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Chemical Structure| 1038866-44-2 Chemical Structure| 1038866-44-2

Structure of 1038866-44-2

Chemical Structure| 1038866-44-2

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Product Details of [ 1038866-44-2 ]

CAS No. :1038866-44-2
Formula : C11H14ClN3O2
M.W : 255.70
SMILES Code : O=C(NC1=NC=CC=C12)OC32CCNCC3.[H]Cl
MDL No. :MFCD21608029
InChI Key :FXDRAWOUSLBHGT-UHFFFAOYSA-N
Pubchem ID :66687106

Safety of [ 1038866-44-2 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H317-H319
Precautionary Statements:P280-P305+P351+P338

Computational Chemistry of [ 1038866-44-2 ] Show Less

Physicochemical Properties

Num. heavy atoms 17
Num. arom. heavy atoms 6
Fraction Csp3 0.45
Num. rotatable bonds 0
Num. H-bond acceptors 4.0
Num. H-bond donors 2.0
Molar Refractivity 71.68
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

63.25 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

0.0
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

1.05
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

0.96
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

0.58
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

1.18
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.75

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-2.35
Solubility 1.15 mg/ml ; 0.00449 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-1.97
Solubility 2.75 mg/ml ; 0.0107 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-3.41
Solubility 0.0986 mg/ml ; 0.000385 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

High
BBB permeant?

BBB permeation: according to the yolk of the BOILED-Egg

Yes
P-gp substrate?

P-glycoprotein substrate: SVM model built on 1033 molecules (training set)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

Yes
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

No
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

Yes
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-7.11 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

0.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

0.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<0.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

3.12

Application In Synthesis of [ 1038866-44-2 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 1038866-44-2 ]

