WO2022156792A1 - Heterocyclic compounds as sos1 inhibitors - Google Patents
Heterocyclic compounds as sos1 inhibitors Download PDFInfo
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- WO2022156792A1 WO2022156792A1 PCT/CN2022/073365 CN2022073365W WO2022156792A1 WO 2022156792 A1 WO2022156792 A1 WO 2022156792A1 CN 2022073365 W CN2022073365 W CN 2022073365W WO 2022156792 A1 WO2022156792 A1 WO 2022156792A1
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- WO
- WIPO (PCT)
- Prior art keywords
- alkylene
- formula
- mmol
- membered
- cycloalkyl
- Prior art date
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- 239000003112 inhibitor Substances 0.000 title claims abstract description 22
- 150000002391 heterocyclic compounds Chemical class 0.000 title description 3
- 101100421901 Caenorhabditis elegans sos-1 gene Proteins 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 76
- 150000003839 salts Chemical class 0.000 claims abstract description 53
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 32
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 5
- 108700022176 SOS1 Proteins 0.000 claims abstract description 4
- 230000001404 mediated effect Effects 0.000 claims abstract description 4
- 101100404726 Arabidopsis thaliana NHX7 gene Proteins 0.000 claims abstract 3
- 101100197320 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) RPL35A gene Proteins 0.000 claims abstract 3
- 101150100839 Sos1 gene Proteins 0.000 claims abstract 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 399
- 238000000034 method Methods 0.000 claims description 282
- -1 hydroxy, amino Chemical group 0.000 claims description 262
- 229910052717 sulfur Inorganic materials 0.000 claims description 48
- 229910052760 oxygen Inorganic materials 0.000 claims description 46
- 125000004432 carbon atom Chemical group C* 0.000 claims description 38
- 125000000217 alkyl group Chemical group 0.000 claims description 31
- 125000003118 aryl group Chemical group 0.000 claims description 24
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 21
- 125000004429 atom Chemical group 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 17
- 125000005843 halogen group Chemical group 0.000 claims description 16
- 125000005842 heteroatom Chemical group 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 102000016914 ras Proteins Human genes 0.000 claims description 12
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 11
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 108010014186 ras Proteins Proteins 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 239000000651 prodrug Substances 0.000 claims description 7
- 229940002612 prodrug Drugs 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 238000002560 therapeutic procedure Methods 0.000 claims description 5
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000004043 oxo group Chemical group O=* 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
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- 150000002431 hydrogen Chemical class 0.000 claims description 3
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- 108010062302 rac1 GTP Binding Protein Proteins 0.000 claims description 3
- 125000006714 (C3-C10) heterocyclyl group Chemical group 0.000 claims description 2
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- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 2
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- 238000009169 immunotherapy Methods 0.000 claims description 2
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- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 230000004083 survival effect Effects 0.000 claims description 2
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- 101000868154 Homo sapiens Son of sevenless homolog 2 Proteins 0.000 claims 1
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- 239000004037 angiogenesis inhibitor Substances 0.000 claims 1
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- 229940034982 antineoplastic agent Drugs 0.000 claims 1
- 239000002246 antineoplastic agent Substances 0.000 claims 1
- 230000006907 apoptotic process Effects 0.000 claims 1
- 230000004663 cell proliferation Effects 0.000 claims 1
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- 208000029742 colonic neoplasm Diseases 0.000 claims 1
- 229940121647 egfr inhibitor Drugs 0.000 claims 1
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- 206010017758 gastric cancer Diseases 0.000 claims 1
- 201000010536 head and neck cancer Diseases 0.000 claims 1
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- XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 description 1
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- 125000001624 naphthyl group Chemical group 0.000 description 1
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
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- 238000007254 oxidation reaction Methods 0.000 description 1
- MHOVLDXJDIEEMJ-UHFFFAOYSA-N oxolan-3-amine;hydrochloride Chemical compound Cl.NC1CCOC1 MHOVLDXJDIEEMJ-UHFFFAOYSA-N 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
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- 230000000144 pharmacologic effect Effects 0.000 description 1
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
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- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
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- 125000004928 piperidonyl group Chemical group 0.000 description 1
- 229920001308 poly(aminoacid) Polymers 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
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- 125000006684 polyhaloalkyl group Polymers 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
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- CBPYOHALYYGNOE-UHFFFAOYSA-M potassium;3,5-dinitrobenzoate Chemical compound [K+].[O-]C(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1 CBPYOHALYYGNOE-UHFFFAOYSA-M 0.000 description 1
- VZOPRCCTKLAGPN-ZFJVMAEJSA-L potassium;sodium;(2r,3r)-2,3-dihydroxybutanedioate;tetrahydrate Chemical compound O.O.O.O.[Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O VZOPRCCTKLAGPN-ZFJVMAEJSA-L 0.000 description 1
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- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
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- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 239000008159 sesame oil Substances 0.000 description 1
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- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- CQSFZPDGBPHCHV-UHFFFAOYSA-M sodium;cyclopropanesulfinate Chemical compound [Na+].[O-]S(=O)C1CC1 CQSFZPDGBPHCHV-UHFFFAOYSA-M 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
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- NDEIKFCAPOYPHU-LURJTMIESA-N tert-butyl (2s)-2-carbamoylazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC[C@H]1C(N)=O NDEIKFCAPOYPHU-LURJTMIESA-N 0.000 description 1
- HNINFCBLGHCFOJ-UHFFFAOYSA-N tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate Chemical compound C1NCC2CCC1N2C(=O)OC(C)(C)C HNINFCBLGHCFOJ-UHFFFAOYSA-N 0.000 description 1
- HKIGXXRMJFUUKV-UHFFFAOYSA-N tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CO)C1 HKIGXXRMJFUUKV-UHFFFAOYSA-N 0.000 description 1
- HFGWLJGLWDUUJP-UHFFFAOYSA-N tert-butyl n-(2-ethoxyethyl)carbamate Chemical compound CCOCCNC(=O)OC(C)(C)C HFGWLJGLWDUUJP-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- ZVQXQPNJHRNGID-UHFFFAOYSA-N tetramethylsuccinonitrile Chemical compound N#CC(C)(C)C(C)(C)C#N ZVQXQPNJHRNGID-UHFFFAOYSA-N 0.000 description 1
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- GYUURHMITDQTRU-UHFFFAOYSA-N tributyl(pyridin-2-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=CC=N1 GYUURHMITDQTRU-UHFFFAOYSA-N 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
- BPLKQGGAXWRFOE-UHFFFAOYSA-M trimethylsulfoxonium iodide Chemical compound [I-].C[S+](C)(C)=O BPLKQGGAXWRFOE-UHFFFAOYSA-M 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
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- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
- C07D513/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/10—Spiro-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
Definitions
- the present invention relates to heterocyclic compounds as inhibitors of SOS1 that are useful for treatment of SOS1 mediated diseases and conditions such as cancer.
- RAS proteins are small, membrane-bound guanine nucleotide-binding proteins; they act as molecular switches by cycling between active GTP-bound and inactive GDP-bound conformations.
- GEFs guanine nucleotide exchange factors
- SOS1 Session Inactivation factor 1
- GTPase RAC1 Ras-related C3 botulinum toxin substrate 1
- SOS1 inhibitors are expected to consequently inhibit signaling in cells downstream of RAS proteins (e.g. ERK phosphorylation) and exhibit anti-cancer efficacy in treatment of cancers associated with dependence on RAS proteins.
- the present invention describes inhibitors of SOS1.
- the present invention further describes pharmaceutical formulations that include an inhibitor of SOS1.
