4.52(2H，d，J＝6.1Hz)，3.97-3.94(2H，m)，3.82-3.80(2H，m)，2.55(3H，s)，1.54(6H，s)；LCMS(⁺ESI，M+H⁺)m/z 461.HRMS(ESI⁺)C₂₀H₂₂FN₆O₄S[M+H⁺]The calculated value of (a): 461.1407, respectively; measurement value: 461.1425.

example 117

6H-pyrimido [2, 1-c][1，4]Oxazazem-2-carboxamide, N- [ [ 4-fluoro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ]Methyl radical]-4, 7, 8, 10-tetrahydro-3-hydroxy-10, 10-dimethyl-4-oxo-a solution of intermediate 33, 2- (2- (3-chloropropoxy) propan-2-yl) -5-hydroxy-6-oxo-1, 6-dihydropyrimidine-4-carboxylic acid ethyl ester (0.208 g, 0.65mmol) in anhydrous dimethylformamide (2 ml) was stirred with anhydrous potassium carbonate (0.366 g, 2.6mmol) at 60 ℃ for 16 h. It was treated with intermediate 69, (4-fluoro-2- (1H-1, 2, 4-triazol-1-yl) phenyl) methylamine hydrochloride (0.451 g, 2.08mmol) and triethylamine (0.5 ml, 3.6mmol) and stirring was continued at 100 ℃ for 16H. The solvent was removed by rotary evaporator and preparative HPLC by reverse phase (C18, 10% -35% CH)₃CN/H₂O-0.1% trifluoroacetic acid). The product-containing fractions were pooled and concentrated by rotary evaporator. The resulting aqueous solution was extracted with ethyl acetate (2 × 50mL) and the combined organic fractions were dried (sodium sulfate), filtered and concentrated to dryness. The resulting residue was triturated with a minimum volume of 95% ethanol and the solid collected by filtration to give 103mg (0.24mmol, 37% yield) of the title compound as a white solid:¹H NMR(500MHz，CDCl₃)δppm：11.96(1H，br s)，8.83(1H，t，J＝6.6Hz)，8.46(1H，s)，8.17(1H，s)，7.71(1H，dd，J＝8.5，6.1Hz)，7.21(1H，dt，J＝8.2，2.6Hz)，7.11(1H，dd，J＝8.4，2.6Hz)，4.55(2H，br)，4.44(2H，d，J＝6.7Hz)，3.67(2H，t，J＝6.4Hz)，1.91-1.97(2H，pJ＝6.10Hz)，1.63(6H，s).¹³C NMR(125.76MHz，CDCl₃)δppm：167.97，163.19，161.20，158.28，153.35，152.90，147.34，143.94，136.89，134.45，134.37，128.65，128.62，125.01，117.09，116.93，112.42，112.23，82.46，60.88，39.13，38.56，27.73，27.36。HRMS[M+H]⁺C₂₀H₂₂N₆O₄calculated value of F: 429.16867, respectively; measurement value:429.1687.C₂₀H₂₁N₆O₄F·0.06H₂analytical calculation of O: c, 55.93; h, 4.96; n, 19.57, F, 4.42; measurement value: c, 55.80; h, 5.14; n, 19.74, F, 4.46.

Example 118

6H-pyrimido [2, 1-c][1，4]Oxazazem-2-carboxamide, N- [ [ 4-fluoro-2- [ (methylamino) carbonyl ] carbonyl]Phenyl radical]Methyl radical]-4, 7, 8, 10-tetrahydro-3-hydroxy-10, 10-dimethyl-4-oxo-following the procedure described in example 46, starting from intermediate 148, N- (4-fluoro-2- (methylcarbamoyl) benzyl) -3- (benzyloxy) -10, 10-dimethyl-4-oxo-6, 7, 8, 10-tetrahydro-4H-pyrimido [2, 1-c ]][1，4]Oxazazem-2-carboxamide the title compound was prepared. A white powder;¹H NMR(500MHz，DMSO-D6)δppm：12.17(1H，s)，9.23(1H，t，J＝6.4Hz)，8.56(1H，q，J＝4.3Hz)，7.41(1H，dd，J＝8.6，5.8Hz)，7.34(1H，dd，J＝9.2，2.8Hz)，7.30(1H，dt，J＝8.6，2.8Hz)，4.55(2H，d，J＝6.4Hz)，4.37(2H，br)，3.64(2H，t，J＝6.4Hz)，2.80(3H，d，J＝4.6Hz)，1.80-1.86(2H，m)，1.57(6H，s)；HRMS[M+H]⁺C₂₀H₂₃N₄O₅calculated value of F: 419.17308, respectively; measurement value: 419.1713.

example 119

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, 9, 9-diethyl-N- [ [ 4-fluoro-2- (1H-1, 2, 4-triazol-1-yl) phenyl]Methyl radical]4, 6, 7, 9-tetrahydro-3-hydroxy-4-oxo-following the procedures described in examples 1, 19 and 20, one may proceed from intermediate 31, 9, 9-diethyl-3-hydroxy-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ]][1，4]Oxazine-2-carboxylic acid ethyl ester and intermediate 69, (4-fluoro-2- (1H-1, 2, 4-triazol-1-yl) phenyl) methylamine hydrochloride the title compound was prepared. A white powder;¹H NMR(500MHz，CDCl₃)δppm：11.89(1H，br s)，8.81(1H，t，J＝6.6Hz)，8.46(1H，s)，8.15(1H，s)，7.69(1H，dd，J＝8.6，5.8Hz)，7.22(1H，dt，J＝8.2，2.6Hz)，7.12(1H，dd，J＝8.4，2.6Hz)，4.45(2H，d，J＝6.7Hz)，3.95-4.02(4H，m)，1.95-2.03(2H，m)，1.87-1.96(2H，m)，0.86(6H，t，J＝7.5Hz).¹³C NMR(125.76MHz，CDCl₃)δppm：167.98，163.19，161.20，157.88，152.81，151.29，146.05，143.97，137.00，136.93，134.28，134.21，128.62，128.59，125.85，117.10，116.94，112.58，112.38，80.93，58.63，43.02，39.20，31.43，7.86。HRMS[M+H]⁺C₂₁H₂₄N₆O₄calculated value of F: 443.18432, respectively; measurement value: 443.1845.

example 120

Pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide, 9, 9-diethyl-N- [ [ 4-fluoro-2- [ (methylamino) carbonyl ] phenyl ] methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-4-oxo-intermediate 31, 9, 9-diethyl-3-hydroxy-4-oxo-4, 6, 7, 9-tetrahydropyrimido [2, 1-c ] [1, 4] oxazine-2-carboxylic acid ethyl ester (0.228 g, 0.77mmol) in anhydrous dimethylformamide (5 ml) was treated with anhydrous potassium carbonate (0.279 g, 2.0mmol) followed by benzyl bromide (0.145 g, 0.85mmol) and the mixture was stirred for 16 h. The mixture was treated with lithium hydroxide (0.042g, 1.75mmol) and water (2mL) and stirred for 20 h. The reaction mixture was diluted with water (30mL) and adjusted to pH 1 with 6N hydrochloric acid. The crude product was extracted with ethyl acetate (2 × 30 mL). The combined organic layers were dried (sodium sulfate), filtered and concentrated to dryness.

A solution of this material in dry dimethylformamide (4mL) was treated with HATU (0.32g, 0.83mmol) and stirred for 10 min. The reaction mixture was treated with intermediate 39, 2-aminomethyl-5-fluoro-N-methyl-benzamide trifluoroacetate, (0.281 g, 0.94mmol) followed by dimethylaminopyridine, DMAP, (0.140 g, 1.125mmol) and stirred at 60 ℃ for 3 h. The solvent was removed using a rotary evaporator and the residue was purified by flash column chromatography eluting with 50% to 60% ethyl acetate in hexanes. The product containing fractions were pooled and concentrated to dryness to give a white glassy solid. The sample (approximately 10mg) was further dried in vacuo, and the remainder was used in the following reaction:¹H NMR(500MHz，CDCl₃)δppm：8.47(1H，t，J＝6.2Hz)，7.36-7.45(3H，m)，7.23-7.27(2H，m)，7.10(1H，dd，J＝8.8，2.9Hz)，7.04(1H，dt，J＝8.3，2.7Hz)，6.60-6.69(1H，br)，5.25(2H，s)，4.50(2H，d，J＝6.2Hz)，3.94(4H，s)，2.95(3H，d，J＝5.1Hz)，1.90-2.02(5H，m)，0.75-0.82(6H，m)。

a solution of the above compound in dichloromethane (5mL) and trifluoroacetic acid (5mL) was stirred for 2 hours. The solvent was removed and the crude product was passed through reverse phase preparative HPLC (C-18 column, 10% to 40% CH)₃CN/H₂O-0.1％CF₃CO₂H) And (5) purifying. The product containing fractions were pooled and concentrated in vacuo. The resulting aqueous suspension was extracted with dichloromethane (4x100mL) and the combined organic extracts were dried (sodium sulfate), filtered and concentrated to dryness. The residue was taken up in ethanol/H₂Recrystallization from O provided 0.012g (0.028mmol, 4% yield) of the title compound as a white solid. ¹HNMR(500MHz，DMSO-D6)δppm：12.10(1H，s)，9.30(1H，t，J＝6.4Hz)，8.52(1H，m)，7.39(1H，dd，J＝8.4，5.7Hz)，7.26-7.35(2H，m)，4.57(2H，d，J＝6.4Hz)，3.94(2H，t，J＝4.9Hz)，3.84(2H，t，J＝4.9Hz)，2.79(3H，d，J＝4.6Hz)，1.99-2.09(2H，m)，1.81-1.91(2H，m)，0.77(6H，t，J＝7.3Hz).¹³C NMR(125.76MHz，DMSO-D6)δppm：167.86，167.57，159.65，156.86，151.21，145.10，137.26，137.21，132.52，130.75，130.68，125.39，116.69，116.52，114.71，114.53，80.04，57.60，42.62，40.05，30.04，26.03，7.47。HRMS[M+H]⁺ C₂₁H₂₆N₄O₅Calculated value of F: 433.18873, respectively; measurement value: 433.1872.

example 121-

Example 121-130 can be prepared from the indicated intermediates following the procedures described for examples 121 and 122. Alternatively, this example may be formed by treating the indicated intermediate with trifluoroacetic acid.