[ 1038866-44-2 ] Synthesis Path-Downstream   1~29

  • 1
  • [ 912463-13-9 ]
  • [ 1038866-44-2 ]
  • [ 7693-46-1 ]
  • [ 1038866-30-6 ]
YieldReaction ConditionsOperation in experiment
EXAMPLE 4A^-rcyig^^-Chloro-S-oxo-P^^^-trifluoroethylVS.J.S^.lO-hexahvdroazepinofSLambda-elindazol-?- yl]-2'-oxo-r.2'-dihydro-lH-spiro[piperidine-4,4'-pyrido[2,3-</][l,3]oxa2ine]-l-carboxamideTo a solution of (7i?)-7-amino-4-chloro-9-(2,2,2-trifluoroethyl)-6,7,9,10- tetrahydroazepino[3,4-e]indazol-8(3H)-one (100 mg, 0.3 mmol) [Chaturvedula et al. WO 2006/052378],and triethylamine (120 uL, 0.9 mmole) is added ^-nitrophenyl chloroformate (60 mg, 0.3 mmmol) and stirred at 0 0C for 1 hr. Spiro[piperidine-4,4'-pyrido[2,3-c/][l,3]oxazin]- 2'(l'H)-one hydrochloride [Burgey et al. WO 2006/044504], (77'mg, 0.3mmole is then added with triethylamine (120 uL, 0.675 mmol) and the reaction mixture is stirred at ambient temperature for 16 hrs. Saturated aqueous sodium carbonate (50 mL) is added and the mixture is extracted with dichloromethane (3 * 25 mL). The organic layer is washed with saturated aqueous sodium bicarbonate (3 x), brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography, eluting with a gradient of CHCl3 :MeOEta - 100:0 to 90:10, provides the title compound.
  • 3
  • [ 1038866-44-2 ]
  • [ 1158918-75-2 ]
  • [ 1158918-23-0 ]
YieldReaction ConditionsOperation in experiment
72% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; Example 39 1-(6-(5-fluoroindoline-1-carbonyl)pyrimidin-4-yl)spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one 0.10 g (0.36 mmol) (6-chloro-pyrimidin-4-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone were added to 92 mg (0.36 mmol) spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one-hydrochloride and 146 muL (0.84 mmol) DIPEA in 1.8 mL DMF. The reaction mixture was stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product fractions were combined and lyophilised. Yield: 120 mg (72% of theory) ESI-MS: m/z=461 (M+H)+ Rt (HPLC-MS): 2.90 min (method E)
  • 4
  • [ 883984-95-0 ]
  • [ 1038866-44-2 ]
YieldReaction ConditionsOperation in experiment
50% With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃; for 9h; Step 3: spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride 16.4 g (42.4 mmol) benzyl 7'-chloro-2'-oxo-1'.2'-dihydrospiro[piperidine-4,4'-pyrido[2,3d][1,3]oxazine]-1-carboxylate and 2.00 g palladium(Pd/C 10%) in 500 mL EtOH were hydrogenated in a hydrogen atmosphere for 6 h at RT. Then another 1.0 g palladium (Pd/C 10%) were added the mixture was hydrogenated for a further 3 h at RT in a hydrogen atmosphere. After filtration of the reaction mixture the solvent was eliminated in vacuo. The residue was triturated with EtOH, the precipitate formed was suction filtered, washed with EtOH and dried. Yield: 5.40 g (50% of theoretical) ESI-MS: m/z=220 (M+H)+ Rt(HPLC): 0.90 min (method C)
50% With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃; for 9h; Step 3: spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride 16.40 g (0.04 mol) benzyl 7'-chloro-2'-oxo-1',2'-dihydrospiro[piperidine-4,4'-pyrido[2,3d]-[1,3]oxazine]-1-carboxylate and 2.00 g palladium(Pd/C 10%) in 500 mL EtOH were hydrogenated for 6 h at RT in a hydrogen atmosphere. Then 1 g of palladium (Pd/C 10%) were additionally added and the mixture was hydrogenated for a further 3 h at RT in a hydrogen atmosphere. After filtration of the reaction mixture the solvent was eliminated in vacuo. The residue was triturated with EtOH, the precipitate formed was suction filtered, washed with EtOH and dried in the drying cupboard for 3 h at 50 C.Yield: 5.40 g (50% of theoretical)ESI-MS: m/z=220 (M+H)+ Rt(HPLC): 0.90 min (method C)
  • 5
  • [ 1038866-44-2 ]
  • [ 1158918-76-3 ]
  • [ 1158918-28-5 ]
YieldReaction ConditionsOperation in experiment