- the invention features a compound of Formula I, or a pharmaceutically acceptable salt thereof:
- Q 1 is CR 3a or N
- Q 2 and Q 3 are independently CR 3 or N, provided that one of Q 2 or Q 3 is N; Q 2 and Q 3 can be connected to form a 5-membered or 6-membered heterocyclic ring;
- Q 4 is N or CR 6 ;
- Q 5 is O, N or NR 1 ;
- Y is O, S, NR 1 ; or Y is hydrogen, -C 1-10 alkyl, -C 1- 10haloalkyl, -C 0-6 alkylene-C 6-10 aryl, C 0-6 alkylene-5-10-membered heteroaryl, -C 0-6 alkylene-C 3-6 cycloalkyl, C 0-6 alkylene-3-6 membered heterocyclyl, OR 1 , SR 1 , NR c R 1 when Q 5 is N; R 1 and R c may be taken together with the atom (s) to which they are attached to form an optionally substituted 5-10 membered carbocyclyl, or heterocyclyl which contains 1-3 heteroatoms and is optionally substitute with 0-5 occurrences of R 10 ; R 1 and R c are independently substituted with 0-5 occurrences of R 10 ;
- Y and Q 5 may be connected with two atoms, independently selected from O, N, S or C, to form a five- membered heterocycle or five membered heteroaryl;
- R 1 is independently selected from the group consisting of hydrogen, -C 1-10 alkyl, -C 0-6 alkylene-C 6-10 aryl, C 0- 6 alkylene-5-10-membered heteroaryl, -C 0-6 alkylene-C 3-6 cycloalkyl, C 0-6 alkylene-3-6 membered heterocyclyl;
- R 1 is optionally substituted with one or two R 2a ;
- L 1 and L 3 are independently -C 0-10 alkylene, -C 3- 10cycloalkylene -C 2-10 alkenylene, -C 2-10 alkynylene, -C 0- 6 alkylene-C 6-10 aryl, -C 0-6 alkylene-heteroaryl, -C 0-10 alkylene-3-6 membered heterocyclyl or L 1 and L 3 are absent and L 2 is directly connected with R 2 and the carbon atom of the ring with chemical bonds;
- L 2 is O, S, S (O) , S (O) 2 , C (O) NR 1a S (O) 2 , S (O) (NH) , S (O) (NCN) , C (O) , C (O) -C (O) , C (O) O, NR 1a , NR 1a C (O) , NR 1a C (O) -C (O) NR 1a , NR 1a S (O) 2 , NR 1a S (O) 2 NR 1a or L 2 is absent and L 1 and L 3 are connected with a chemical bond;
- R 1a is independently selected from the group consisting of hydrogen, -C 1-4 alkyl, -C 0-10 alkylene-C 6-10 aryl, -C 0- 10 alkylene-5-10-membered heteroaryl, -C 0-10 alkylene-C 3-6 cycloalkyl, -C 0-10 alkylene-3-6 membered heterocyclyl;
- R 2 is selected from the group consisting of -C 1-6 alkyl, -C 1-6 haloalkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 0-10 alkylene-C 3-10 cycloalkyl, -C 4-10 cycloalkenyl, -C 0-10 alkylene-3-10-membered heterocyclyl, -C 0-10 alkylene-C 6-10 aryl, -C 0- 10 alkylene-5-10-membered heteroaryl, -C 0-10 alkyleneNR a R b , -C 0-10 alkylene-P (O) R a R b , -C 0-10 alkylene-P (O) (OR a ) (OR b ) , -C 0-10 alkylene-NR c C (O) NR a R b , -C 0-10 alkylene-NR c C (O) R 1a
- R a may be connected with Y through a bond to form an additional 5 to 7 membered ring
- R 2 may be directly connected to Y through a bond when R 1a is absent;
- R 2a is independently selected from the group consisting of halo, OH, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, -SC 1-6 alky, C 3-6 cycloalkyloxy, hydroxy, amino, -C (O) NR a R b , S (O) 2 R a , -S (O) (NCN) R a , -P (O) R a R b , -P (O) (OR a ) (OR b ) , -NR c C (O) NR a 2 , -NR c S (O) 2 NR a 2 , -NR c S (O) 2 R a , -NR a R b , -NR a C (O) OR a , -S (O) 2 NR a R b , -NR c S (O) 2 NR a R b , -
- R a , R b and R c are independently hydrogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3 - 10 cycloalkyl, -C 4-10 cycloalkenyl, -3-10-membered heterocyclyl, -C 6-10 aryl, -5-10-membered heteroaryl; R a and R b , R b and R c or R 1 and R c may be taken together with the atom (s) to which they are attached to form an optionally substituted 5-10 membered carbocyclyl, or heterocyclyl which contains 0-3 heteroatoms and is optionally substitute with 0-5 occurrences of R 10 ; R a , R b and R c are independently substituted with 0-5 occurrences of R 10 ;
- R 10 is independently selected from C 1-6 alkyl, C 1-6 alkoxy, halo, hydroxy, oxo, amino, C 0-6 alkylene-C (OH) R a R b , C 0-6 alkylene-NR b R c , C 0-6 alkylene-NR b R c , C 0-6 alkylene-C (O) NR a R b , C 0-6 alkylene-NR c C (O) R b , C 0-6 alkylene-S (O) 2 R b , C 0-6 alkylene-S (O) 2 NR a R b , C 0-6 alkylene-NR c S (O) 2 R b , C 0-6 alkylene-NR c S (O) 2 NR a R b , C 0-6 alkylene-NR c S (O) 2 NR a R b , C 0-6 alkylene-P (O) R a R
- R 3 and R 3a are selected from hydrogen, CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3 - 6 cycloalkyl, -NR a R b , -OR 3a , -SR 3a ; where R 3a is H, C 1-6 alkyl, C 1-6 hahoalkyl, -C 3-6 cycloalkyl, 5-6 membered heterocyclyle;
- R 4 and R 4a are selected from H, -C 1-6 alkyl, -C 1-6 haloalkyl; R 4 and R 4a together with the atom to which they are attached to form a 2-6membered cycloalkyl; or R 4 can be connected with an atom of ring A to form a 5-10 membered carbocyclyle or 5-10 membered heterocyclyle;
- R 5 is independently selected from -C 1-6 alkyl, -C 1-6 haloalkyl, -OC 1-6 alk, -OC 1-6 haloalkyl, halo, hydroxy, oxo, -C 0-6 alkylene-NR a R b , -C 0-6 alkylene-C (O) NR a R b , -C 0-6 alkylene-NR c C (O) R b , -C 0-6 alkylene-S (O) 2 R b , -C 0- 6 alkylene-S (O) 2 NR a R b , -C 0-6 alkylene-NR c S (O) 2 R b , -C 0-6 alkylene-NR c S (O) 2 NR a R b , -C 0-6 alkylene-NR c S (O) 2 R b , -C 0-6 alkylene-NR c S (
- R 6 is selected from hydrogen, -C 1-6 alkyl, -OC 1-6 alkyl, -C 1-6 haloalkyl, halo, hydroxy, -C 0-6 alkylene-NR a R b , -C 0-6 alkylene-C (O) NR a R b , -C 0-6 alkylene-NR c C (O) R b , -C 0-6 alkylene-S (O) 2 R b , -C 0-6 alkylene-S (O) 2 NR a R b , -C 0- 6 alkylene-NR c S (O) 2 R b , -C 0-6 alkylene-NR c S (O) 2 NR a R b , -C 0-6 alkylene-NR c S (O) 2 NR a R b , -C 0-6 alkylene-NR c S (O) 2 NR a R b
- n 1, 2 or 3.
- the invention further provides a compound of Formula II or a pharmaceutically acceptable salt thereof:
- R 1 , R 2 , R 3 , R 4 , R 4a , R 5 , L 1 , L 2 , L 3 , ring A and n are as defined in Formula I.
- the invention further provides a compound of Formula III or a pharmaceutically acceptable salt thereof:
- R 1 , R 2 , R 3 , R 4 , R 4a , R 5 , L 1 , L 2 , L 3 and n are as defined in Formula I.
- the invention further provides a compound of Formula IV or a pharmaceutically acceptable salt thereof:
- R 1 , R 2 , R 3 , R 4 , R 5 , L 1 , L 2 , L 3 and n are as defined in Formula I.
- the invention further provides a compound of Formula V or a pharmaceutically acceptable salt thereof:
- R 1 , R 3 , R 4 , R 4a , R 5 , R a , R b and n are as defined in Formula I.
- the invention further provides a compound of Formula VI or a pharmaceutically acceptable salt thereof:
- R 1 , R 3 , R 4 , R 5 , R a , R b and n are as defined in Formula I.
- the invention further provides a compound of Formula VII or a pharmaceutically acceptable salt thereof:
- R 1 , R 2 , R 3 , R 4 , R a , R b , R c , R 5 and n are as defined in Formula I, provided that R 2 is not -NR a R b or -NR c C (O) R a R b ; X is O or S.
- the invention further provides a compound of Formula VIII or a pharmaceutically acceptable salt thereof:
- R 1 , R 1a , R 2 , R 3 , R 4 , R a , R b , R 5 and n are as defined in Formula I, provided that R 2 is not -P (O) R a R b , -P (O) (OR a ) (OR b ) .
- the invention further provides a compound of Formula IX or a pharmaceutically acceptable salt thereof:
- R 1 , R 2 , R 3 , R 4 , R 4a , R 5 , Q 1 , Q 3 , L 1 , L 2 , L 3 and n are as defined in Formula I;
- Q 6 and Q 7 are each independently CH, N, NH, O or S, provided at least one of Q 6 and Q 7 is N, NH, O or S.
- the invention further provides a compound of Formula X or a pharmaceutically acceptable salt thereof:
- R 1 , R 2 , R 3 , R 4 , R 4a , R 5 , Q 1 , Q 3 , L 1 , L 2 , L 3 and n are as defined in Formula I;
- Q 6 and Q 7 are each independently CH, N, NH, O or S, provided at least one of Q 6 and Q 7 is N, NH, O or S.
- the invention further provides a compound of Formula XI or a pharmaceutically acceptable salt thereof:
- R 1 , R 2 , R 3 , R 4 , R c , R 4a , R 5 , L 1 , L 2 , L 3 , ring A and n are as defined in Formula I;
- Y 1 is O, S, NR c or absent.
- R 1 , R 2 , R 3 , R 4 , R c , R 4a , R 5 , Q 1 , Q 3 , L 1 , L 2 , L 3 and n are as defined in Formula I;
- Y 1 is O, S, NR c or absent;
- Q 6 and Q 7 are each independently CH, N, NR c , O or S, provided at least one of Q 6 and Q 7 is N, NR c , O or S.
- R 1 , R 2 , R 3 , R 4 , R c , R 4a , R 5 , Q 1 , Q 3 , L 1 , L 2 , L 3 and n are as defined in Formula I;
- Y 1 is O, S, NR c or absent;
- Q 6 and Q 7 are each independently CH, N, NR c , O or S, provided at least one of Q 7 and Q 8 is N, NR c , O or S.
- Y is O, S or NR 1 .