Example 121

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- (2-oxo-1-piperidinyl) phenyl]Methyl radical]To intermediate 145 in ethyl acetate (10ml), N- (4-fluoro-2- (2-oxopiperidin-1-yl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ] was added][1，4]To oxazin-4 (9H) -one (100 mg, 0.187mmol) was added palladium (10% on activated carbon) (30 mg). The reaction mixture was stirred at 23 ℃ under a hydrogen atmosphere (balloon) for 3 hours. The catalyst was removed by filtration through celite. The filtrate was concentrated in vacuo and the resulting residue triturated with ether (10ml) and dried in vacuo to give 37mg (45% yield) of the title compound. IR (KBr, cm)^-1)3397，2943，1636，1539，1173.¹HNMR 400MHz(MeOD)δppm：7.51(1H，dd，(t)，J＝7.0Hz)，7.11(2H，m)，4.70(1H，d，J＝15.3Hz)，4.24(1H，d，J＝15.3Hz)，4.05(2H, m), 3.96(2H, m'), 3.73(1H, m), 3.62(1H, m), 2.63-2.48(2H, m), 2.03(4H, width s), 1.62(6H, s). LCMS (M + H) ⁺m/z 445。

Example 122

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, 4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-N- [ [2- (2-oxo-3-oxazolidinyl) phenyl]Methyl radical]To intermediate 161, N- (4-fluoro-2- (2-oxopiperidin-1-yl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ] in ethyl acetate (10ml)][1，4]To oxazin-4 (9H) -one (100 mg, 0.187mmol) was added palladium (10% on activated carbon) (30 mg). The reaction mixture was stirred at 23 ℃ under a hydrogen atmosphere (balloon) for 3 hours. The catalyst was removed by filtration through celite. The filtrate was concentrated in vacuo and the resulting residue triturated with ether (10ml) and dried in vacuo to give 37mg (45%) of the title compound. IR (KBr, cm)^-1)3397，2943，1636，1539，1173.¹HNMR 400MHz (MeOD) δ ppm: 7.51(1H, dd, (t), J ═ 7.0Hz), 7.11(2H, m), 4.70(1H, d, J ═ 15.3Hz), 4.24(1H, d, J ═ 15.3Hz), 4.05(2H, m), 3.96(2H, m'), 3.73(1H, m), 3.62(1H, m), 2.63-2.48(2H, m), 2.03(4H, width s), 1.62(6H, s). LCMS (M + H)⁺m/z 445。

Example 123

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, 4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-N- [ [2- (2-oxo-1-azetidinyl) phenyl ]Methyl radical]From intermediate 162, N- (2-)(2-Oxoazetidin-1-yl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c][1，4]Oxazine-2-carboxamide the title compound was prepared.¹HNMR(400MHz，CDCl₃)δppm：12.15(1H，brs)，9.65(1H，brs)，7.33-7.20(4H，m)，4.54(2H，d，J＝6.6Hz)，3.96-3.94(2H，m)，3.82-3.79(2H，m)，3.76(2H，t，J＝4.3Hz)，3.10(2H，t，J＝4.3Hz)，1.53(6H，s)；LCMS(⁺ESI，M+H⁺)m/z 399。

Example 124

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- (2-oxo-1-pyrrolidinyl) phenyl]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo can be synthesized from intermediate 159, N- (4-fluoro-2- (2-oxopyrrolidin-1-yl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide the title compound was prepared. IR (KBr, cm)^-1)3432，2980，1689，1543，1183.¹HNMR 400MHz(MeOD)δppm：7.53(1H，dd，J＝9.2，6.3Hz)，7.11(2H，m)，4.52(2H，s)，4.05(2H，t，J＝5.0Hz)，3.96(2H，m)，3.87(2H，t，J＝7.1Hz)，2.61(2H，t，J＝8.0Hz)，2.26(2H，m)，1.6(6H，s).HRMS(ESI⁺)C₂₁H₂₄FN₄O₅[M+H⁺]The calculated value of (a): 431.1731, respectively; measurement value: 431.1714.

example 125

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- (hexahydro-2-oxo-1H-aza-1-yl) phenyl]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-can be prepared from intermediate 160, N- (4-fluoro-2- (2-oxoazepan-1-yl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2 carboxamide the title compound was prepared. IR (KBr, cm)^-1)3392，2934，1646，1522，1292.¹HNMR 400MHz (MeOD) δ ppm: 7.50(1H, width s), 7.06(1H, width s), 7.01(1H, d, J ═ 9.0Hz), 4.64(1H, d, J) _AB＝15.0Hz)，4.31(1H，d，J_AB＝15Hz)，4.04(2H，m)，3.96(3H，m)，3.66(1H，m)，2.86(1H，m)，2.65(1H，m)，2.03-1.80(6H，m)，1.62(6H，s)，(2H，m)。LCMS(M+H)⁺m/z 459。

Example 126

N- (4-fluoro-2- (2-oxoazetidin-1-yl) benzyl) -3-hydroxy-9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide may be prepared from intermediate 146, N- (4-fluoro-2- (2-oxoazetidin-1-yl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ]][1，4]Oxazine-2-carboxamide the title compound was prepared.¹HNMR(400MHz，DMSO-d₆)δ：9.46(d，J＝6.4Hz)，7.34(1H，dd，J＝8.5，6.4Hz)，7.25(1H，dd，J＝10.2，2.6Hz)，7.08(1H，td，J＝8.5，2.6Hz)，6.90(1H，m)，4.52(2H，d，J＝6.4Hz)，3.96(2H，t，J＝5.0Hz)，3.83-3.77(4H，m)，3.11(2H，t，J＝5.0Hz)，1.53(6H，s)；LCMS(M+H)⁺m/z 417。

Example 127

N- (4-fluoro-2- (2-oxooxazolidin-3-yl) benzyl) -3-hydroxy-9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide may be prepared from intermediate 165, N- (4-fluoro-2- (2-oxooxazolidin-3-yl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ]][1，4]Oxazine-2-carboxamide the title compound was prepared.¹H NMR(400MHz，DMSO-d₆)δppm：12.12(1H，s)，9.34(1H，t，J＝6.2Hz)，7.41(1H，m)，7.23(1H，td，J＝8.6，2.5Hz)，4.48(4H，m)，4.06(2H，t，J＝7.7Hz)，3.97(2H，t，J＝5.0Hz)，3.83(2H，t，J＝5.0Hz)，1.55(6H，s)。LCMS(M+H)⁺m/z 433。

Example 128

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- [ (2R) -2- (hydroxymethyl) -5-oxo-1-pyrrolidinyl]Phenyl radical]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-can be prepared from intermediate 192, (R) -N- (4-fluoro-2- (2- (hydroxymethyl) -5-oxopyrrolidin-1-yl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c) ][1，4]Oxazine-2-carboxamide the title compound was prepared. IR (KBr, cm)^-1)3441，2979，1684，1540，1172.¹HNMR 400MHz (MeOD) δ ppm: 7.56(1H, m), 7.15(2H, m), 4.86-4.31(3H, m), 4.06(2H, t, 5.0Hz), 3.98(2H, t, 5.0Hz), 3.57(2H, width s), 2.72-2.55(2H, m), 2.41(1H, m), 2.25(1H, m), 1.62(6H, s). LCMS (M + H)⁺m/z 461。

Example 129

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [2- [ (2R) -2- [ (acetoxy) methyl]-5-oxo-1-pyrrolidinyl]-4-fluorophenyl group]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-can be prepared from intermediate 193, (R) - (1- (2- ((3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazin-2-carboxamido) methyl) -5-fluorophenyl) -5-oxopyrrolidin-2-yl) methyl acetate the title compound was prepared.¹HNMR 400MHz(MeOD)δppm：7.58(1H，m)，7.21-7.04(2H，m)，5.24(2H，s)，4.66-4.21(3H，m)，4.02-3.92(5H，m)，2.73-2.34(3H，m)，2.23-1.61(5H，m)，1.60(6H，s)。LCMS(M+H)⁺m/z 503。