13% With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 20 - 130℃; Example 44 1-(4-(4,5-difluoroindoline-1-carbonyl)pyridin-2-yl)spiro[piperidine-4,4'-pyrido[2,3-d][1,3]-oxazin]-2'(1'H)-one 0.23 g (0.78 mmol) (2-chloro-pyridin-4-yl)-(4,5-difluoro-2,3-dihydro-indol-1-yl)-methanone were added to 0.20 g (0.78 mmol) spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one-hydrochloride and 0.11 g (0.78 mmol) potassium carbonate in 3.0 mL NMP. The reaction mixture was first of all stirred for 10 h at 130 C., then cooled to RT and then stirred overnight at RT. The crude product was combined with water/acetonitrile and purified by preparative HPLC-MS. The product fractions were combined and evaporated down. The residue was triturated with diisopropylether, suction filtered and dried in the air. Yield: 50 mg (13% of theory) ESI-MS: m/z=478 (M+H)+ Rt (HPLC-MS): 3.00 min (method E)
  • 6
  • [ 1038866-44-2 ]
  • [ 1231749-44-2 ]
  • [ 1231748-60-9 ]
YieldReaction ConditionsOperation in experiment
9% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; Example 231-(6-(4-methyl-2-oxo-2,3-dihydrobenz-[d]oxazol-6-yloxy)pyrimidin-4-yl)spiro[piperidin-4,4'-pyrido[2,3-d][1.3]oxazin]-2'(1'H)-one; 20 mg (0.078 mol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 20 mg (0.072 mmol) 6-(6-chloro-pyrimidin-4-ylamino)-4-methyl-3H-benzoxazol-2-one and 0.10 mL (0.57 mmol) DIPEA were combined in 1.0 mL DMF and stirred overnight at RT. The reaction mixture was purified by preparative HPLC. The product-containing fractions were combined and freeze-dried.Yield: 3 mg (9% of theory)ESI-MS: m/z=461 (M+H)+ Rt (HPLC): 1.24 min (method B)
  • 7
  • [ 1038866-44-2 ]
  • [ 1231749-76-0 ]
  • [ 1231748-69-8 ]
YieldReaction ConditionsOperation in experiment
48% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 50℃; Example 301-(6-(2,4-dimethyl-1H-benzo[d]imidazol-6-yloxy)pyrimidin-4-yl)spiro[piperidine-4,4'-pyrido-[2,3-d][1,3]oxazin]-2'(1'H)-one; 0.15 g (0.59 mmol) <strong>[1038866-44-2]spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 0.15 g (0.55 mmol) 6-(6-chloro-pyrimidin-4-yloxy)-2,4-dimethyl-1H-benzimidazole and 0.31 mL (1.8 mmol) DIPEA were combined in 1.5 mL DMF and stirred first of all overnight at RT then for 2 h at 50 C. The reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and the acetonitrile was evaporated down. The residue was made alkaline with 4N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried under HV.Yield: 130 mg (48% of theory)ESI-MS: m/z=458 (M+H)+ Rt(HPLC): 0.96 min (method B)
  • 8
  • [ 1038866-44-2 ]
  • [ 1231749-91-9 ]
  • [ 1231748-79-0 ]
YieldReaction ConditionsOperation in experiment
40% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 40℃; Example 391-{6-[2-(methoxymethyl)-4-methyl-1H-benzo[d]imidazol-6-yloxy]pyrimidin-4-yl}spiro-(piperidin-4,4'-pyrido[2,3-d][1,3]oxazin)-2'(1'H)-one; 49 mg (0.19 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 50 mg (0.16 mmol) 6-(6-chloropyrimidin-4-yloxy)-2-(methoxymethyl)-4-methyl-1H-benzo-[d]imidazole and 0.10 mL (0.57 mmol) DIPEA in 2.0 mL DMF were stirred at 40 C. over the weekend. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were partially evaporated down i.vac. and neutralised with 4M sodium hydroxide solution. The precipitate formed was suction filtered, washed and dried.Yield: 37 mg (40% of theory)ESI-MS: m/z=488 (M+H)+ Rt (HPLC): 0.99 min (method B)
  • 9
  • [ 1038866-44-2 ]
  • [ 1231749-92-0 ]
  • [ 1231748-82-5 ]
YieldReaction ConditionsOperation in experiment
43% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 90℃; for 3h; Example 411-[2-methoxy-6-(4-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yloxy)pyrimidin-4-yl]spiro-[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one; 58 mg (0.23 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 70 mg (0.20 mmol) 6-(6-chloro-2-methoxypyrimidin-4-yloxy)-4-methylbenzo[d]oxazol-2(3H)-one and 0.10 mL DIPEA (0.57 mmol) in 1.0 mL DMF were stirred for 3 h at 90 C. The reaction mixture was mixed with water, the precipitate w suction filtered, washed and dried. The residue was purified by preparative HPLC-MS. The fractions containing product were combined and freeze-dried.Yield: 45 mg (43% of theory)ESI-MS: m/z=491 (M+H)+ Rt (HPLC): 1.26 min (method B)
  • 10
  • [ 1038866-44-2 ]
  • [ 1231749-95-3 ]