- the invention further provides a compound of Formula XIV or a pharmaceutically acceptable salt thereof:
- R 3 , R 4 , R 4a , R 5 and n are as defined in Formula I;
- L 2 is O, -C (O) , NR c or absent;
- R 2 is -C 0-10 alkylene-C 3 - 10 cycloalkyl, -C 0-10 alkylene-3-10-membered heterocyclyl, -C 0-10 alkylene-5-10-membered heteroaryl, -C 0- 10 alkylene-NR a R b ;
- R 2 is optionally substituted by one or more R 2a ;
- Ring B is selected from -C 0-10 alkylene-C 3 - 10 cycloalkyl, -C 0-10 alkylene-3-10-membered heterocyclyl, -C 0-10 alkylene-5-10-membered heteroaryl;
- Ring B is optionally substituted by one or more R 2a ;
- R a , R b , R c and R 2a
- the invention further provides a compound of Formula XV or a pharmaceutically acceptable salt thereof:
- R 3 , R 4 , R 4a , R 5 and n are as defined in Formula I;
- L 2 is O, -C (O) , NR c or absent;
- R 2 is -C 0-10 alkylene-C 3 - 10 cycloalkyl, -C 0-10 alkylene-3-10-membered heterocyclyl, -C 0-10 alkylene-5-10-membered heteroaryl, -C 0- 10 alkylene-NR a R b ;
- R 2 is optionally substituted by one or more R 2a ;
- Ring B is selected from -C 0-10 alkylene-C 3 - 10 cycloalkyl, -C 0-10 alkylene-3-10-membered heterocyclyl, -C 0-10 alkylene-5-10-membered heteroaryl;
- Ring B is optionally substituted by one or more R 2a ;
- R a , R b , R c and R 2a
- R 3 , R 4 , R 4a , R 5 , Q 1 , Q 3 and n are as defined in Formula I;
- Q 6 and Q 7 are each independently CH, N, NR c , O or S, provided at least one of Q 6 and Q 7 is N, NR c , O or S;
- L 2 is O, -C (O) , NR c or absent;
- R 2 is -C 0-10 alkylene-C 3 - 10 cycloalkyl, -C 0-10 alkylene-3-10-membered heterocyclyl, -C 0-10 alkylene-5-10-membered heteroaryl, -C 0- 10 alkylene-NR a R;
- R 2 is optionally substituted by one or more R 2a ;
- Ring B is selected from -C 0-10 alkylene-C 3 - 10 cycloalkyl, -C 0-10 alkylene-3-10-membered heterocyclyl, -C
- R 3 , R 4 , R 4a , R 5 , Q 1 , Q 3 and n are as defined in Formula I;
- Q 6 and Q 7 are each independently CH, N, NR c , O or S, provided at least one of Q 6 and Q 7 is N, NR c , O or S;
- L 2 is O, -C (O) , NR c or absent;
- R 2 is -C 0-10 alkylene-C 3 - 10 cycloalkyl, -C 0-10 alkylene-3-10-membered heterocyclyl, -C 0-10 alkylene-5-10-membered heteroaryl, -C 0- 10 alkylene-NR a R b ;
- R 2 is optionally substituted by one or more R 2a ;
- Ring B is selected from -C 0-10 alkylene-C 3 - 10 cycloalkyl, -C 0-10 alkylene-3-10-membered heterocyclyl,
- R 3 , R 4 , R 4a , R 5 , Q 1 , Q 3 and n are as defined in Formula I;
- Q 6 and Q 7 are each independently CH, N, NR c , O or S, provided at least one of Q 6 and Q 7 is N, NR c , O or S;
- L 2 is O, -C (O) , NR c or absent;
- R 2 is -C 0-10 alkylene-C 3 - 10 cycloalkyl, -C 0-10 alkylene-3-10-membered heterocyclyl, -C 0-10 alkylene-5-10-membered heteroaryl, -C 0- 10 alkylene-NR a R b ;
- R 2 is optionally substituted by one or more R 2a ;
- Ring B is selected from -C 0-10 alkylene-C 3 - 10 cycloalkyl, -C 0-10 alkylene-3-10-membered heterocyclyl,
- R 3 , R 4 , R 4a , R 5 , Q 1 , Q 3 and n are as defined in Formula I;
- Q 6 and Q 7 are each independently CH, N, NR c , O or S, provided at least one of Q 6 and Q 7 is N, NR c , O or S;
- L 2 is O, -C (O) , NR c or absent;
- R 2 is -C 0-10 alkylene-C 3 - 10 cycloalkyl, -C 0-10 alkylene-3-10-membered heterocyclyl, -C 0-10 alkylene-5-10-membered heteroaryl, -C 0- 10 alkylene-NR a R b ;
- R 2 is optionally substituted by one or more R 2a ;
- Ring B is selected from -C 0-10 alkylene-C 3 - 10 cycloalkyl, -C 0-10 alkylene-3-10-membered heterocyclyl,
- the invention further provides a compound of Formula XX or a pharmaceutically acceptable salt thereof:
- R 1 , R 2 , R 3 , R 4 , R 4a , R 5 , Y 1 , L 1 , L 2 , L 3 , ring A and n are as defined in Formula I.
- the invention further provides a compound of Formula XXI or a pharmaceutically acceptable salt thereof:
- Q 1 , Q 2 , Q 3 , R 1 , R 4 , R 4a , R 5 and n are defined as in Formula I;
- X is C (O) , C (R 7 ) 2 ;
- R 7 is independently selected from hydrogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 0-6 alkylene-NR a R b , -C 0-6 alkylene-C (O) NR a R b , -C 0-6 alkylene-NR c C (O) R b , -C 0-6 alkylene-S (O) 2 R b , -C 0-6 alkylene-S (O) 2 NR a R b , -C 0-6 alkylene-NR c S (O) 2 R b , -C 0-6 alkylene-NR c S (O) 2 NR a R b , -C 0-6 alkylene
- R 4 , R 4a , R 5 , Q 1 , Q 2 , Q 3 and n are defined as in Formula I;
- X is C (O) , C (R 7 ) 2 ;
- R 7 is independently selected from hydrogen, -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, -C 0-6 alkylene-NR a R b , -C 0-6 alkylene-C (O) NR a R b , -C 0-6 alkylene-NR c C (O) R b , -C 0-6 alkylene-S (O) 2 R b , -C 0-6 alkylene-S (O) 2 NR a R b , -C 0-6 alkylene-NR c S (O) 2 R b , -C 0- 6 alkylene-NR c S (O) 2 NR a R b ,
- the invention further provides a compound of Formula XXIII or a pharmaceutically acceptable salt thereof:
- Ring A, R 2 , R 4 , R 4a , R 5 , Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , L 1 , L 2 , L 3 and n are defined as in Formula I;
- Q 6 , Q 7 and Q 8 are independently selected from N and CR 10 ;
- R 10 is as defined in Formula I.
- the invention further provides a compound of Formula XXIV or a pharmaceutically acceptable salt thereof:
- Ring A, R 2 , R 4 , R 4a , R 5 , Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , L 1 , L 2 , L 3 , Y and n are as defined in Formula I;
- Q 6 , Q 7 and Q 8 are independently selected from N and CR 10 ;
- R 10 is as defined in Formula I.
- the present invention also relates to all forms of prodrugs of Formula I to XXIV, which e.g. bear ester or amide groups that are cleaved under physiological conditions.
- a compound of Formula I to XXIV is selected from the group consisting of the compounds below, or a pharmaceutically acceptable salt thereof:
- the invention features a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound disclosed herein.
- alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e. unbranched) or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono-or polyunsaturated and can include di-and multivalent radicals, having the number of carbon atoms designated (i.e. C 1-10 means one to ten carbons) .
- saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
- An unsaturated alkyl group is one having one or more double bonds or triple bonds.
- alkyl groups examples include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl) , 2, 4-pentadienyl, 3- (1, 4-pentadienyl) , ethynyl, 1-and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
- Alkyl groups which are limited to hydrocarbon groups are termed "homoalkyl” .
- the alkyl is optionally substituted with one or more halogen atom (s) .
- halogenated alkyl means alkyl as defined above wherein one or more hydrogen atoms have been replaced by halogen atoms.
- the alkylene radical may be optionally substituted independently with one or more substituents described herein, and includes radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations.
- an alkyl (or alkylene) group has from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention.
- a "lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
- the alkylene is optionally substituted with one or more halogen atom (s) .
- alkynyl means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like. The alkynyl is optionally substituted with one or more halogen atom (s) .
- alkylamino refers to an amino substituent which is further substituted with one or two alkyl groups.
- aminoalkyl refers to an alkyl substituent which is further substituted with one or more amino groups.
- hydroxyalkyl refers to an alkyl substituent which is further substituted with one or more hydroxyl groups.
- alkyl or aryl portion of alkylamino, aminoalkyl, mercaptoalkyl, hydroxyalkyl, mercaptoalkoxy, sulfonylalkyl, sulfonylaryl, alkylcarbonyl, and alkylcarbonylalkyl may be optionally substituted with one or more substituents.
- cycloalkyl or “carbococyclyl” means mono-, bicyclic or spiro-bicyclic carbocyclic rings, each of which has from 3 to 10 carbon atoms.
- a “fused analog” of cycloalkyl means a monocyclic ring fused to an aryl or heteroaryl group in which the point of attachment is on the non-aromatic portion. Examples of cycloalkyl and fused analogs thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl, and the like.
- the spiro-bicyclic carbocyclic rings are bicyclic (having just two rings) or have a bicyclic portion as part of the larger ring system, in either case with the two rings connected through the defining single common carbon atom.
- the cycloalkyl is optionally substituted with one or more halogen atom (s) .
- alkoxy means alkoxy groups of a straight or branched having the indicated number of carbon atoms.
- C 1-6 alkoxy for example, includes methoxy, ethoxy, propoxy, isopropoxy, and the like.
- heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of at least one carbon atoms and at least one heteroatom selected from the group consisting of O, N, P, Si and S, and wherein the nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
- the heteroatom (s) O, N, P and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which alkyl group is attached to the remainder of the molecule.
- heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH 2 -CH 2 -S-CH 2 -CH 2 -and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -.
- heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, and the like) .
- chain termini e.g., alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, and the like.
- no orientation of the linking group is implied by the direction in which the formula of the linking group is written.
- heteroalkyl groups include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C (O) R', -C (O) NR', -NR'R", -OR', -SR', and/or -SO 2 R'.
- heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R” or the like, it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R” or the like.
- cycloalkoxy means cycloalkyl as defined above bonded to an oxygen atom, such as cyclopropyloxy.
- halogenated alkoxy means alkoxy as defined above wherein one or more hydrogen atoms have been replaced by halogen atoms.
- aryl means mono-or bicyclic aromatic rings containing only carbon atoms.