Example 130

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- [ (2S) -2- (hydroxymethyl) -5-oxo-1-pyrrolidinyl]Phenyl radical]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-can be synthesized from intermediate 167, (S) -N- (2- (2- ((tert-butyldimethylsilyloxy) methyl) -5-oxopyrrolidin-1-yl) -4-fluorobenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c) ][1，4]Oxazine-2-carboxamide the title compound was prepared.¹HNMR 400mhz (dmso) δ ppm: 7.36(1H, m), 7.18(2H, m), 5.07(1H, width s), 4.66-4.11(3H, m), 3.95(2H, t, 5.1Hz), 3.80(2H, t, 5.1Hz), 3.39(2H, s), 2.43(1H, m), 2.25(1H, m), 2.08(1H, m), 1.51(6H, s). LCMS (M + H)⁺m/z 461。

Example 131

(R) -N- (2- (2- ((dimethylamino) methyl) -5-oxopyrrolidin-1-yl) -4-fluorobenzyl) -3-hydroxy-9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide to intermediate 195, (R) -N- (2- (2- (azidomethyl) -5-oxopyrrolidin-1-yl) -4-fluorobenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c][1，4]To a solution of oxazine-2-carboxamide (0.050 g, 0.087mmol) in MeOH (5 ml) was added activated palladium on carbon (10%) (0.020 g) and formaldehyde (0.30 ml, 10 mmol). The reaction mixture was heated at 23 ℃ under H₂Stirring under (balloon) conditions for 5 hours. The palladium/activated carbon was then removed by filtration and the solvent was evaporated in vacuo. The residue was purified by preparative HPLC (YMC-Pack C-18) to give the title compound (0.013g, 29% yield):¹H NMR(400MHz，MeOD)δppm：7.56(1H，dd，J＝7.0Hz)，7.30-7.17(2H，m)，4.70(2H，m)，4.15(1H，d，J＝15.3Hz)，4.07(2H，m)，3.99(2H，m，)，3.54(1H，m)，2.93(6H，s)，2.84-2.64(4H，m)，2.20(1H，m)，1.65(6H，s)。HRMS C₂₄H₃₁N₅O₅calculated value of F: 488.2309, respectively; measurement value: 488.2328.

example 132

(R) -N- (2- (2- (azidomethyl) -5-oxopyrrolidin-1-yl) -4-fluorobenzyl) -3-hydroxy-9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide to intermediate 195, (R) -N- (2- (2- (azidomethyl) -5-oxopyrrolidin-1-yl) -4-fluorobenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ] at 23 deg.C][1，4]Oxazine-2-carboxamide (0030 g, 0.052mmol) in CH₂Cl₂(1 ml) solution CF was added₃CO₂H (1 ml). Will be reversedThe mixture was stirred at 23 ℃ for 3 hours. Toluene (20ml) was then added and the solvent evaporated in vacuo. The residue was purified by preparative HPLC (YMC-Pack C-18) to give the title compound (0.008g, 31%):¹H NMR(400MHz，MeOD)δppm：7.55(1H，dd，J＝6.6Hz)，7.16(2H，m)，4.47-4.24(2H，m)，4.05(2H，m)，3.98(2H，m)，3.56(2H，s)，2.70-2.45(4H，m)，2.11(1H，m)，1.64(3H，s)，1.61(3H，s)。HRMS C₂₂H₂₅N₇O₅calculated value of F: 486.1901, respectively; measurement value: 486.1923.

example 133

(R) -N- (2- (2- (aminomethyl) -5-oxopyrrolidin-1-yl) -4-fluorobenzyl) -3-hydroxy-9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide may be prepared by intermediate 195, (R) -N- (2- (2- (azidomethyl) -5-oxopyrrolidin-1-yl) -4-fluorobenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c][1，4]Hydrogenolysis of oxazine-2-carboxamides (H) ₂10% pd-C) to prepare the title compound.¹H NMR(400MHz，MeOD)δppm：7.54(1H，dd，J＝7.0Hz)，7.25-7.13(2H，m)，4.62(2H，m)，4.17(1H，d，J＝15.6Hz)，4.07(2H，m)，3.99(2H，m，)，3.23(2H，d，J＝3.1Hz)，2.79-2.59(3H，m)，2.14(1H，m)，1.66(6H，s)。HRMSC₂₂H₂₇N₅O₅Calculated value of F: 460.1996, respectively; measurement value: 460.2014.

example 134-

Example 134-136 can be prepared from the indicated intermediates by hydrogenolysis or trifluoroacetic acid mediated hydrolysis.

Example 134

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (2-amino-4-fluorophenyl) methyl]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-can be prepared from intermediate 169, N- (2-amino-4-fluorobenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ]][1，4]Oxazine-2-carboxamide the title compound was prepared. IR (KBr, cm)^-1)3383，2979，1636，1540，1288.¹HNMR 400MHz (MeOD) δ ppm: 7.14(1H, dd, J ═ 7.3Hz), 6.44-6-31(2H, m), 4.69(1H, width s), 4.48(2H, width s), 4.03(2H, t, J ═ 4.6Hz), 3.95(2H, t, J ═ 4.6Hz), 1.62(6H, s). HRMS (ESI)⁺)C₁₇H₂₀FN₄O₄[M+H⁺]The calculated value of (a): : 363.1469, respectively; measurement value: 363.1454.

example 135

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [2- (acetylamino) -4-fluorophenyl]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-can be synthesized from intermediate 189, N- (2-acetylamino 4-fluorobenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ] ][1，4]Oxazine-2-carboxamide the title compound was prepared.¹HNMR 400MHz (MeOD) δ ppm: 7.66(1H, width d, J ═ 10.5Hz), 7.40(1H, width t, 6.5Hz), 6.87(1H, width t, J ═ 6.5Hz), 4.55(2H, m), 4.02(2H, t, J ═ 5.0Hz), 3.92(2H, t, J ═ 5.0Hz), 2.28(3H, s), 1.62(6H, s). HRMS (ESI)⁺)C₁₉H₂₂FN₄O₅[M+H⁺]The calculated value of (a): : 405.1574, respectively; measurement value: 405.1571.

example 136

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [2- (acetylmethylamino) -4-fluorophenyl]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-can be prepared from intermediate 168, N- (4-fluoro-2- (N-methylacetamido) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c- ] -][1，4]Oxazine-2-carboxamide the title compound was prepared. IR (KBr, cm)^-1)3407，2979，1653，1539，1116.¹HNMR 400MHz(MeOD)δppm：7.53(1H，m)，7.24-7.06(2H，m)，4.61-4.45(2H，m)，4.08(2H，t，J＝5.1Hz)，4.00(2H，t，J＝5.1Hz)，3.40(0.6H，s)，3.25(2.4H，s)，1.85(2.4H，s)，1.81(0.6H，s)，1.65(2.4H，s)，1.64(2.4H，s)，1.62(1.2H，s)。LCMS(M+H)⁺m/z 419。

Example 137

N- (2- (2, 5-dioxo-2H-pyrrol-1 (5H) -yl) benzyl) -3-hydroxy-9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide to N- (2-aminobenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c][1，4]To a solution of oxazine-2-carboxamide (0050 g, 0.114mmol) in acetic acid (1.5 ml) was added maleic anhydride (0.013g, 0.131mmol) and the reaction mixture was stirred in a sealed tube at 115 ℃ for 18 h. Acetic acid was evaporated in vacuo and the residue was purified by preparative HPLC (YMC-Pack C-18) to give the title compound (0.013g, 27% yield): ¹H NMR(400MHz，CDCl₃) δ ppm: 8.03(1H, width t), 7.59(1H, m), 7.48(2H, m), 7.19(1H, m), 6.92(2H, s), 4.48(2H, d, J ═ 6.1Hz), 4.04(4H, s), 1.62(6H, s);HRMSC₂₁H₂₁N₄O₆the calculated value of (a): 425.1461, respectively; measurement value: 425.1451.

example 138

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- (benzo [ b ]]Thien-7-ylmethyl) -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-to intermediate 147, N- (benzo [ b ] b at 23 deg.C]Thien-7-ylmethyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide (60 mg, 0.13mmol) to which CF was added₃CO₂H (2 ml). The reaction mixture was stirred at 23 ℃ for 1.5 hours. Toluene (20ml) was then added and the solvent evaporated in vacuo. The residue was purified by preparative HPLC (YMC-Pack C-18) to give the title compound (0.017g, 34% yield):¹H NMR(400MHz，CDCl₃) δ: 8.00(1H, width t), 7.86(1H, d, J ═ 8.0Hz), 7.51-7.28(3H, m), 4.93(2H, d, J ═ 3.9Hz), 4.05(4H, s), 1.58(6H, s). HRMS C₁₉H₂₀N₃O₄Calculated value of S: 386.1175, respectively; measurement value: 386.1165.