  • [ 1231748-88-1 ]
YieldReaction ConditionsOperation in experiment
39% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 40℃; Example 441-(6-(2-cyclopropyl-4-methyl-1H-benzo[d]imidazol-6-yloxy)pyrimidin-4-yl)spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one; 41 mg (0.16 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 40 mg (0.13 mmol) 6-(6-chloropyrimidin-4-yloxy)-2-cyclopropyl-4-methyl-1H-benzo[d]-imidazole and 0.08 mL (0.48 mmol) DIPEA in 2.0 mL DMF were stirred overnight at 40 C. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were partially evaporated down i.vac. and neutralised with 4M sodium hydroxide solution. The precipitate formed was suction filtered, washed and dried.Yield: 30 mg (39% of theory)ESI-MS: m/z=484 (M+H)+ Rt (HPLC): 1.04 min (method B)
  • 11
  • [ 1038866-44-2 ]
  • [ 1231750-04-1 ]
  • [ 1231748-98-3 ]
YieldReaction ConditionsOperation in experiment
30% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 40℃; for 7h; Example 511-(6-(7-chloro-2-methyl-1H-benzo[d]imidazol-5-yloxy)pyrimidin-4-yl)spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one; 90 mg (0.35 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 110 mg (0.37 mmol) 7-chloro-5-(6-chloropyrimidin-4-yloxy)-2-methyl-1H-benzo[d]imidazole and 0.14 mL (0.81 mmol) DIPEA in 2.0 mL DMF were stirred for 3 h at RT and 4 h at 40 C. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were combined and freeze-dried.Yield: 50 mg (30% of theory)ESI-MS: m/z=478/480 (Cl) (M+H)+ Rt (HPLC): 1.07 min (method B)
  • 12
  • [ 1038866-44-2 ]
  • [ 1231750-08-5 ]
  • [ 1231749-02-2 ]
YieldReaction ConditionsOperation in experiment
18% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 40℃; Example 54(S)-1-(6-(4-methyl-2-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazol-6-yloxy)pyrimidin-4-yl)-spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one; 59 mg (0.23 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 70 mg (0.21 mmol) (S)-6-(6-chloropyrimidin-4-yloxy)-4-methyl-2-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazole and 0.12 mL (0.70 mmol) DIPEA in 2.0 mL DMF were stirred overnight at 40 C. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were partially evaporated down i.vac. and neutralised with 4M sodium hydroxide solution. The precipitate formed was suction filtered, washed and dried.Yield: 21 mg (18% of theory)ESI-MS: m/z=514 (M+H)+ Rt (HPLC): 1.09 min (method B)
  • 13
  • [ 1038866-44-2 ]
  • [ 1231750-13-2 ]
  • [ 1231749-19-1 ]
YieldReaction ConditionsOperation in experiment
73% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; Example 695-methyl-7-(6-(2'-oxo-1'.2'-dihydrospiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-1-yl)-pyrimidin-4-yloxy)-2H-benzo[b][1.4]oxazin-3(4H)-one; 72 mg (0.28 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 70 mg (0.22 mmol) 7-(6-chloropyrimidin-4-yloxy)-5-methyl-2H-benzo[b][1.4]oxazin-3(4H)-one and 100 muL (0.58 mmol) DIPEA in 2.0 mL DMF were stirred overnight at RT. The reaction mixture was combined with methanol and water. The precipitate formed was suction filtered, washed with methanol and dried.Yield: 75 mg (73% of theory)ESI-MS: m/z=475 (M+H)+ Rt(HPLC): 1.18 min (method B)
  • 14
  • [ 1038866-44-2 ]
  • [ 1231750-23-4 ]
  • [ 1231749-10-2 ]
YieldReaction ConditionsOperation in experiment
51% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; Example 611-(6-(7-chloro-2-(tetrahydrofuran-3-yl)-1H-benzo[d]imidazol-5-yloxy)pyrimidin-4-yl)spiro-[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one; 36 mg (0.14 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 50 mg (0.14 mmol) 7-chloro-5-(6-chloropyrimidin-4-yloxy)-2-(tetrahydrofuran-3-yl)-1H-benzo[d]imidazole and 50 muL (0.30 mmol) DIPEA in 2.0 mL DMF were stirred overnight at RT. The reaction mixture was purified by chromatography. The fractions containing product were combined and lyophilised.Yield: 38 mg (51% of theory)ESI-MS: m/z=534 (M+H)+ Rt(HPLC): 1.04 min (method B)
  • 15
  • [ 1038866-44-2 ]
  • [ 1231750-27-8 ]
  • [ 1231749-11-3 ]
YieldReaction ConditionsOperation in experiment
8% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 40℃; for 6h; Example 621-(6-(7-chloro-2-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-5-yloxy)pyrimidin-4-yl)-spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one; 49 mg (0.19 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 70 mg (0.19 mmol) 7-chloro-5-(6-chloropyrimidin-4-yloxy)-2-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole and 70 muL (0.40 mmol) DIPEA in 2.0 mL DMF were stirred for 3 h at RT and for 3 h at 40 C. The reaction mixture was purified by chromatography. The fractions containing product were combined and evaporated down i.vac.Yield: 8 mg (8% of theory)ESI-MS: m/z=548 (M+H)+ Rt(HPLC): 1.07 min (method B)
  • 16
  • [ 1038866-44-2 ]
  • [ 1231750-30-3 ]
  • [ 1231749-13-5 ]
YieldReaction ConditionsOperation in experiment
72% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; for 14h; Example 641-(6-(4-methyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yloxy)pyrimidin-4-yl)spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one; 90 mg (0.35 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 105 mg (0.36 mmol) 6-(6-chloropyrimidin-4-yloxy)-4-methylbenzo[d]thiazol-2(3H)-one and 200 muL (1.16 mmol) DIPEA in 2.0 mL DMF were stirred for 14 h at 60 C. The reaction mixture was cooled, mixed with water and stirred for 30 min. The precipitate formed was suction filtered, stirred with methanol, suction filtered again and dried.Yield: 120 mg (72% of theory)ESI-MS: m/z=477 (M+H)+ Rt(HPLC): 3.25 min (method C)
  • 17
  • [ 1038866-44-2 ]
  • [ 1231750-34-7 ]
  • [ 1231749-14-6 ]
YieldReaction ConditionsOperation in experiment
51% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; Example 651-(6-(7-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-5-yloxy)pyrimidin-4-yl)-spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one; 33 mg (0.13 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 40 mg (0.12 mmol) 7-methyl-5-(6-chloropyrimidin-4-yloxy)-2-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole and 70 muL (0.39 mmol) DIPEA in 2.0 mL DMF were stirred overnight at 60 C. The reaction mixture was poured onto ice water and the precipitate formed was suction filtered. The precipitate was dissolved and then purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with an aqueous NaHCO3 solution. The precipitate formed was suction filtered, washed and dried.Yield: 35 mg (51% of theory)ESI-MS: m/z=528 (M+H)+ Rt(HPLC): 0.96 min (method B)
  • 18
  • [ 1038866-44-2 ]
  • [ 1231750-40-5 ]
  • [ 1231749-25-9 ]
YieldReaction ConditionsOperation in experiment
97% With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 60℃; for 14h; Example 741-(6-(4-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yloxy)-2-(trifluoromethyl)pyrimidin-4-yl)-spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one; 90 mg (0.35 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 125 mg (0.36 mmol) 6-(6-chloro-2-trifluoromethyl-pyrimidin-4-yloxy)-4-methyl-3H-benzoxazol-2-one and 0.20 mL (1.16 mmol) DIPEA in 2.0 mL NMP were stirred for 14 h at 60 C. After cooling the reaction mixture was mixed with water and stirred for 30 min. The precipitate formed was suction filtered and dried.Yield: 0.18 mg (97% of theory)ESI-MS: m/z=529 (M+H)+ Rt(HPLC): 1.40 min (method B)
  • 19
  • [ 1038866-44-2 ]
  • [ 1231750-36-9 ]
  • [ 1231749-15-7 ]
YieldReaction ConditionsOperation in experiment
51% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 50℃; Example 661-(6-(2-(2-methoxyethyl)-4-methyl-1H-benzo[d]imidazol-6-yloxy)pyrimidin-4-yl)spiro-[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one; 29 mg (0.11 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 29 mg (0.09 mmol) 6-(6-chloropyrimidin-4-yloxy)-2-(2-methoxyethyl)-4-methyl-1H-benzo-[d]imidazole and 50 muL (0.39 mmol) DIPEA in 2.0 mL DMF were stirred overnight at 50 C. The reaction mixture was purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with a 1M aqueous NaOH solution. The precipitate formed was suction filtered, washed and dried.Yield: 55 mg (51% of theory)ESI-MS: m/z=502 (M+H)+ Rt(HPLC): 2.72 min (method C)