- a “fused analog” of aryl means an aryl group fused to a monocyclic cycloalkyl or monocyclic heterocyclyl group in which the point of attachment is on the aromatic portion. Examples of aryl and fused analogs thereof include phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2, 3-dihydrobenzofuranyl, dihydrobenzopyranyl, 1, 4-benzodioxanyl, and the like.
- heteroaryl means a mono-or bicyclic aromatic ring containing at least one heteroatom selected from N, O and S, with each ring containing 5 to 6 atoms.
- a “fused analog” of heteroaryl means a heteroaryl group fused to a monocyclic cycloalkyl or monocyclic heterocyclyl group in which the point of attachment is on the aromatic portion.
- heteroaryl examples include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, furo (2, 3-b) pyridyl, quinolyl, indolyl, isoquinolyl, and the like.
- heterocyclyl means mono-, bicyclic, tricyclic, spirocyclic, fused or bridged saturated ring systems containing at least one heteroatom selected from N, S and O, each of said ring having from 3 to 10 atoms in which the point of attachment may be carbon or nitrogen.
- a “heterocyclyl” includes a “fused analog” which means a monocyclic heterocycle fused to a heterocycle, a carbocycle, an aryl or heteroaryl group in which the point of attachment is on the non-aromatic portion.
- heterocyclyl and fused analogs thereof include azeridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dioxolanyl, oxazolodinyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, quinuclidinyl, thiomorpholinyl, thiomorphonulyl 1, 1-dioxide, morpholinyl, azapanyl, oxazepanyl, azabicyclohexanyls, azabicycloheptanyl, azabicyclooctanyl, azabycyclononanyl, azaspiroheptanyl, dihydro-1H, 3H, 5H-oxazolo [3, 4-c] oxazolyl, tetroxazolyl,
- the term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2-or 4-pyridones attached through the nitrogen or N-substituted- (1H, 3H) -pyrimidine-2, 4-diones (N-substituted uracils) .
- alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups referred to in the definitions are unsubstituted or are substituted by at least one substituent selected from the group consisting of substituents.
- the substituents are selected from the group consisting of halogen atoms, alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, haloalkyl groups having from 1 to 4 carbon atoms, haloalkoxy groups having from 1 to 4 carbon atoms, cyano groups, alkynyl groups having from 2 to 6 carbon atoms, alkanoyl groups having from 1 to 5 carbon atoms, cycloalkyl groups having from 3 to 7 ring atoms, heteroaryl groups, aryl groups, aralkoxy groups having from 7 to 10 carbon atoms, arylcarbonyl groups, two adjacent-x groups are optionally joined together to form an alkylene or an alkenylene chain having 3 or 4 carbon atoms, aminocarbonyl groups, alkenyl groups having from 2 to 5 carbon atoms, alkylthio groups having from 1 to 4 carbon atoms, aminosulfinyl groups, aminosulfony
- halo or halogen, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl, “ or “halogenated alkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo (C 1 -C 4 ) alkyl” is meant to include, but not be limited to, trifluoromethyl, 2, 2, 2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
- prodrug refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrugs may also have improved solubility in pharmaceutical compositions over the parent drug.
- An example, without limitation, of a prodrug would be a compound of any of Formula I, which is administered as an ester (the "prodrug” ) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility, but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial.
- a further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
- Compounds of the present invention may contain one or more asymmetric centers and may thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers.
- the present invention is meant to comprehend all such isomeric forms of the compounds.
- Some of the compounds of described herein may contain one or more than one cyclic ring systems and may thus exist in cis-and trans-isomers.
- the present invention is meant to include all such cis-and trans-isomers.
- tautomers Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of the present invention.
- any enantiomer of a compound described herein may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
- One or more than one of the protons (hydrogen atoms) in compounds of the present invention can be replaced with deuterium atom (s) , thus providing deuterated analogs that may have improved pharmacokinetic properties or pharmacological activities.
- the compounds described herein can be useful as the free base or as a salt.
- salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
- Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
- Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N, N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydramine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
- basic ion exchange resins such as arg
- salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
- acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
- Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
- Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients are mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
- an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
- an oil medium for example peanut oil, liquid paraffin, or olive oil.
- Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
- excipients are suspending agents, for example sodium carboxymethyl-cellulose, methylcellulose, hydroxypropylmethy-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene- oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene
- the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
- preservatives for example ethyl, or n-propyl, p-hydroxybenzoate
- coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
- coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
- flavoring agents such as sucrose, saccharin or aspartame.
- sweetening agents such as sucrose, saccharin or aspartame.
- Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
- the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
- Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
- a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
- the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions.
- the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
- Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
- the emulsions may also contain sweetening and flavouring agents.
- Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
- the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1, 3-butane diol.
- Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono-or diglycerides.
- fatty acids such as oleic acid find use in the preparation of injectables.
- the compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomiser (preferably an I atomiser using electrohydrodynamics to produce a fine mist) , or nebuliser, with or without the use of a suitable propellant, such as 1, 1, 1, 2-tetrafluoroethane or 1, 1, 1, 2, 3, 3, 3-heptafluoropropane.
- the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
- the pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the compound (s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, a propellant (s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
- a solution or suspension of the compound (s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, a propellant (s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
- the drug product Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns) .
- This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.
- Capsules (made, for example, from gelatin or HPMC) , blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol, or magnesium stearate.
- the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
- Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
- a suitable solution formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from l mg to 20 mg of the compound of the invention per actuation and the actuation volume may vary from 1 L to 100 L.
- a typical formulation may comprise a compound of Formula (A) propylene glycol, sterile water, ethanol and sodium chloride.
- Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
- Suitable flavors such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
- Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, poly (DL-lactic-coglycolic acid (PGLA) .
- Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
- the dosage unit is determined by means of a valve which delivers a metered amount.
- Units in accordance with the invention are typically arranged to administer a metered dose or "puff" containing from 1 pg to 1 mg of the compound of the present invention.
- the overall daily dose will typically be in the range 1 pg to 1 mg which may be administered in a single dose or, more usually, as divided doses throughout the day.
- compositions of the present invention may also be administered in the form of suppositories for rectal administration of the drug.
- These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
- suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
- suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
- Such materials are cocoa butter and polyethylene glycols.
- creams, ointments, jellies, solutions or suspensions, etc., containing the compound of the present invention are employed.
- topical application shall include mouth washes and gargles.
- Dosage levels of the order of from about 0.01 mg to about 140 mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5 mg to about 7 g per patient per day.
- a condition may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day, preferably 2.5 mg to 1 g per patient per day.
- the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
- a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
- Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
- Compounds of the present invention may be used for treatment of conditions such as cancer.
- the SOS1 inhibitors disclosed herein can be combined with other cancer treatments.
- the SOS1 inhibitors can be administered in combination with surgical treatments, radiation, or other therapeutic agents such as antibodies, other kinase inhibitors (such as RTK inhibitors) , target therapies, inhibitors for RAS signaling pathway (e.g a SHP2 inhibitor, a KRAS inhibitor, a RAF inhibitor, A MEK inhibitor or an ERK inhibitor) , or chemotherapeutics.
- the inhibitors may also be administered in combination with RNAi therapy, antisense therapy, vaccines, or immunotherapies including adoptive cell transfer therapy such as CAR-T therapy.
- the SOS1 inhibitors described herein may be combined with one, two, or more other therapeutic agents.
- second therapeutic agent also includes more than one therapeutic agent other than the SOS1 inhibitor.
- the compounds disclosed herein may be combined with an agent such as a kinase inhibitor, a KRAS inhibitor, a PD-1 antibody, a PD-L1 antibody, a CTLA4 antibody, or any other checkpoint protein antibodies.
- the compounds of the present invention can be prepared according to the following synthetic schemes:
- HTRF time-resolved fluorescence
- HTRF ratio was calculated using the following equation: (emission signal at 665 nm) / (emission signal at 620 nm) x 10,000. IC 50 value was determined as the concentration for 50%inhibition of HTRF ratio compared to DMSO.
- IC 50 values of the example compounds determined using the HTRF assay are disclosed in the following table (A + : IC 50 ⁇ 0.01 ⁇ M; A: IC 50 between 0.01 ⁇ M and 0.1 ⁇ M B: IC 50 between 0.1 ⁇ M and 1.0 ⁇ M; C: IC 50 between 1.0 ⁇ M and 10.0 ⁇ M; D: IC 50 > 10.0 ⁇ M; ND: not determined) .
- EA means ethyl acetate
- CIP means 2-chloro-1, 3-dimethylimidazolidium hexafluorophosphate
- DBU means l, 8-diazabicyclo [5.4.0] undec-7-ene
- DIBAL means diisobutylaluminum hydride
- DCM means dichloromethane
- DIEA means diisopropylethylamine
- DMAP means N, N-dimethylaminopyridine
- DME means 1, 2-dimethoxyethane
- DMF means N, N-dimethylformamide
- dmpe means l, 2-bis (dimethyl ⁇ hosphino) ethane
- DMSO means dimethylsulfoxide
- dppb means l, 4-bis (diphenylphosphino) butane
- dppe means 1, 2-bis (diphenylphosphino) ethane
- dppf means 1, 1’-bis (
- T3P means propylphosphonic anhydride
- TCFH means N, N, N’, N’-tetramethylchloroformaidinium hexafluorophosphate
- MTBE means methyl tert-butyl ether
- NBS means N-Bromosuccinimide
- DMA means N, N-Dimethylacetamide, *in structures means undetermined R or S chiral center.
- Step 4 (E) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylidene) -2-methylpropane-2-sulfinamide
- Step 5 N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpropane-2-sulfinamide
- Step 12 ( ⁇ ) 4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methylpyrido [2, 3-d] pyrimidin-7 (8H) -one
- Step 1 (R, E) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylidene) -2-methylpropane-2-sulfinamide
- Step 4 (R) -4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid
- step 4 was prepared by using the same method as described in Step 1 to step 3 of EXAMPLE 9.