example 139

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (1, 1-benzenedio [ b ] oxide]Thien-7-yl) methyl]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-to intermediate 196, N- (benzo [ b ] b at 23 ℃ ]Thiophene-1, 1-dione-7-ylmethyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]To oxazine-2-carboxamide (0.080 g, 0.16mmol) was added CF₃CO₂H (2 ml). The reaction mixture was stirred at 23 ℃ for 2.5 hours. Toluene (20ml) was then added and the solvent evaporated in vacuo. The residue was purified by crystallization from MeOH (10mL) to give the title compound (0.037g, 55% yield).¹H NMR(400MHz，DMSO-d₆)δ：11.87(1H，s)，9.44(1H，t，J＝6.5Hz)，7.65(2H，m)，7.51(1H，d，J＝7.0Hz)，7.42-7.37(2H，m)，4.84(2H，d，J＝6.2Hz)，3.99(2H，t，5.4Hz)，3.85(2H，t，J＝5.4Hz)，1.59(6H，s)。HRMSC₁₉H₂₀N₃O₆Calculated value of S: 418.1073, respectively; measurement value: 418.1078.

pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (2, 3-dihydro-1, 1-dioxobenzo [ b ]]Thien-7-yl) methyl]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-by reacting at H₂Reduction of palladium on activated carbon (10%) under conditions to obtain intermediate 196, N- (benzo [ b ]]Thiophene-1, 1-dione-7-ylmethyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide the title compound was obtained.¹HNMR(400MHz，CDCl₃)δ：8.65(1H，s)，7.58-7.49(2H，m)，7.32(1H，d，J＝7.0Hz)，4.86(2H，d，J＝6.8Hz)，3.99(4H，s)，3.54(2H，t，J＝6.8Hz)，3.40(2H，t，J＝6.8)，1.61(6H，s)。LCMS(M+H)⁺m/z 420。

Example 141-

Example 141-146, listed in Table 9, was prepared as described in examples 1, 19 and 20 from intermediate 25, 3-hydroxy-9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ]][1，4]Preparing oxazine-2-carboxylic acid ethyl ester. The compounds in the table were characterized by LCMS; (Xterra MS-C18, 4.6X50 mm); elution with 10% to 100% B, gradient 4.5 min, (a ═ H) ₂O-0.1％CF₃CO₂H，B＝CH₃CN-0.1％CF₃CO₂H) (ii) a The flow rate was 2.5 mL/min. UV detection at 220 nm). Product retention time (RT, min) and molecular weight (MS [ M +1 ]]) The results are shown in the table.

Table 9.

Example 147

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (2-bromophenyl) methyl]4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-following the procedures described in examples 1, 19 and 20, one may proceed from intermediate 25, 3-hydroxy-9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ]][1，4]Oxazine-2-carboxylic acid ethyl ester and 2-bromobenzylamine.¹H NMR(300MHz，DMSO-D6)δppm：1.58(s，1)，3.84(t，2)，3.98(t，2)，4.54(d，2)，7.25(m，2)，7.38(m，2)，7.64(d，1)，9.43(brm，1)，12.01(s，1)。

Example 148-

Example 148-200, listed in Table 10, was synthesized according to the following procedure. Adding Pd into a microwave reaction vessel provided with a stirring bar(Ph₃P)₄(30mg, 25. mu. mol), followed by addition of anhydrous dioxane (0.5 mL). To this was added example 147, pyrimido [2, 1-c ]][1，4]Oxazine-2-carboxamide, N- [ (2-bromophenyl) methyl]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo- (50 μmol), boronic acid or boronic ester reagent (200 μmol), anhydrous dioxane (0.5ml) and 2MK₃PO₄Aqueous solution (0.25 ml). The reaction vessel was flushed with nitrogen, capped and heated in a 120 ℃ microwave reactor for 10 minutes. The reaction mixture was filtered through a Whatman 0.45 μm syringe filter and the crude product was purified using preparative HPLC (Xterra MS-C18, 30X50 mm); elution with 30% to 100% B, 8 min gradient, (a ═ 10mM NH ₄OAC (aqueous solution), B ═ CH₃CN); flow rate 30mL/min, UV detection at 220 nm) to give the title compound.

The compounds in the table were characterized by LCMS; (Xterra MS-C18, 4.6X50 mm); elution with 10% to 100% B, gradient 4.5 min, (a ═ H)₂O-0.1％CF₃CO₂H，B＝CH₃CN-0.1％CF₃CO₂H) (ii) a Flow rate 2.5mL/min, UV detection at 220 nm). Product retention time (RT, min) and determined molecular weight (MS [ M +1 ]]) The results are shown in the table.

Table 10.

Example 201

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (4-fluoro-2, 5-dibromophenyl) methyl]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo (2, 5-dibromo-4-fluorophenyl) methylamine (1mmol), intermediate 25(0.268 g, 1mmol) and triethylamine (0.5 ml, 3.5mmol) in ethanol/dimethylformamide (1: 1, 3 ml) were mixed at 100 ℃ CThe mixture was heated for 6 hours. After cooling, the reaction mixture was purified by preparative HPLC to give the title compound (0.31g, 62% yield) as an off-white solid.¹H NMR(500MHz，CDCl₃)δppm：11.72(1H，s)，8.08(1H，t，J＝6.1Hz)，7.61(1H，d，J＝7.0Hz)，7.38(1H，d，J＝7.6Hz)，4.61(2H，d，J＝6.4Hz)，4.02(4H，s)，1.59(6H，s)。

Example 202

6H-pyrimido [2, 1-c][1，4]Oxazazem-2-carboxamide, N- [ [ 4-fluoro-2- (methylsulfonyl) phenyl]Methyl radical]-4, 7, 8, 10-tetrahydro-3-hydroxy-10, 10-dimethyl-4-oxo-. off-white solid.¹H NMR(500MHz，CDCl₃)δppm：11.77(1H，br s)，8.55(1H，t，J＝6.3Hz)，7.75(1H，dd，J＝8.1，2.6Hz)，7.72(1H，dd，J＝8.5，5.2Hz)，7.34(1H，td，J＝8.0，2.6Hz)，4.81(2H，d，J＝6.7Hz)，4.54(2H，br)，3.65(2H，t，J＝6.1Hz)，3.18(3H，s)，1.93(2H，m)，1.59(6H，s)；¹³CNMR(126MHz，CDCl₃)δppm：168.14，163.14，161.13，158.23，153.73，147.26，140.77，140.72，135.31，135.25，132.83，132.80，124.83，121.69121.52，117.63，117.43，82.56，60.80，45.14，40.24，38.62，27.76，27.35。HRMS(ESI)C₁₉H₂₃N₃O₆Calculated value of FS (M + H): 440.1292, respectively; measurement value: 440.1300.C ₁₉H₂₂N₃O₆FS·0.06H₂Analytical calculation of O: c51.80, H5.06, N9.54, F4.31; measurement value: c51.83, H4.97, N9.29, F4.12.

Example 203

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, 9, 9-diethyl-N- [ [ 4-fluoro-2- (methylsulfonyl) phenyl]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-4-oxo-.¹H NMR(500MHz，CDCl₃)δppm：11.74(1H，s)，8.54(1H，t，J＝6.6Hz)，7.75(1H，dd，J＝8.2，2.7Hz)，7.71(1H，dd，J＝8.5，5.2Hz)，7.34(1H，td，J＝8.0，2.6Hz)，4.82(2H，d，J＝7.0Hz)，3.94-4.00(4H，m)，3.17(3H，s)，1.93-2.00(2H，m)，1.84-1.92(2H，m)，0.83(6H，t，J＝7.3Hz)；¹³C NMR(126MHz，CDCl₃)δppm：168.26，163.13，161.11，157.83，151.66，146.05，140.69，140.64，135.13，135.07，132.80，132.77，125.63，121.65，121.48，117.65，117.45，81.03，58.51，45.14，43.08，40.33，31.38，7.87。HRMS(ESI)C₂₀H₂₅N₃O₆Calculated value of FS (M + H): 454.1448, respectively; measurement value: 454.1448.C₂₀H₂₄N₃O₆Analytical calculation of FS: c52.97, H5.33, N9.27, S7.07; measurement value: c53.01, H5.60, N9.10, S7.00.

Example 204

6H-pyrimido [2, 1-c][1，4]Oxazazem-2-carboxamide, N- [ [2- [ (dimethylamino) sulfonyl ] amino]-4-fluorophenyl group]Methyl radical]-4, 7, 8, 10-tetrahydro-3-hydroxy-10, 10-dimethyl-4-oxo-. light orange solid.¹H NMR(500MHz，CDCl₃)δppm：11.87(1H，br s)，8.59(1H，t，J＝6.4Hz)，7.69(1H，dd，J＝8.5，5.2Hz)，7.49(1H，dd，J＝8.2，2.4Hz)，7.26(1H，td，J＝7.7，3.2Hz)，4.79(2H，d，J＝6.7Hz)，4.53(2H，br)，3.65(2H，t，J＝6.1Hz)，2.90(6H，s)，1.89-1.96(2H，m)，1.57-1.61(6H，s)；¹³C NMR(126MHz，CDCl₃)δppm：168.03，162.71，160.70，158.29，153.57，147.23，138.51，138.46，135.30，135.25，132.70，132.67，124.99，120.40，120.24，116.93，116.73，82.59，60.79，58.57，40.26，38.58，37.59，27.74，27.36，18.55。HRMS(ESI)C₂₀H₂₆N₄O₆Calculated value of FS (M + H): 469.1557, respectively; measurement value: 469.1557.C₂₀H₂₆N₄O₆FS·CH₃CH₂Analytical calculation of OH: c51.29, H6.07, N10.89, S6.01, F3.69; measurement value: c51.29, H6.33, N10.85, S6.01, F3.54.