  • 20
  • [ 1038866-44-2 ]
  • [ 1231750-48-3 ]
  • [ 1231749-18-0 ]
YieldReaction ConditionsOperation in experiment
38% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; Example 681-(6-(7-methyl-1H-indazol-5-yloxy)pyrimidin-4-yl)spiro[piperidin-4,4'-pyrido[2,3-d]-[1,3]oxazin]-2'(1'H)-one; 60 mg (0.23 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 60 mg (0.23 mmol) 5-(6-chloropyrimidin-4-yloxy)-7-methyl-1H-indazole and 100 muL (0.58 mmol) DIPEA in 0.8 mL DMF were stirred at RT over the weekend. The reaction mixture was purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with an aqueous saturated NaHCO3 solution. The precipitate formed was suction filtered and dried.Yield: 40 mg (38% of theory)ESI-MS: m/z=444 (M+H)+ Rt(HPLC): 3.06 min (method C)
  • 21
  • [ 1038866-44-2 ]
  • [ 1231750-49-4 ]
  • [ 1231749-20-4 ]
YieldReaction ConditionsOperation in experiment
35% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 50℃; Example 70(R)-1-(6-(4-methyl-2-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazol-6-yloxy)pyrimidin-4-yl)-spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one; 166 mg (0.65 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 205 mg (0.62 mmol) (R)-6-(6-chloropyrimidin-4-yloxy)-4-methyl-2-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazole and 320 muL (1.86 mmol) DIPEA in 5.0 mL DMF were stirred overnight at 50 C. The reaction mixture was purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with an aqueous NaHCO3 solution. The precipitate formed was suction filtered, washed and dried.Yield: 110 mg (35% of theory)ESI-MS: m/z=514 (M+H)+ Rt(HPLC): 0.98 min (method B)
  • 22
  • [ 1038866-44-2 ]
  • [ 1231750-41-6 ]
  • [ 1231749-26-0 ]
YieldReaction ConditionsOperation in experiment
36% With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 140℃; for 1h; Example 754-(4-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yloxy)-6-(2'-oxo-1'.2'-dihydrospiro-[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-1-yl)nicotinonitrile; 40 mg (0.16 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 40 mg (0.12 mmol) 6-chloro-4-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-yloxy)-nicotino-nitrile and 0.08 mL (0.47 mmol) DIPEA in 0.80 mL NMP were stirred for 1 h at 140 C. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were partially evaporated down i.vac. and neutralised with aqueous NaHCO3 solution. The precipitate formed was suction filtered and dried.Yield: 47 mg (36% of theory)ESI-MS: m/z=485 (M+H)+ Rt(HPLC): 1.34 min (method B)
  • 23
  • [ 1038866-44-2 ]
  • [ 1231749-69-1 ]
  • [ 1231749-21-5 ]
YieldReaction ConditionsOperation in experiment
68% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 60℃; Example 714-methyl-6-(2-methyl-6-(2'-oxo-1'.2'-dihydrospiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-1-yl)pyrimidin-4-yloxy)benzo[d]oxazol-2(3H)-one; 90 mg (0.35 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 90 mg (0.31 mmol) 6-(6-chloro-2-methylpyrimidin-4-yloxy)-4-methylbenzo[d]oxazol-2(3H)-one and 200 muL (1.16 mmol) DIPEA in 1.5 mL DMF were stirred overnight at RT. Another 90 mg (0.35 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong> and 200 muL (1.16 mmol) DIPEA were added and the mixture was stirred for 8 h at 60 C. The reaction mixture was mixed with water and stirred overnight. Then DCM was added and the mixture was stirred for a further 30 min. DCM was removed and the aqueous phase was suction filtered. The precipitate was washed with EtOH and dried.Yield: 100 mg (68% of theory)ESI-MS: m/z=475 (M+H)+ Rt(HPLC): 1.04 min (method B)
  • 24
  • [ 1038866-44-2 ]
  • [ 1231750-18-7 ]
  • [ 1231749-06-6 ]
YieldReaction ConditionsOperation in experiment
18% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; Example 581-(6-(7-methyl-2-(tetrahydrofuran-3-yl)-1H-benzo[d]imidazol-5-yloxy)pyrimidin-4-yl)spiro-[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one; 138 mg (0.54 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 180 mg (0.54 mmol) 5-(6-chloropyrimidin-4-yloxy)-7-methyl-2-(tetrahydrofuran-3-yl)-1H-benzo[d]imidazole and 280 muL (1.62 mmol) DIPEA in 5.0 mL DMF were stirred overnight at 60 C. The reaction mixture was combined with ice water. The precipitate formed was suction filtered and purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with an aqueous NaHCO3 solution and extracted with ethyl acetate. The organic phase was dried and evaporated down i.vac.Yield: 50 mg (18% of theory)ESI-MS: m/z=514 (M+H)+ Rt(HPLC): 2.88 min (method L)
  • 25
  • [ 1038866-44-2 ]
  • [ 1231750-29-0 ]
  • [ 1231749-12-4 ]
YieldReaction ConditionsOperation in experiment
44% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 50℃; Example 631-(6-(7-methyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yloxy)pyrimidin-4-yl)spiro-[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one; 21 mg (0.08 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 22 mg (0.07 mmol) 5-(6-chloropyrimidin-4-yloxy)-7-methyl-2-(trifluoromethyl)-1H-benzo[d]-imidazole and 40 muL (0.24 mmol) DIPEA in 2.0 mL DMF were stirred at 50 C. over the weekend. The reaction mixture was purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with a 1M aqueous NaOH solution. The precipitate formed was suction filtered, washed and dried.Yield: 18 mg (44% of theory)ESI-MS: m/z=512 (M+H)+ Rt(HPLC): 1.30 min (method B)
  • 26
  • [ 1038866-44-2 ]
  • [ 1231750-39-2 ]
  • [ 1231749-17-9 ]
YieldReaction ConditionsOperation in experiment
17% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; Example 671-(6-(2-methoxy-7-methyl-1H-benzo[d]imidazol-5-yloxy)pyrimidin-4-yl)spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one; 64 mg (0.25 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 57 mg (0.20 mmol) 5-(6-chloropyrimidin-4-yloxy)-2-methoxy-7-methyl)-1H-benzo[d]-imidazole and 130 muL (0.75 mmol) DIPEA in 2.0 mL DMF were stirred overnight at 60 C. The reaction mixture was purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with a 1M aqueous NaOH solution. The precipitate formed was suction filtered, washed and dried.Yield: 20 mg (17% of theory)ESI-MS: m/z=474 (M+H)+ Rt(HPLC): 1.10 min (method B)
  • 27
  • [ 1038866-44-2 ]
  • [ 1231750-45-0 ]
  • [ 1231749-28-2 ]
YieldReaction ConditionsOperation in experiment
25% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 10h; Example 781-{1-[6-(2.7-dimethyl-3H-benzimidazol-5-yloxy)-pyrimidin-4-yl]-spiro[piperidin-4,4'-pyrido-[2,3-d][1,3]oxazin]-2'(1'H)-one; 128 mg (0.500 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 167 mg (0.500 mmol) 6-(6-chloro-pyrimidin-4-yloxy)-2-methyl-4-trifluoromethyl-1H-benzimidazole and 0.261 mL (1.50 mmol) DIPEA in 1.5 mL DMF were stirred for 10 h at RT. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were combined and freeze-dried.Yield: 65 mg (25% of theory)ESI-MS: m/z=512 (M+H)+ Rt (HPLC): 3.0 min (method C)
  • 28
  • [ 45644-21-1 ]
  • [ 1038866-44-2 ]
  • 29
  • [ 1038866-44-2 ]
  • [ 1185274-82-1 ]
  • [ 7693-46-1 ]
  • [ 1185274-53-6 ]
YieldReaction ConditionsOperation in experiment
To a solution of (7lambda)-4-chloro-10-[l-(trifluoromethyl)cyclopropyl]-3,6,7,12- tetrahydroimidazo[r,2':l,7]azepino[3,4-e]indazol-7-amine (100 mg, 0.3 mmol)],and triethylamine (120 uL, 0.9 mmole) is added p-nitrophenyl chloroformate (60 mg, 0.3 mmmol) and stirred at 0C for 1 hr. Spiro[piperidine-4,4'-pyrido[2,3-d][l,3]oxazin]-2'(1'H)-one hydrochloride [Burgey et ah WO 2006/044504], (77 mg, 0.3mmole is then added with triethylamine (120 uL, 0.675 mmol) and the reaction mixture is stirred at ambient temperature for 16 hrs. Saturated aqueous sodium carbonate (50 mL) is added and the mixture is extracted with dichloromethane (3 * 25 mL). The organic layer is washed with saturated aqueous sodium bicarbonate (3 x), brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography [100% dichloromethane ? 93% dichloromethane/ methanol] gives the title compound
 

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[ 1038866-44-2 ]

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