- Step 6 (R) -4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrido [2, 3-d] pyrimidin-7 (8H) -one
- Step 1 ( ⁇ ) tert-butyl4- (4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidin-6-yl) -1H-pyrazole-1-carboxylate
- Step 2 ( ⁇ ) 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6- (1H-pyrazol-4-yl) pyrido [2, 3-d] pyrimidin-7 (8H) -one
- Step 1 ( ⁇ ) 4-chloro-6- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methylpyrimidine-5-carbaldehyde
- Step 3 4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid
- Example 10 To a stirred solution of Example 10 (60 mg, 0.143 mmol) in DMF (1.0 mL) were added Cs 2 CO 3 (93 mg, 0.286 mmol) and CH 3 I (26 mg, 0.186 mmol) at rt. The resulting mixture was stirred for 1 h at rt, quenched with water. The solid was collected by filtration and dried to give 21.5 mg of the title product as a white solid. MS (ES+) : 434.0 [M+1] + .
- Step 4 (E) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylidene) -2-methylpropane-2-sulfinamide
- Step 5 N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpropane-2-sulfinamide
- Step 8 ( ⁇ ) 4-chloro-6- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methylpyrimidine-5-carbaldehyde
- Step 9 ( ⁇ ) 4-amino-6- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methylpyrimidine-5-carbaldehyde
- Step 10 ( ⁇ ) 4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid
- Step 11 ( ⁇ ) 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 2-trimethyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxamide
- Step 12 ( ⁇ ) 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
- Step 1 (R, E) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylidene) -2-methylpropane-2-sulfinamide
- Step 4 (R) -4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid
- Step 5 4- ( (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -6- (2, 6-dimethylpiperidine-1-carbonyl) -2-methylpyrido [2, 3-d] pyrimidin-7 (8H) -one
- Step 1 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -8- (4-methoxybenzyl) -2-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) amino) pyrido [2, 3-d] pyrimidin-7 (8H) -one
- Step 2 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) amino) pyrido [2, 3-d] pyrimidin-7 (8H) -one
- Step 2 4- ( ( (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) pyrido [2, 3-d] pyrimidin-7 (8H) -one
- Step 2 4- ( ( (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6- ( ( (R) -tetrahydrofuran-3-yl) oxy) pyrido [2, 3-d] pyrimidin-7 (8H) -one
- Step 1 (R) -7-chloro-4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
- Step 2 (R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -7- (dimethylamino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
- Step 1 4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -6-iodo-8- (4-methoxybenzyl) -2-methylpyrido [2, 3-d] pyrimidin-7 (8H) -one
- Step 2 4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -6-iodo-2-methylpyrido [2, 3-d] pyrimidin-7 (8H) -one
- Step 2 (R) -4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 2-trimethyl-7- (piperazin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
- Step 1 7-chloro-N- ( (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) pyrido [2, 3-d] pyrimidin-4-amine
- Step 2 N4- ( (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -N7, N7, 2-trimethyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) pyrido [2, 3-d] pyrimidine-4, 7-diamine
- Step 1 3-nitro-5- (trifluoromethyl) phenyl) ethanone
- Step 2 (R, E) -2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylidene) propane-2-sulfinamide
- Step 5 (R) -4-chloro-6- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methylpyrimidine-5-carbaldehyde
- Step 6 (R) -4-amino-2-methyl-6- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrimidine-5-carbaldehyde
- Step 7 (R) -2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid
- Step 8 (R) -N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxamide
- Step 9 (R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -N, N, 2-trimethyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxamide
- Step 1 (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
- Step 2 (R) -7- (dimethylamino) -N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
- Step 3 (R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (dimethylamino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
- Step 1 (R) -N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
- Step 2 (R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
- Step 1 (R) -7- (azetidin-1-yl) -N, N, 2-trimethyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxamide
- Step 2 (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (azetidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamid
- Step 1 (R) -N, N, 2-trimethyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (piperidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
- Step 2 (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -N, N, 2-trimethyl-7- (piperidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
- Step 1 (R) -N, N, 2-trimethyl-7-morpholino-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxamide
- Step 2 (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -N, N, 2-trimethyl-7-morpholinopyrido [2, 3-d] pyrimidine-6-carboxamide
- Step 1 (R) -N, N, 2-trimethyl-7- (4-methylpiperazin-1-yl) -4- ( (1- (3-nitro-5 (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxamide
- Step 2 (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -N, N, 2-trimethyl-7- (4-methylpiperazin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
- Step 1 (R) -7- (4, 4-difluoropiperidin-1-yl) -N, N, 2-trimethyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxamide
- Step 2 (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (4, 4-difluoropiperidin-1-yl) -N, N, 2-trimethyl pyrid o [2, 3-d] pyrimidine-6-carboxamide
- Step 1 (R) -7- (3, 3-difluoroazetidin-1-yl) -N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
- Step 2 (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (3, 3-difluoroazetidin-1-yl) -N, N, 2-trimethylpyrid o [2, 3-d] pyrimidine-6-carboxamide
- Step 1 (R) -4- (1- (3-bromo-5- (trifluoromethyl) phenyl) ethylamino) -7- (dimethylamino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
- Step 2 (R) -7- (dimethylamino) -N, N, 2-trimethyl-4- (1- (3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
- Step 1 (R) -methyl 2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine -6-carboxylate
- Step 2 (R) -methyl 7-chloro-2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxylate
- Step 3 (R) -methyl 7- (dimethylamino) -2-methyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxylate
- Step 4 (R) -7- (dimethylamino) -2-methyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxylic acid
- Step 6 (R) - (4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (dimethylamino) -2-methylpyrido [2, 3-d] pyrimidin-6-yl) (morpholino) methanone
- Step 1 (R) - (7- (dimethylamino) -2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidin-6-yl) (piperidin-1-yl) methanone
- Step 2 (R) - (4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (dimethylamino) -2-methylpyrido [2, 3-d] pyrimidin-6-yl) (piperidin-1-yl) methanone
- Step 1 (R) - (7- (dimethylamino) -2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidin-6-yl) (pyrrolidin-1-yl) methanone
- Step 2 (R) - (4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (dimethylamino) -2-methylpyrido [2, 3-d] pyrimidin-6-yl) (pyrrolidin-1-yl) methanone
- Step 1 (R) -7- (3, 3-difluoropyrrolidin-1-yl) -N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
- Step 2 (R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (3, 3-difluoropyrrolidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
- Step 1 (R) -7- (4-fluoropiperidin-1-yl) -N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
- Step 2 (R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (4-fluoropiperidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
- Step 1 (R) -methyl2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine -6-carboxylate
- Step 2 (R) -2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxylic acid
- Step 3 (R) - (2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) (piperidin-1-yl) methanone
- Step 4 (R) - (4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) (piperidin-1-yl) methanone
- Step 1 (R) - (2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) (morpholino) methanone
- Step 2 (R) - (4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) (morpholino) methanone
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Abstract
This disclosure relates to heterocyclics as inhibitors of SOS1, in particular relates to a compound of Formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising said compound that are useful for treatment of SOS1 mediated diseases and conditions such as cancer.
Description
Field of Technology
The present invention relates to heterocyclic compounds as inhibitors of SOS1 that are useful for treatment of SOS1 mediated diseases and conditions such as cancer.
RAS proteins are small, membrane-bound guanine nucleotide-binding proteins; they act as molecular switches by cycling between active GTP-bound and inactive GDP-bound conformations. There are 3 major isoforms of RAS proteins: KRAS, NRAS and HRAS. They play a crucial role in the regulation of cell proliferation, differentiation and survival. Hyperactivating mutations of major RAS isoforms are among the most common lesions found in cancer, with KRAS mutations being by far the most common in human cancer. Most of these mutations have been shown to cause an increase in the active GTP-bound population, leading to oncogenic transformation. The binding of guanine nucleotide exchange factors (GEFs) such as SOS1 (Son of Sevenless 1) promote release of GDP from RAS proteins, enabling GTP binding, thus activating RAS protein signaling in cancer via mechanisms other than mutations in RAS proteins. In addition, SOS1 is also a GEF for the activation of the GTPase RAC1 (Ras-related C3 botulinum toxin substrate 1) which is implicated in the pathogenesis of various forms of human cancers and other diseases. Selective pharmacological inhibition of the binding of the catalytic site of SOS1 to RAS proteins by SOS1 inhibitors is expected to prevent SOS1-mediated activation of RAS proteins to the GTP-bound form. Therefore, SOS1 inhibitors are expected to consequently inhibit signaling in cells downstream of RAS proteins (e.g. ERK phosphorylation) and exhibit anti-cancer efficacy in treatment of cancers associated with dependence on RAS proteins.
Summary of the Invention
The present invention describes inhibitors of SOS1. The present invention further describes pharmaceutical formulations that include an inhibitor of SOS1.