Example 205

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [2- [ (dimethylamino) sulfonyl ] carbonyl]-4-fluorophenyl group]Methyl radical]-9, 9-diethyl-4, 6, 7, 9-tetrahydro-3-hydroxy-4-oxo-. white glassy solid.¹H NMR(500MHz，CDCl₃)δppm：11.85(1H，br)，8.59(1H，t，J＝6.4Hz)，7.68(1H，dd，J＝8.5，5.2Hz)，7.49(1H，dd，J＝8.2，2.4Hz)，7.24-7.30(1H，m)，4.80(2H，d，J＝7.0Hz)，3.94-4.01(4H，m)，2.90(6H，s)，1.93-2.01(2H，m)，1.85-1.93(2H，m)，0.83(6H，t，J＝7.3Hz)；¹³CNMR(126MHz，CDCl₃)δppm：168.04，162.70，160.70，158.06，151.44，145.95，138.53，138.49，135.17，135.12，132.62，132.59，125.95，120.37，120.21，116.87，116.68，81.08，58.51，43.11，40.32，37.58，31.35，7.87。HRMS(ESI)C₂₁H₂₈N₄O₆Calculated value of FS (M + H): 483.1714, respectively; measurement value: 483.1702.C₂₁H₂₇N₄O₆FS·0.15 CF₃CO₂Analytical calculation of H: c51.20, H5.48, N11.21, F5.51, S6.42; measurement value: c51.10, H5.23, N11.21, F5.49, S6.32.

Example 206

6H-pyrimido [2, 1-c][1，4]Oxazazem-2-carboxamide, 4, 7, 8, 10-tetrahydro-3-hydroxy-10, 10-dimethyl-4-oxo-N- [ [2- (tetrahydro-1, 1-dioxido-2H-1, 2-thiazin-2-yl) phenyl]Methyl radical]A white-like solid.¹H NMR(500MHz，CDCl₃)δppm：12.18(1H，brs)，8.14-8.25(1H，br)，7.41-7.50(2H，m)，7.31-7.39(2H，m)，4.96(1H，dd，J＝14.0，8.9Hz)，4.54(2H，br s)，4.44(1H，dd，J＝14.2，3.2Hz)，3.83-3.92(1H，m)，3.65(2H，br)，3.38-3.46(1H，m)，3.18-3.28(2H，m)，2.32-2.42(2H，m)，1.89-1.98(4H，m)，1.55(6H，d，J＝15.9Hz)；¹³C NMR(126MHz，CDCl₃)δppm：168.22，158.38，153.54，147.32，138.80，137.00，130.88，129.47，129.29，127.68，125.17，82.60，60.74，54.15，51.05，39.11，38.63，27.76，27.73，27.36，25.04，24.32。HRMS(ESI)C₂₂H₂₉N₄O₆Calculated value of S (M + H): 477.1808, respectively; measurement value: 477.1794.C₂₂H₂₈N₄O₆S·0.5CH₃CH₂Analytical calculation of OH: c55.45, H5.92, N11.76, S6.73; measurement value: c55.36, H6.11, N11.46, S6.48.

Example 207

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, 4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-diethyl-4-oxo-N- [ [2- (tetrahydro-1, 1-dioxido-2H-1, 2-thiazin-2-yl) phenyl]Methyl radical]An off-white crystalline solid.¹H NMR(500MHz，CDCl₃)δppm：12.11(1H，br s)，8.20(1H，br)，7.42-7.48(2H，m)，7.33-7.40(2H，m)，4.93(1H，dd，J＝14.2，8.4Hz)，4.45(1H，dd，J＝14.2，3.8Hz)，3.94-4.02(4H，m)，3.87(1H，ddd，J＝13.0，9.9，3.7Hz)，3.39-3.46(1H，m)，3.15-3.24(2H，m)，2.29-2.46(2H，m)，1.79-2.04(6H，m)，0.81(3H，t，J＝6.7Hz)，0.78(3H，t，J＝7.3Hz)；¹³C NMR(126MHz，CDCl₃)δppm：168.25，157.91，151.43，146.14，139.14，136.81，130.79，129.46，129.25，127.90，125.96，81.15，58.55，54.22，51.09，43.03，39.57，31.21，25.03，24.34，7.82，7.68。HRMS(ESI)C₂₃H₃₁N₄O₆Calculated value of S (M + H): 491.1964, respectively; measurement value: 491.1953.C₂₃H₃₀N₄O₆Analytical calculation of S: c56.12, H6.48, N10.91, S6.24; measurement value: c56.14, H6.44, N11.07, S6.05.

Example 208

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (4-fluorophenyl) methyl]-4, 6, 7, 9-tetrahydro-3-hydroxy-9- [2- (methylthio) ethyl]Intermediate 141, N- (4-fluorobenzyl) -3- (benzyloxy) -9- (2- (methylthio) ethyl) -4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ] ][1，4]4ml CF of oxazine-2-carboxamide₃CO₂The H solution was stirred at 60 ℃ for 1 hour and then concentrated. The residue was dissolved in CH₂Cl₂Washed with water and then concentrated. Trituration with hexanes afforded the title compound as a solid.¹H NMR(300MHz，CDCl₃)δppm：12.03(1H，s)7.75(1H，m)6.84-7.40(4H，m)4.39-4.72(3H，m)4.04-4.36(2H，m)3.68-3.92(2H，m)2.49-2.73(2H，m)2.07-2.50(2H，m)2.02(3H，s)；HRMS(ESI)C₁₈H₂₀FN₃O₄Calculated value of S (M + H): 394.1237, measurement: 394.1234.

example 209

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (4-fluorophenyl) methyl]-4, 6, 7, 9-tetrahydro-3-hydroxy-9- [2- (methylsulfonyl) ethyl]Example 208, pyrimido [2, 1-c ]][1，4]Oxazine-2-carboxamide, N- [ (4-fluorophenyl) methyl]-4, 6, 7, 9-tetrahydro-3-hydroxy-9- [2- (methylthio) ethyl]-4-oxo- (40mg, 0.11mmol) of 2ml CH₂Cl₂The solution was treated with an excess of m-chloroperbenzoic acid (100mg, 0.4mmol) and stirred at room temperature for 20 h. The reaction mixture was washed with water and concentrated. By reverse phase HPLC (C18, 12% CH)₃CN/H₂O) purifying the crude product. The product containing fractions were concentrated and lyophilized to yield 5mg (12% yield) of the title compound.¹H NMR(300MHz，CDCl₃)δppm：12.10-12.27(1H，s)7.80-8.02(1H，m)7.25-7.39(2H，m)6.90-7.09(2H，m)4.05-4.72(5H，m)3.73-3.99(2H，m)3.02-3.34(2H，m)2.86-2.91(3H，s)2.35-2.78(2H，m)；HRMS(ESI)C₁₈H₂₀FN₃O₆Calculated value of S (M + H): 426.1135, measurement: 426.1143.

example 210

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [ 4-fluoro-2- (3-methyl-5-isoxazolyl) phenyl]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-can be synthesized from intermediate 180, N- (4-fluoro-2- (3-methylisoxazol-5-yl) benzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c) ][1，4]Oxazine-2-carboxamide the title compound was prepared.¹HNMR400MHz(CDCl₃)δppm：1.59(6H，s，2xCH₃)，2.42(3H，s，CH₃)，4.03(4H，s，2xCH₂)，4.74(2H，d，J＝6.6Hz，NCH₂) 6.40(1H, s, arene), 7.18(1H, m, arene), 7.32(1H, dd, J ═ 2.5Hz and J ═ 9.1Hz, arene), 7.59(1H, dd, J ═ 5.6Hz and J ═ 8.6Hz, arene), 8.29(1H, width t, NH), 11.87(1H, s, OH). HRMS (ESI)⁺)C₂₁H₂₂FN₄O₅[M+H⁺]The calculated value of (a): 429.1574, respectively; measurement value: 429.1584.

example 211

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [2- [ (2Z) -3-amino-1-oxo-2-butenyl]-4-fluorophenyl group]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-.¹HNMR400MHz(CDCl₃)δppm：1.63(6H，s，2xCH₃)，2.11(3H，s，CH₃)，4.03(4H，s，2xCH₂)，4.58(2H，d，J＝6.5Hz，NCH₂) 5.38(1H, broad, NH), 5.49(1H, s, CH), 7.09(1H, m, arene), 7.29(1H, dd, J ═ 3.0Hz and J ═ 9.1Hz, arene), 7.48(1H, dd, J ═ 5.6Hz and J ═ 8.6Hz, arene), 9.19(1H, broad, t, NH), 10.26(1H, broad, NH), 12.21(1H, s, OH).