In one aspect, the invention features a compound of Formula I, or a pharmaceutically acceptable salt thereof:
wherein
Q
1 is CR
3a or N;
Q
2 and Q
3 are independently CR
3 or N, provided that one of Q
2 or Q
3 is N; Q
2 and Q
3 can be connected to form a 5-membered or 6-membered heterocyclic ring;
Q
4 is N or CR
6;
Q
5 is O, N or NR
1;
Y is O, S, NR
1; or Y is hydrogen, -C
1-10alkyl, -C
1-10haloalkyl, -C
0-6alkylene-C
6-10aryl, C
0-6alkylene-5-10-membered heteroaryl, -C
0-6alkylene-C
3-6cycloalkyl, C
0-6alkylene-3-6 membered heterocyclyl, OR
1, SR
1, NR
cR
1 when Q
5 is N; R
1 and R
c may be taken together with the atom (s) to which they are attached to form an optionally substituted 5-10 membered carbocyclyl, or heterocyclyl which contains 1-3 heteroatoms and is optionally substitute with 0-5 occurrences of R
10; R
1 and R
c are independently substituted with 0-5 occurrences of R
10;
Y and Q
5 may be connected with two atoms, independently selected from O, N, S or C, to form a five- membered heterocycle or five membered heteroaryl;
R
1 is independently selected from the group consisting of hydrogen, -C
1-10alkyl, -C
0-6alkylene-C
6-10aryl, C
0-
6alkylene-5-10-membered heteroaryl, -C
0-6alkylene-C
3-6cycloalkyl, C
0-6alkylene-3-6 membered heterocyclyl;
R
1 is optionally substituted with one or two R
2a;
L
1 and L
3 are independently -C
0-10alkylene, -C
3-10cycloalkylene -C
2-10alkenylene, -C
2-10alkynylene, -C
0-
6alkylene-C
6-10aryl, -C
0-6alkylene-heteroaryl, -C
0-10alkylene-3-6 membered heterocyclyl or L
1 and L
3 are absent and L
2 is directly connected with R
2 and the carbon atom of the ring with chemical bonds;
L
2 is O, S, S (O) , S (O)
2, C (O) NR
1aS (O)
2, S (O) (NH) , S (O) (NCN) , C (O) , C (O) -C (O) , C (O) O, NR
1a, NR
1aC (O) , NR
1aC (O) -C (O) NR
1a, NR
1aS (O)
2, NR
1aS (O)
2NR
1a or L
2 is absent and L
1 and L
3 are connected with a chemical bond;
R
1a is independently selected from the group consisting of hydrogen, -C
1-4alkyl, -C
0-10alkylene-C
6-10aryl, -C
0-
10alkylene-5-10-membered heteroaryl, -C
0-10alkylene-C
3-6cycloalkyl, -C
0-10alkylene-3-6 membered heterocyclyl;
R
2 is selected from the group consisting of -C
1-6alkyl, -C
1-6haloalkyl, -C
2-6alkenyl, -C
2-6alkynyl, -C
0-10alkylene-C
3-10cycloalkyl, -C
4-10cycloalkenyl, -C
0-10alkylene-3-10-membered heterocyclyl, -C
0-10alkylene-C
6-10aryl, -C
0-
10alkylene-5-10-membered heteroaryl, -C
0-10alkyleneNR
aR
b, -C
0-10alkylene-P (O) R
aR
b, -C
0-10alkylene-P (O) (OR
a) (OR
b) , -C
0-10alkylene-NR
cC (O) NR
aR
b, -C
0-10alkylene-NR
cC (O) R
1a, wherein the -C
1-6alkyl, -C
1-
6haloalkyl, -C
2-6alkenyl, -C
2-6alkynyl, -C
3-10cycloalkyl, -C
4-10cycloalkenyl, -3-10-membered heterocyclyl, -C
6-
10aryl, -5-10-membered heteroaryl are all optionally substituted by one or more R
2a; R
2 and R
1a together with N atom to which they are attached, can form a 5-6 membered heterocyclyl which may contain an additional heteroatom such as O, NR
1a or S;
R
a may be connected with Y through a bond to form an additional 5 to 7 membered ring;
-NR
cC (CO) -of R
2 may be directly connected to Y through a bond when R
1a is absent;
R
2a is independently selected from the group consisting of halo, OH, cyano, C
1-6 alkyl, C
3-6cycloalkyl, C
1-6 alkoxy, -SC
1-6alky, C
3-6cycloalkyloxy, hydroxy, amino, -C (O) NR
aR
b, S (O)
2R
a, -S (O) (NCN) R
a, -P (O) R
aR
b, -P (O) (OR
a) (OR
b) , -NR
cC (O) NR
a
2, -NR
cS (O)
2NR
a
2, -NR
cS (O)
2R
a, -NR
aR
b, -NR
aC (O) OR
a, -S (O)
2NR
aR
b, -NR
cS (O)
2NR
aR
b, -C (O) R
a, -C
1-6heteroalkyl, 5-10-membered heteroaryl, 3-10-membered heterocyclyl, or heterocyclylalkyl;
R
a, R
b and R
c are independently hydrogen, -C
1-6alkyl, -C
1-6haloalkyl, -C
2-6alkenyl, -C
2-6alkynyl, -C
3-
10cycloalkyl, -C
4-10cycloalkenyl, -3-10-membered heterocyclyl, -C
6-10aryl, -5-10-membered heteroaryl; R
a and R
b, R
b and R
c or R
1 and R
c may be taken together with the atom (s) to which they are attached to form an optionally substituted 5-10 membered carbocyclyl, or heterocyclyl which contains 0-3 heteroatoms and is optionally substitute with 0-5 occurrences of R
10; R
a, R
b and R
c are independently substituted with 0-5 occurrences of R
10;
R
10 is independently selected from C
1-6 alkyl, C
1-6alkoxy, halo, hydroxy, oxo, amino, C
0-6alkylene-C (OH) R
aR
b, C
0-6alkylene-NR
bR
c , C
0-6alkylene-NR
bR
c, C
0-6alkylene-C (O) NR
aR
b, C
0-6alkylene-NR
cC (O) R
b, C
0-6alkylene-S (O)
2R
b, C
0-6alkylene-S (O)
2NR
aR
b, C
0-6alkylene-NR
cS (O)
2R
b, C
0-6alkylene-NR
cS (O)
2NR
aR
b, C
0-6alkylene-P (O) R
aR
b, C
0-6alkylene-P (O) (OR
a) (OR
b) , C
0-6alkylene-cyano, C
0-6alkylene-C
3-8 cycloalkyl, C
0-6alkylene-5-10 membered heterocyclyl, C
0-6alkylene-C
6-10 aryl, C
0-6alkylene-5-10 membered heteroaryl; two adjacent R
10 are taken together with the atom (s) to which they are attached to form an optionally substituted 5-10 membered carbocyclyl or 5-10 membered heterocyclyl;
R
3 and R
3a are selected from hydrogen, CN, -C
1-6alkyl, -C
1-6haloalkyl, -C
2-6alkenyl, -C
2-6alkynyl, -C
3-
6cycloalkyl, -NR
aR
b, -OR
3a, -SR
3a; where R
3a is H, C
1-6alkyl, C
1-6hahoalkyl, -C
3-6cycloalkyl, 5-6 membered heterocyclyle;
R
4 and R
4a are selected from H, -C
1-6alkyl, -C
1-6haloalkyl; R
4 and R
4a together with the atom to which they are attached to form a 2-6membered cycloalkyl; or R
4 can be connected with an atom of ring A to form a 5-10 membered carbocyclyle or 5-10 membered heterocyclyle;
is selected from the group consisting of C
6-10aryl, 5-10-membered heteroaryl and 8-10-membered bicyclic heterocycle;
R
5 is independently selected from -C
1-6alkyl, -C
1-6haloalkyl, -OC
1-6alk, -OC
1-6haloalkyl, halo, hydroxy, oxo, -C
0-6alkylene-NR
aR
b, -C
0-6alkylene-C (O) NR
aR
b, -C
0-6alkylene-NR
cC (O) R
b, -C
0-6alkylene-S (O)
2R
b, -C
0-
6alkylene-S (O)
2NR
aR
b, -C
0-6alkylene-NR
cS (O)
2R
b, -C
0-6alkylene-NR
cS (O)
2NR
aR
b, -C
0-6alkylene-P (O) R
aR
b, -C
0-6alkylene-P (O) (OR
a) (OR
b) , -C
0-6alkylene-P (O) R
a) R
b, -C
0-6alkylene-cyano, -C
0-6alkylene-C
3-8cycloalkyl, -C
0-6alkylene-3-10-membered heterocyclyl, -C
0-6alkylene-C
6-10aryl, -C
0-6alkylene-5-10-membered heteroaryl; -C
2-6alkenyl, -C
2-6alkynyl, -C
0-6alkylene-C
3-10cycloalkyl, -C
4-10cycloalkenyl, -C
0-6alkylene-5-10-membered heteroaryl; two adjacent R
5 are taken together with the atom (s) to which they are attached to form an optionally substituted 5-10 membered carbocyclyl or 5-10-membered heterocyclyl; R
5 is optionally substituted with one or more R
10;
R
6 is selected from hydrogen, -C
1-6 alkyl, -OC
1-6alkyl, -C
1-6haloalkyl, halo, hydroxy, -C
0-6alkylene-NR
aR
b , -C
0-6alkylene-C (O) NR
aR
b, -C
0-6alkylene-NR
cC (O) R
b, -C
0-6alkylene-S (O)
2R
b, -C
0-6alkylene-S (O)
2NR
aR
b, -C
0-
6alkylene-NR
cS (O)
2R
b, -C
0-6alkylene-NR
cS (O)
2NR
aR
b, -C
0-6alkylene-P (O) R
aR
b, -C
0-6alkylene-P (O) (OR
a) (OR
b) , -C
0-6alkylene-cyano, -C
0-6alkylene-C
3-8 cycloalkyl, -C
0-6alkylene-3-10-membered heterocyclyl, C
0-6alkylene-C
6-10 aryl, -C
0-6alkylene-5-10-membered heteroaryl, -C
2-6alkenyl, -OC
2-6alkenyl, -C
2-6alkynyl, -OC
0-6alkyleneC
3-10cycloalkyl, -C
4-10cycloalkenyl, -OC
0-6alkylene-C
6-10aryl, -O-C
0-6alkylene-5-10-membered heteroaryl;
n is 1, 2 or 3.
In an embodiment, the invention further provides a compound of Formula II or a pharmaceutically acceptable salt thereof:
R
1, R
2, R
3, R
4, R
4a, R
5, L
1, L
2, L
3, ring A and n are as defined in Formula I.