Example 212

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ [2- (3-bromo-5-isoxazolyl) -4-fluorophenyl]Methyl radical]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-can be synthesized from intermediate 181, N- (2- (3-bromoisoxazol-5-yl) -4-fluorobenzyl) -3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazine-2-carboxamide the title compound was prepared. ¹HNMR400MHz(CDCl₃)δppm：1.60(6H，s，2xCH₃)，4.03(4H，s，2xCH₂)，4.74(2H，d，J＝7.1Hz，NCH₂) 6.63(1H, s, arene), 7.24(1H, m, arene), 7.32(1H, dd, J ═ 2.5Hz and J ═ 9.1Hz, arene), 7.63(1H, dd, J ═ 5.5Hz and J ═ 8.6Hz, arene), 8.20(1H, wide t, NH), 11.77(1H, s, OH).

Example 213

Phosphonic acid, [ 5-fluoro-2- [ [ [ (4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxopyrimidino [2, 1-c ]][1，4]Oxazin-2-yl) carbonyl]Amino group]Methyl radical]Phenyl radical]-, diethyl ester intermediate 187, 2- ((3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Hydrogenolysis of oxazin-2-carboxamido) methyl) -5-fluorophenylphosphonic acid diethyl ester (0.089 g, 0.15mmol) gave 0.065 g (90% yield) of the title compound as a white solid: melting point 124 ℃.¹HNMR 400MHz(CDCl₃)δppm：1.39(6H，t，J＝7.1Hz，2xCH₃)，1.63(6H，s，2xCH₃)，4.02(4H，s，2xCH₂)，4.20(4H，m，2xOCH₂)，4.78(2H，d，J＝6.6Hz，NCH₂) 7.25(1H, m, arene), 7.49(1H, m, arene), 7.63(1H, m, arene), 9.12(1H, broad t, NH.), 12.1(1H, broad, OH). HRMS (ESI)⁺)C₂₁H₂₈FN₃O₇P[M+H⁺]The calculated value of (a): 484.1649, respectively; measurement value: 484.1646.

example 214

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (4-fluorophenyl) methyl]-4, 6, 7, 9-tetrahydro-3-hydroxy-N-methoxy-9, 9-dimethyl-4-oxo-. can be synthesized from intermediate 171, N- (4-fluorobenzyl) -3- (benzyloxy) -N-methoxy-9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c ] ][1，4]Oxazine-2-carboxamide the title compound was prepared.¹HNMR 400MHz(DMSO-d₆) δ ppm: (mixture of rotamers) 1.52(6H, s, 2 xCH)₃)，3.59(3H，s，OCH₃) 3.89(2H, broad, CH)₂) 4.01(2H, broad, CH)₂) 4.68 and 4.91(2H, broad, NCH)₂) 7.18(2H, m, arene), 7.43(2H, m, arene), 9.88 and 10.2(1H, broad, OH).

Example 215

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, 4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-N- [ [2- (tetrahydro-1, 1-dioxido-2H-1, 2-thiazin-2-yl) phenyl]Methyl radical]The title compound may be prepared from intermediate 101. Light brown solid.¹H-NMR(300MHz，CDCl₃)δppm：12.11(1H，s)，8.32-8.29(1H，m)，7.46-7.42(2H，m)，7.36-7.32(2H，m)，4.92(1H，dd，J＝14.3，8.8Hz)，4.40(1H，dd，J＝14.1，3.5Hz)，3.97(4H，s)，3.90-3.81(1H，m)，3.47-3.37(1H，m)，3.24-3.18(2H，m)，2.42-2.28(2H，m)，1.97-1.86(2H，m)，1.54(3H，s)，1.50(3H，s)。HRMS[M+H]⁺C₂₁H₂₇N₄SO₆The calculated value of (a): 463.1651, respectively; measurement value: 463.1669.C₂₁H₂₆N₄SO₆Analytical calculation of (a): c, 54.53; h, 5.67; n, 12.11; s, 6.93; measurement value: c, 54.53; h, 5.41; n, 12.40; s, 6.69.

Example 216

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, 4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-N- [ [2- (1H-1, 2, 4-triazol-1-yl) phenyl]Methyl radical]White solid.¹H-NMR(300MHz，CDCl₃)δppm：11.94(1H，s)，8.86(1H，t，J＝6.2Hz)，8.42(1H，s)，8.16(1H，s)，7.66(1H，dd，J＝7.3，1.8Hz)，7.51-7.42(2H，m)，7.35-7.32(1H，m)，4.45(2H，d，J＝6.6Hz)，3.98(4H，s)，1.59(6H，s)。HRMS[M+H]⁺C₁₉H₂₁N₆O₄The calculated value of (a): 397.1624, respectively; measurement value: 397.1609.C₁₉H₂₀N₆O₄Analytical calculation of (a): c, 57.57; h, 5.08; n, 21.20; measurement value: c, 57.40; h, 4.96; and N, 21.09.

Example 217

Pyrimido [2, 1-c ] s ][1，4]Oxazine-2-carboxamide, 4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-N- (3-phenylpropyl) -¹H NMR(500MHz，DMSO-D6)δppm：1.56(s，6H)1.82-1.89(m，2H)2.62(t，J＝7.48Hz，2H)3.31(m，2H)3.82(t，J＝5.04Hz，2H)3.97(t，J＝5.04Hz，2H)7.16-7.24(m，3H)7.29(m，2H)8.91(s，1H)12.41(s，1H).C₁₉H₂₃N₃O₄Analytical calculation of (a): c, 63.85; h, 6.48; n, 11.75. Measurement value: c, 63.56; h, 6.67; and N, 12.01.

Example 218-

Example 218-259 in table 11 was prepared using a similar method to that described in examples 1, 19, 20. The compounds were characterized by LCMS and the retention times (RT, min) and molecular weights (MS [ M +1]) determined are shown in the table.

Table 11.

Example 260-

Example 260-278 was prepared according to the procedure used to prepare the compounds in table 3 and characterized by LCMS.

Example 260

Pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide, 4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-N- [ [2- (4-morpholinyl) phenyl ] methyl ] -4-oxo-. LCMS: HPLC retention time 4.03min, MS [ M +1] 415.23.

Example 261

1-piperazinecarboxylic acid, 4- [2- [ [ [ (4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxopyrimidino [2, 1-c ] [1, 4] oxazin-2-yl) carbonyl ] amino ] methyl ] phenyl ] -, 1, 1-dimethylethyl ester LCMS: HPLC retention time 4.93min, MS [ M +1] 514.24.

Example 262

Pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide, 4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-N- [ [2- (1-methylethoxy) phenyl ] methyl ] -4-oxo-. LCMS: HPLC retention time 4.66min, MS [ M +1] 388.21.

Example 263

Pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide, 4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-N- [ [3- (1-methylethoxy) phenyl ] methyl ] -4-oxo-. LCMS: HPLC retention time 3.97min, MS [ M +1] 4388.21.

Example 264

Benzoic acid, 3- [ [ [ (4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxopyrimidino [2, 1-c ] [1, 4] oxazin-2-yl) carbonyl ] amino ] methyl ] -, methyl ester. LCMS: HPLC retention time 3.97min, MS [ M +1] 388.18.

Example 265

Pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide, N- [ (4-cyanophenyl) methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-. LCMS: HPLC retention time 3.59min, MS [ M +1] 355.2.

Example 266

Pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide, N- [ (3-chloro-2-fluorophenyl) methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-. LCMS: HPLC retention time 4.47min, MS [ M +1] 382.14.

Example 267

Pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide, N- [ (2, 3-dihydro-1, 4-benzodioxin-5-yl) methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-. LCMS: HPLC retention time 4.15min, MS [ M +1] 388.2.

Example 268

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, N- [ (3, 4-dihydro-2H-1, 5-benzodioxan-6-yl (dioxapynyl)) methyl]-4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-. LCMS: HPLC retention time 4.12min, MS [ M +1]]402.21。

Example 269

Pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide, N- [ (2, 5-dimethylphenyl) methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-. LCMS: HPLC retention time 4.64min, MS [ M +1] 358.22.

Example 270

Pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide, N- [ (5-chloro-2-fluorophenyl) methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-. LCMS: HPLC retention time 4.44min, MS [ M +1] 382.15.

Example 271

Pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide, N- [ (2, 4-dichlorophenyl) methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-. LCMS: HPLC retention time 4.88min, MS [ M +1] 398.11.

Example 272

Pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide, N- [ (4-chloro-2-methylphenyl) methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-. LCMS: HPLC retention time 4.69min, MS [ M +1] 378.17.

Example 273

Pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide, N- [ (2-chloro-6-fluorophenyl) methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-. LCMS: HPLC retention time 4.39min, MS [ M +1] 382.13.

Example 274

Pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide, N- [ (6-chloro-2-fluoro-3-methylphenyl) methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-. LCMS: HPLC retention time 4.74min, MS [ M +1] 396.14.