In another embodiment, the invention further provides a compound of Formula III or a pharmaceutically acceptable salt thereof:
R
1, R
2, R
3, R
4, R
4a, R
5, L
1, L
2, L
3 and n are as defined in Formula I.
In another embodiment, the invention further provides a compound of Formula IV or a pharmaceutically acceptable salt thereof:
R
1, R
2, R
3, R
4, R
5, L
1, L
2, L
3 and n are as defined in Formula I.
In another embodiment, the invention further provides a compound of Formula V or a pharmaceutically acceptable salt thereof:
R
1, R
3, R
4, R
4a, R
5, R
a, R
b and n are as defined in Formula I.
In another embodiment, the invention further provides a compound of Formula VI or a pharmaceutically acceptable salt thereof:
R
1, R
3, R
4, R
5, R
a, R
b and n are as defined in Formula I.
In another embodiment, the invention further provides a compound of Formula VII or a pharmaceutically acceptable salt thereof:
R
1, R
2, R
3, R
4, R
a, R
b, R
c, R
5 and n are as defined in Formula I, provided that R
2 is not -NR
aR
b or -NR
cC (O) R
aR
b; X is O or S.
In another embodiment, the invention further provides a compound of Formula VIII or a pharmaceutically acceptable salt thereof:
R
1, R
1a, R
2, R
3, R
4, R
a, R
b, R
5 and n are as defined in Formula I, provided that R
2 is not -P (O) R
aR
b, -P (O) (OR
a) (OR
b) .
In another embodiment, the invention further provides a compound of Formula IX or a pharmaceutically acceptable salt thereof:
R
1, R
2, R
3, R
4, R
4a, R
5, Q
1, Q
3, L
1, L
2, L
3 and n are as defined in Formula I;
Q
6 and Q
7 are each independently CH, N, NH, O or S, provided at least one of Q
6 and Q
7 is N, NH, O or S.
In another embodiment, the invention further provides a compound of Formula X or a pharmaceutically acceptable salt thereof:
R
1, R
2, R
3, R
4, R
4a, R
5, Q
1, Q
3, L
1, L
2, L
3 and n are as defined in Formula I;
Q
6 and Q
7 are each independently CH, N, NH, O or S, provided at least one of Q
6 and Q
7 is N, NH, O or S.
In another embodiment, the invention further provides a compound of Formula XI or a pharmaceutically acceptable salt thereof:
R
1, R
2, R
3, R
4, R
c, R
4a, R
5, L
1, L
2, L
3, ring A and n are as defined in Formula I; Y
1 is O, S, NR
c or absent.
Further provided are compounds of Formula XII, or a pharmaceutical acceptable salt thereof:
R
1, R
2, R
3, R
4, R
c, R
4a, R
5, Q
1, Q
3, L
1, L
2, L
3 and n are as defined in Formula I; Y
1 is O, S, NR
c or absent;
Q
6 and Q
7 are each independently CH, N, NR
c, O or S, provided at least one of Q
6 and Q
7 is N, NR
c, O or S.
Further provided are compounds of Formula XIII, or a pharmaceutical acceptable salt thereof:
R
1, R
2, R
3, R
4, R
c, R
4a, R
5, Q
1, Q
3, L
1, L
2, L
3 and n are as defined in Formula I; Y
1 is O, S, NR
c or absent;
Q
6 and Q
7 are each independently CH, N, NR
c, O or S, provided at least one of Q
7 and Q
8 is N, NR
c, O or S.
In another aspect the invention relates to all tautomeric forms of Formula I to XIII which e.g. are illustrated as the following:
wherein Y is O, S or NR
1.
In another embodiment, the invention further provides a compound of Formula XIV or a pharmaceutically acceptable salt thereof:
R
3, R
4, R
4a, R
5 and n are as defined in Formula I; L
2 is O, -C (O) , NR
c or absent; R
2 is -C
0-10alkylene-C
3-
10cycloalkyl, -C
0-10alkylene-3-10-membered heterocyclyl, -C
0-10alkylene-5-10-membered heteroaryl, -C
0-
10alkylene-NR
aR
b; R
2 is optionally substituted by one or more R
2a; Ring B is selected from -C
0-10alkylene-C
3-
10cycloalkyl, -C
0-10alkylene-3-10-membered heterocyclyl, -C
0-10alkylene-5-10-membered heteroaryl; Ring B is optionally substituted by one or more R
2a; R
a, R
b, R
c and R
2a are defined as in Formula I.
In another embodiment, the invention further provides a compound of Formula XV or a pharmaceutically acceptable salt thereof:
R
3, R
4, R
4a, R
5 and n are as defined in Formula I; L
2 is O, -C (O) , NR
c or absent; R
2 is -C
0-10alkylene-C
3-
10cycloalkyl, -C
0-10alkylene-3-10-membered heterocyclyl, -C
0-10alkylene-5-10-membered heteroaryl, -C
0-
10alkylene-NR
aR
b; R
2 is optionally substituted by one or more R
2a; Ring B is selected from -C
0-10alkylene-C
3-
10cycloalkyl, -C
0-10alkylene-3-10-membered heterocyclyl, -C
0-10alkylene-5-10-membered heteroaryl; Ring B is optionally substituted by one or more R
2a; R
a, R
b, R
c and R
2a are defined as in Formula I.
Further provided are compounds of Formula XVI, or a pharmaceutical acceptable salt thereof:
R
3, R
4, R
4a, R
5, Q
1, Q
3 and n are as defined in Formula I; Q
6 and Q
7 are each independently CH, N, NR
c, O or S, provided at least one of Q
6 and Q
7 is N, NR
c, O or S; L
2 is O, -C (O) , NR
c or absent; R
2 is -C
0-10alkylene-C
3-
10cycloalkyl, -C
0-10alkylene-3-10-membered heterocyclyl, -C
0-10alkylene-5-10-membered heteroaryl, -C
0-
10alkylene-NR
aR; R
2 is optionally substituted by one or more R
2a; Ring B is selected from -C
0-10alkylene-C
3-
10cycloalkyl, -C
0-10alkylene-3-10-membered heterocyclyl, -C
0-10alkylene-5-10-membered heteroaryl; Ring B is optionally substituted by one or more R
2a; R
a, R
b, R
c and R
2a are defined as in Formula I.
Further provided are compounds of Formula XVII, or a pharmaceutical acceptable salt thereof:
R
3, R
4, R
4a, R
5, Q
1, Q
3 and n are as defined in Formula I; Q
6 and Q
7 are each independently CH, N, NR
c, O or S, provided at least one of Q
6 and Q
7 is N, NR
c, O or S; L
2 is O, -C (O) , NR
c or absent; R
2 is -C
0-10alkylene-C
3-
10cycloalkyl, -C
0-10alkylene-3-10-membered heterocyclyl, -C
0-10alkylene-5-10-membered heteroaryl, -C
0-
10alkylene-NR
aR
b; R
2 is optionally substituted by one or more R
2a; Ring B is selected from -C
0-10alkylene-C
3-
10cycloalkyl, -C
0-10alkylene-3-10-membered heterocyclyl, -C
0-10alkylene-5-10-membered heteroaryl; Ring B is optionally substituted by one or more R
2a; R
a, R
b, R
c and R
2a are defined as in Formula I.
Further provided are compounds of Formula XVIII, or a pharmaceutical acceptable salt thereof:
R
3, R
4, R
4a, R
5, Q
1, Q
3 and n are as defined in Formula I; Q
6 and Q
7 are each independently CH, N, NR
c, O or S, provided at least one of Q
6 and Q
7 is N, NR
c, O or S; L
2 is O, -C (O) , NR
c or absent; R
2 is -C
0-10alkylene-C
3-
10cycloalkyl, -C
0-10alkylene-3-10-membered heterocyclyl, -C
0-10alkylene-5-10-membered heteroaryl, -C
0-
10alkylene-NR
aR
b; R
2 is optionally substituted by one or more R
2a; Ring B is selected from -C
0-10alkylene-C
3-
10cycloalkyl, -C
0-10alkylene-3-10-membered heterocyclyl, -C
0-10alkylene-5-10-membered heteroaryl; Ring B is optionally substituted by one or more R
2a; R
a, R
b, R
c and R
2a are defined as in Formula I.
Further provided are compounds of Formula XIX, or a pharmaceutical acceptable salt thereof:
R
3, R
4, R
4a, R
5, Q
1, Q
3 and n are as defined in Formula I; Q
6 and Q
7 are each independently CH, N, NR
c, O or S, provided at least one of Q
6 and Q
7 is N, NR
c, O or S; L
2 is O, -C (O) , NR
c or absent; R
2 is -C
0-10alkylene-C
3-
10cycloalkyl, -C
0-10alkylene-3-10-membered heterocyclyl, -C
0-10alkylene-5-10-membered heteroaryl, -C
0-
10alkylene-NR
aR
b; R
2 is optionally substituted by one or more R
2a; Ring B is selected from -C
0-10alkylene-C
3-
10cycloalkyl, -C
0-10alkylene-3-10-membered heterocyclyl, -C
0-10alkylene-5-10-membered heteroaryl; Ring B is optionally substituted by one or more R
2a; R
a, R
b, R
c and R
2a are defined as in Formula I.
In another embodiment, the invention further provides a compound of Formula XX or a pharmaceutically acceptable salt thereof:
R
1, R
2, R
3, R
4, R
4a, R
5, Y
1, L
1, L
2, L
3, ring A and n are as defined in Formula I.