Example 275

Pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide, N- [ (2, 6-difluoro-3-methylphenyl) methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-. LCMS: HPLC retention time 4.49min, MS [ M +1] 380.18.

Example 276

Pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide, N- [ (2, 3-difluoro-4-methylphenyl) methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-. LCMS: HPLC retention time 4.53min, MS [ M +1] 380.18.

Example 277

Pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide, N- [ (4-chloro-2-fluorophenyl) methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-. LCMS: HPLC retention time 4.57min, MS [ M +1] 382.13.

Example 278

Pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide, N- [ (2-chloro-6-fluoro-3-methylphenyl) methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-. LCMS: HPLC retention time 4.68min, MS [ M +1] 396.16.

Example 279

Pyrimido [2, 1-c ] s][1，4]Oxazine-2-carboxamide, 4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-N- [ (1-methyl-1H-indol-4-yl) methyl]-4-oxo-.¹H NMR(500MHz，DMSO-d₆) δ ppm: 1.56(s, 6), 3.79(s, 3), 3.82(m, 2), 3.97(m, 2), 4.76(d, 2), 6.62(d, 1), 6.96(d, 1), 7.12(m, 1), 7.27-7.38 (overlap m, 2). HRMS [ M +1]]C₂₀H₂₃N₄O₄The calculated value of (a): 383.1641; measurement value: 383.1717.C₂₀H₂₂N₄O₄Analytical calculation of (a): c, 62.81; h, 5.79; n, 14.65. Measurement value: c, 62.88; h, 6.08; n, 13.56.

Example 280

6H-pyrimido [2, 1-c][1，4]Oxazazem-2-carboxamide, N- [ [ 4-fluoro-2- (2-oxo-1-azetidinyl) phenyl]Methyl radical]-4, 7, 8, 10-tetrahydro-3-hydroxy-10, 10-dimethyl-4-oxo-.¹HNMR(400MHz，DMSO-d₆) δ: 12.17(1H, s), 9.28(1H, width s), 7.37(1H, dd, J ═ 8.2, 6.7Hz), 7.23(1H, dd, J ═ 10.2, 2.4Hz), 7.04(1H, m), 4.51(2H, width s), 4.35(2H, width s), 3.79(2H, t, J ═ 4.4Hz), 3.62(2H, m), 3.11(2H, t, J ═ 4.4Hz), 1.81(2H, m), 1.55(6H, s). LCMS (M + H) ⁺m/z 431。

Example 281

Phosphonic acid, [ 5-fluoro-2- [ [ [ (4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxopyrimidino [2, 1-c ]][1，4]Oxazin-2-yl) carbonyl]Amino group]Methyl radical]Phenyl radical]2- ((3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Hydrogenation of dimethyl oxazine-2-carboxamido) methyl) -5-fluorophenylphosphonate (0.030 g, 0.055mmol) gave 0.018 g (72%) of the title compound as a white solid.¹HNMR 400MHz(CDCl₃)δ(ppm)：1.63(6H，s，2xCH₃)，3.84(3H，s，OCH₃)，3.87(3H，s，OCH₃)，4.03(4H，s，2xCH₂)，4.77(2H，d，J＝6.5Hz，NCH₂) 7.28(1H, m, arene), 7.47(1H, m, arene), 7.65(1H, m, arene), 9.0(1H, broad t, NH)12.0(1H, broad, OH). MS (ESI)⁺)m/z 456[M+H⁺]。

Example 282

Phosphonic acid, [ 5-fluoro-2- [ [ [ (4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxopyrimidino [2, 1-c ]][1，4]Oxazin-2-yl) carbonyl]Amino group]Methyl radical]Phenyl radical]The intermediate 188, 2- ((3- (benzyloxy) -9, 9-dimethyl-4-oxo-4, 6, 7, 9-tetrahydropyrimidino [2, 1-c)][1，4]Oxazin-2-carboxamido) methyl) -5-fluorophenylphosphonic acid ethyl ester the title compound was prepared.¹HNMR 400MHz(CDCl₃)δ(ppm)：1.32(3H，t，J＝7.1Hz，CH₃)，1.60(6H，s，2xCH₃)，4.02(4H，s，2xCH₂)，4.12(2H，m，OCH₂) 4.83(2H, broad, NCH)₂) 7.18(1H, m, arene), 7.54(2H, m, arene), 8.49(1H, broad, NH). HRMS (ESI)⁺)C₁₉H₂₄FN₃O₇P[M+H⁺]The calculated value of (a): 456.1336, respectively; measurement value: 456.1353.

Claims (27)

1. A compound of formula I

Wherein:

R¹is C_1-6(Ar¹) Alkyl radical, C_1-6(Ar¹)(CON(R⁸)(R⁹) Alkyl radical, C_1-6(Ar¹)(CO₂R¹⁴) Alkyl radical, C_1-6(Ar¹) Hydroxyalkyl, or C_1-6(Ar¹) An oxyalkyl group;

R²is hydrogen, C_1-6Alkyl, OR OR¹⁴；

R³Is hydrogen, halogen, hydroxy, cyano, C_1-6Alkyl radical, C_3-7Cycloalkyl radical, C_5-7Cycloalkenyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Haloalkoxy, N (R)⁸)(R⁹)，NHAr²，N(R⁶)SO₂R⁷，N(R⁶)COR⁷，N(R⁶)CO₂R⁷，OCOR⁷，OCO₂R⁷，OCON(R⁸)(R⁹)，OCH₂CO₂R⁷，OCH₂CON(R⁸)(R⁹)，COR⁶，CO₂R⁶，CON(R⁸)(R⁹)，SOR⁷，S(＝N)R⁷，SO₂R⁷，SO₂N(R⁶)(R⁶)，PO(OR⁶)₂，C_2-4(R¹²) Alkynyl radical, R¹³，Ar²Or Ar³；

R⁴Is hydrogen, halogen, hydroxy, cyano, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, or N (R)⁶)(R⁶)；

R⁵Is hydrogen, halogen, hydroxy, cyano, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, or N (R)⁶)(R⁶)；

R⁶Is hydrogen, C_1-6Alkyl, or C_3-7A cycloalkyl group;

R⁷is C_1-6Alkyl or C_3-7A cycloalkyl group;

R⁸is hydrogen, C_1-6Alkyl radical, C_1-6Hydroxyalkyl radical, C_1-6(C_1-6Alkoxy) alkyl or C_1-6(C_1-6Dialkylamino) alkyl;

R⁹is hydrogen, C_1-6Alkyl radical, C_1-6Hydroxyalkyl radical, C_1-6(C_1-6Alkoxy) alkyl or C_1-6(C_1-6Dialkylamino) alkyl; or

N(R⁸)(R⁹) Taken together are azetidinyl, pyrrolidinyl, (R)¹⁰) -piperidinyl, N- (R)¹¹) -piperazinyl, morpholinyl, thiomorpholinyl or dioxothiazinyl;

R¹⁰is hydrogen, C_1-6Alkyl, or C_1-6A hydroxyalkyl group;

R¹¹is hydrogen, C_1-6Alkyl radical, C_3-7Cycloalkyl radical, COR⁶Or CO₂R⁶；

R¹²Is hydrogen, hydroxy, N (R)⁶)(R⁶)，SO₂R⁷，OSO₂R⁷Or dioxothiazinyl;

R¹³is azetidinone, pyrrolidinone, valerolactam, caprolactam, maleimide, oxazolidone, or dioxothiazine and is substituted with 0-1 substituents selected from hydroxymethyl, acetoxymethyl, and aminomethyl;

R¹⁴Is hydrogen or C_1-6An alkyl group;

Ar²is tetrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, furyl, thienyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridyl, hydroxypyridinyl, quinolinyl, isoquinolinyl, or indolyl, and is substituted with 0-2 substituents selected from the group consisting of: halogen, cyano, benzyl, C_1-6Alkyl radical, C_1-6Alkoxy radical, N (R)⁸)(R⁹)，CON(R⁸)(R⁹)，CO₂R⁶，CONHSO₂N(R⁶)(R⁶)，CONHSO₂N(R⁶) (phenyl), and CONHSO₂N(R⁶) (halophenyl);

Ar³is phenyl substituted with 0-2 substituents selected from: halogen, cyano, hydroxy, C_1-6Alkyl radical, C_1-6Alkoxy group, (C)_1-6Alkoxy) methyl, C_1-6Haloalkyl, C_1-6Haloalkoxy, N (R)⁸)(R⁹)，CON(R⁶)(R⁶) And CH₂N(R⁸)(R⁹) Or is dioxolanylphenyl; and

X-Y-Z is C (R)¹⁴)₂OC(R¹⁴)₂，C(R¹⁴)₂OC(R¹⁴)₂C(R¹⁴)₂Or C (R)¹⁴)₂OC(R¹⁴)₂C(R¹⁴)₂C(R¹⁴)₂；

Or a pharmaceutically acceptable salt or solvate thereof.

2. The compound of claim 1, wherein R¹Is C_1-6(Ar¹) An alkyl group.

3. The compound of claim 1, wherein R¹Is that

4. The compound of claim 1, wherein R¹Is that

5. The compound of claim 1, wherein R²Is hydrogen.

6. The compound of claim 1, wherein R³Is hydrogen, halogen, N (R)⁸)(R⁹)，N(R⁶)COR⁷，OCON(R⁸)(R⁹)，CON(R⁸)(R⁹)，SOR⁷，SO₂R⁷，SO₂N(R⁶)(R⁶)，PO(OR⁶)₂，R¹³Or Ar²。

7. The compound of claim 1, wherein X-Y-Z is C (R)¹⁴)₂OCH₂，C(R¹⁴)₂OCH₂CH₂Or C (R) ¹⁴)₂OCH₂CH₂CH₂。

8. The compound of claim 1, wherein X-Y-Z is CH₂OCH₂，C(CH₃)HOCH₂，C(CH₃)₂OCH₂，CH₂OCH₂CH₂，C(CH₃)HOCH₂CH₂，C(CH₃)₂OCH₂CH₂，CH₂OCH₂CH₂CH₂，C(CH₃)HOCH₂CH₂CH₂Or C (CH)₃)₂OCH₂CH₂CH₂。

9. The compound of claim 1 selected from

N- [ [ 4-fluoro-2- [ (methylamino) carbonyl ] phenyl ] methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide;

9, 9-diethyl-N- [ [ 4-fluoro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-4-oxo-pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide;

9, 9-diethyl-N- [ [ 4-fluoro-2- (methylsulfonyl) phenyl ] methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-4-oxo-pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide;

n- [ [2- [ (dimethylamino) sulfonyl ] -4-fluorophenyl ] methyl ] -9, 9-diethyl-4, 6, 7, 9-tetrahydro-3-hydroxy-4-oxo-pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide;

n- [ [ 4-fluoro-2- (2-oxo-1-azetidinyl) phenyl ] methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide;

9, 9-diethyl-N- [ [ 4-fluoro-2- [ (methylamino) carbonyl ] phenyl ] methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-4-oxo-pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide;

n- [ [ 4-fluoro-2- (2-oxo-3-oxazolidinyl) phenyl ] methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide;

N- [ [ 4-fluoro-2- (methylsulfonyl) phenyl ] methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide;

n- [ [ 4-fluoro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methyl ester]Methyl radical]-4, 7, 8, 10-tetrahydro-3-hydroxy-10, 10-dimethyl-4-oxo-6H-pyrimido [2, 1-c][1，4]Oxazazem-2-carboxamide;

n- [ [ 4-fluoro-2- (3-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide;

n- [ [ 4-fluoro-2- (2-oxo-1-pyrrolidinyl) phenyl ] methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide;

n- [ [ 4-fluoro-2- (tetrahydro-1, 1-dioxido-2H-1, 2-thiazin-2-yl) phenyl ] methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide;

n- [ [ 4-fluoro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide;

n- [ [ 4-fluoro-2- [ (methylamino) carbonyl ] amino]Phenyl radical]Methyl radical]-4, 7, 8, 10-tetrahydro-3-hydroxy-10, 10-dimethyl-4-oxo-6H-pyrimido [2, 1-c ][1，4]Oxazazem-2-carboxamide;

9, 9-diethyl-4, 6, 7, 9-tetrahydro-3-hydroxy-4-oxo-N- [ [2- (tetrahydro-1, 1-dioxido-2H-1, 2-thiazin-2-yl) phenyl ] methyl ] -pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide;

n- [ [ 4-fluoro-2- (1, 2, 3-thiadiazol-4-yl) phenyl ] methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide;

n- [ [ 4-fluoro-2- (methylsulfonyl) phenyl]Methyl radical]-4, 7, 8, 10-tetrahydro-3-hydroxy-10, 10-dimethyl-4-oxo-6H-pyrimido [2, 1-c][1，4]Oxazazem-2-carboxamide;

n- [ [ 4-fluoro-2- (1-methyl-1H-tetrazol-5-yl) phenyl ] methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide;

n- [ [ 4-fluoro-2- (5-methyl-1H-1, 2, 4-triazol-1-yl) phenyl ] methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide;

n- [ [ 4-fluoro-2- (2-oxo-1-piperidinyl) phenyl ] methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide;

n- [ [2- [ (dimethylamino) sulfonyl ] -4-fluorophenyl ] methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide;

N- [ (4-fluorophenyl) methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide;

4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-N- [ [2- (2-oxo-3-oxazolidinyl) phenyl ] methyl ] -pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide;

n- [ [ 4-fluoro-2- [ (methylamino) sulfonyl ] phenyl ] methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide;

n- [ [2- (acetylamino) -4-fluorophenyl ] methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide;

n- [ [ 4-fluoro-2- [3- [ (4-methyl-1-piperazinyl) carbonyl ] -1H-1, 2, 4-triazol-1-yl ] phenyl ] methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide;

n- [ [ 4-fluoro-2- (4-morpholinylcarbonyl) phenyl ] methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide;

n- [ [ 4-fluoro-2- [ [ (2-hydroxyethyl) amino ] carbonyl ] phenyl ] methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide;

N- [ [ 4-fluoro-2- [3- (4-morpholinylcarbonyl) -1H-1, 2, 4-triazol-1-yl ] phenyl ] methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide;

4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-N- [ [2- (2-oxo-1-azetidinyl) phenyl ] methyl ] -pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide;

n- [ [ 4-fluoro-2- (1H-pyrazol-5-yl) phenyl ] methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide;

n- [ [2- [3- [ (dimethylamino) carbonyl ] -1H-1, 2, 4-triazol-1-yl ] -4-fluorophenyl ] methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide;

n- [ (4-fluorophenyl) methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide;

n- [ [ 3-fluoro-2- (tetrahydro-1, 1-dioxido-2H-1, 2-thiazin-2-yl) phenyl ] methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide;

4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-N- [ [2- (methylsulfonyl) phenyl ] methyl ] -4-oxo-pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide;

N- [ [ 4-fluoro-2- (4-morpholinyl) phenyl ] methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide;

n, N-dimethyl-carbamic acid, 5-fluoro-2- [ [ [ (4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxopyrimidino [2, 1-c ] [1, 4] oxazin-2-yl) carbonyl ] amino ] methyl ] phenyl ester;

n- [ [2- (aminosulfonyl) -4-fluorophenyl ] methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide; and

[ 5-fluoro-2- [ [ [ (4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxopyrimidino [2, 1-c ] [1, 4] oxazin-2-yl) carbonyl ] amino ] methyl ] phenyl ] -phosphonic acid, dimethyl ester;

or a pharmaceutically acceptable salt or solvate thereof.

10. The compound of claim 1

Or a pharmaceutically acceptable salt or solvate thereof.

11. The compound of claim 1

Or a pharmaceutically acceptable salt or solvate thereof.

12. The compound of claim 1

Or a pharmaceutically acceptable salt or solvate thereof.

13. The compound of claim 1

Or a pharmaceutically acceptable salt or solvate thereof.

14. The compound of claim 1

Or a pharmaceutically acceptable salt or solvate thereof.

15. The compound of claim 1

Or a pharmaceutically acceptable salt or solvate thereof.

16. The compound of claim 1

Or a pharmaceutically acceptable salt or solvate thereof.

17. The compound of claim 1

Or a pharmaceutically acceptable salt or solvate thereof.

18. The compound of claim 1

Or a pharmaceutically acceptable salt or solvate thereof.

19. The compound of claim 1

Or a pharmaceutically acceptable salt or solvate thereof.

20. A composition for treating HIV infection comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

21. The composition of claim 20 further comprising a therapeutically effective amount of at least one other agent useful for treating AIDS or HIV infection selected from nucleoside HIV reverse transcriptase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors, and HIV integrase inhibitors, and a pharmaceutically acceptable carrier.

22. The composition of claim 20, wherein the compound of claim 1 is N- [ (4-fluorophenyl) methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide.

23. The composition of claim 22 further comprising a therapeutically effective amount of at least one other agent useful in the treatment of AIDS or HIV infection selected from nucleoside HIV reverse transcriptase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors, and HIV integrase inhibitors, and a pharmaceutically acceptable carrier.

24. Use of a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of HIV infection.

25. The use of claim 24 wherein the compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, is used in combination with at least one other agent useful in the treatment of AIDS or HIV infection selected from nucleoside HIV reverse transcriptase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors, and HIV integrase inhibitors.

26. The use of claim 24, wherein the compound of claim 1 is N- [ (4-fluorophenyl) methyl ] -4, 6, 7, 9-tetrahydro-3-hydroxy-9, 9-dimethyl-4-oxo-pyrimido [2, 1-c ] [1, 4] oxazine-2-carboxamide.

27. The use of claim 26 wherein the compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, is used in combination with at least one other agent useful in the treatment of AIDS or HIV infection selected from nucleoside HIV reverse transcriptase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors, and HIV integrase inhibitors, and a pharmaceutically acceptable carrier.