In another embodiment, the invention further provides a compound of Formula XXI or a pharmaceutically acceptable salt thereof:
Q
1, Q
2, Q
3, R
1, R
4, R
4a, R
5 and n are defined as in Formula I; X is C (O) , C (R
7)
2; R
7 is independently selected from hydrogen, -C
1-6 alkyl, -C
1-6haloalkyl, -C
0-6alkylene-NR
aR
b , -C
0-6alkylene-C (O) NR
aR
b, -C
0-6alkylene-NR
cC (O) R
b, -C
0-6alkylene-S (O)
2R
b, -C
0-6alkylene-S (O)
2NR
aR
b, -C
0-6alkylene-NR
cS (O)
2R
b, -C
0-6alkylene-NR
cS (O)
2NR
aR
b, -C
0-6alkylene-P (O) R
aR
b, -C
0-6alkylene-P (O) (OR
a) (OR
b) , -C
0-6alkylene-cyano, -C
0-6alkylene-C
3-8 cycloalkyl, -C
0-6alkylene-3-10 membered heterocyclyl, C
0-6alkylene-C
6-10 aryl, -C
0-6alkylene-5-10 membered heteroaryl, -C
2-6alkenyl, -C
2-6alkynyl; R
f is selected from R
b, -C (O) R
b and -S (O)
2R
b; R
b is defined as in Formula I.
Further provided are compounds of Formula XXII, or a pharmaceutical acceptable salt thereof:
R
4, R
4a, R
5, Q
1, Q
2, Q
3 and n are defined as in Formula I; X is C (O) , C (R
7)
2; R
7 is independently selected from hydrogen, -C
1-6 alkyl, -C
3-6 cycloalkyl, -C
1-6haloalkyl, -C
0-6alkylene-NR
aR
b , -C
0-6alkylene-C (O) NR
aR
b, -C
0-6alkylene-NR
cC (O) R
b, -C
0-6alkylene-S (O)
2R
b, -C
0-6alkylene-S (O)
2NR
aR
b, -C
0-6alkylene-NR
cS (O)
2R
b, -C
0-
6alkylene-NR
cS (O)
2NR
aR
b, -C
0-6alkylene-P (O) R
aR
b, -C
0-6alkylene-P (O) (OR
a) (OR
b) , -C
0-6alkylene-cyano, -C
0-
6alkylene-C
3-8 cycloalkyl, -C
0-6alkylene-3-10 membered heterocyclyl, C
0-6alkylene-C
6-10 aryl, -C
0-6alkylene-5-10 membered heteroaryl, -C
2-6alkenyl, -C
2-6alkynyl; Ring B is selected from -C
3-10cycloalkyl, -3-10-membered heterocyclyl, -5-10-membered heteroaryl; Ring B is optionally substituted by one or more R
2a; R
f is selected from R
b, -C (O) R
b and -S (O)
2R
b; R
b and R
2a are defined as in Formula I.
In another embodiment, the invention further provides a compound of Formula XXIII or a pharmaceutically acceptable salt thereof:
Ring A, R
2, R
4, R
4a, R
5, Q
1, Q
2, Q
3, Q
4, Q
5, L
1, L
2, L
3 and n are defined as in Formula I; Q
6, Q
7 and Q
8 are independently selected from N and CR
10; R
10 is as defined in Formula I.
In another embodiment, the invention further provides a compound of Formula XXIV or a pharmaceutically acceptable salt thereof:
Ring A, R
2, R
4, R
4a, R
5, Q
1, Q
2, Q
3, Q
4, Q
5, L
1, L
2, L
3, Y and n are as defined in Formula I; Q
6, Q
7 and Q
8 are independently selected from N and CR
10; R
10 is as defined in Formula I.
The present invention also relates to all forms of prodrugs of Formula I to XXIV, which e.g. bear ester or amide groups that are cleaved under physiological conditions.
In some embodiments, a compound of Formula I to XXIV is selected from the group consisting of the compounds below, or a pharmaceutically acceptable salt thereof:
In another aspect, the invention features a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound disclosed herein.
The invention includes all possible combinations of the embodiments described above and below. It should be understood that, within the scope of the present invention, each technical feature of the present invention described above and, in the following, (as examples) may be combined with each other to form a new or preferred technical solution, which is not listed here due to space limitations.
Definitions
The term "alkyl, " by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e. unbranched) or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono-or polyunsaturated and can include di-and multivalent radicals, having the number of carbon atoms designated (i.e. C
1-10 means one to ten carbons) . Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl) , 2, 4-pentadienyl, 3- (1, 4-pentadienyl) , ethynyl, 1-and 3-propynyl, 3-butynyl, and the higher homologs and isomers. Alkyl groups which are limited to hydrocarbon groups are termed "homoalkyl" . The alkyl is optionally substituted with one or more halogen atom (s) .
The term “halogenated alkyl” means alkyl as defined above wherein one or more hydrogen atoms have been replaced by halogen atoms.
The term “alkenyl” means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched, Z-or E-, or combinations thereof. Examples of alkenyl are CH
3CH=CH-, CH
2=CHCH
2-and CH (CH
3)
2CH=CH-.
The term "alkylene" by itself or as part of another substituent means a divalent radical derived from an alkyl, as exemplified, but not limited, by -CH
2CH
2CH
2CH
2-, -CH=CH-, -CH
2CH=CHCH
2-, -CH
2C≡CCH
2-, -CH
2CH
2CH (CH
2CH
2CH
3) CH
2-. The alkylene radical may be optionally substituted independently with one or more substituents described herein, and includes radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations. Typically, an alkyl (or alkylene) group has from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. The alkylene is optionally substituted with one or more halogen atom (s) .
The term "alkynyl" means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like. The alkynyl is optionally substituted with one or more halogen atom (s) .
The term “alkylamino” refers to an amino substituent which is further substituted with one or two alkyl groups. The term “aminoalkyl” refers to an alkyl substituent which is further substituted with one or more amino groups. The term “hydroxyalkyl” refers to an alkyl substituent which is further substituted with one or more hydroxyl groups. The alkyl or aryl portion of alkylamino, aminoalkyl, mercaptoalkyl, hydroxyalkyl, mercaptoalkoxy, sulfonylalkyl, sulfonylaryl, alkylcarbonyl, and alkylcarbonylalkyl may be optionally substituted with one or more substituents.
The term "cycloalkyl" or “carbococyclyl” means mono-, bicyclic or spiro-bicyclic carbocyclic rings, each of which has from 3 to 10 carbon atoms. A “fused analog” of cycloalkyl means a monocyclic ring fused to an aryl or heteroaryl group in which the point of attachment is on the non-aromatic portion. Examples of cycloalkyl and fused analogs thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl, and the like. The spiro-bicyclic carbocyclic rings are bicyclic (having just two rings) or have a bicyclic portion as part of the larger ring system, in either case with the two rings connected through the defining single common carbon atom. The cycloalkyl is optionally substituted with one or more halogen atom (s) .
The term “alkoxy” means alkoxy groups of a straight or branched having the indicated number of carbon atoms. C
1-6alkoxy, for example, includes methoxy, ethoxy, propoxy, isopropoxy, and the like.
The term "heteroalkyl, " by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of at least one carbon atoms and at least one heteroatom selected from the group consisting of O, N, P, Si and S, and wherein the nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom (s) O, N, P and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, -CH
2-CH
2-O-CH
3, -CH
2-CH
2-NH-CH
3, -CH
2-CH
2-N (CH
3) -CH
3, -CH
2-S-CH
2-CH
3, -CH
2-CH
2, -S (O) -CH
3, -CH
2-CH
2-S (O)
2-CH
3, -CH=CH-O-CH
3, -Si (CH
3)
3, -CH
2-CH=N-OCH
3, -CH=CH-N (CH
3) -CH
3, -O-CH
3, -O-CH
2-CH
3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH
2-NH-OCH
3 and -CH
2-O-Si (CH
3)
3. Similarly, the term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH
2 -CH
2-S-CH
2-CH
2-and -CH
2-S-CH
2-CH
2-NH-CH
2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, and the like) . Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C (O) OR'-represents both-C (O) OR'-and -R'OC (O) -. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C (O) R', -C (O) NR', -NR'R", -OR', -SR', and/or -SO
2R'. Where "heteroalkyl" is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R" or the like, it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term "heteroalkyl" should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R" or the like.
The term “cycloalkoxy” means cycloalkyl as defined above bonded to an oxygen atom, such as cyclopropyloxy.
The term “halogenated alkoxy” means alkoxy as defined above wherein one or more hydrogen atoms have been replaced by halogen atoms.
The term "aryl" means mono-or bicyclic aromatic rings containing only carbon atoms. A “fused analog” of aryl means an aryl group fused to a monocyclic cycloalkyl or monocyclic heterocyclyl group in which the point of attachment is on the aromatic portion. Examples of aryl and fused analogs thereof include phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2, 3-dihydrobenzofuranyl, dihydrobenzopyranyl, 1, 4-benzodioxanyl, and the like.
The term "heteroaryl" means a mono-or bicyclic aromatic ring containing at least one heteroatom selected from N, O and S, with each ring containing 5 to 6 atoms. A “fused analog” of heteroaryl means a heteroaryl group fused to a monocyclic cycloalkyl or monocyclic heterocyclyl group in which the point of attachment is on the aromatic portion. Examples of heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, furo (2, 3-b) pyridyl, quinolyl, indolyl, isoquinolyl, and the like.
The term "heterocyclyl" means mono-, bicyclic, tricyclic, spirocyclic, fused or bridged saturated ring systems containing at least one heteroatom selected from N, S and O, each of said ring having from 3 to 10 atoms in which the point of attachment may be carbon or nitrogen. A "heterocyclyl" includes a “fused analog” which means a monocyclic heterocycle fused to a heterocycle, a carbocycle, an aryl or heteroaryl group in which the point of attachment is on the non-aromatic portion. Examples of "heterocyclyl" and fused analogs thereof include azeridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dioxolanyl, oxazolodinyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, quinuclidinyl, thiomorpholinyl, thiomorphonulyl 1, 1-dioxide, morpholinyl, azapanyl, oxazepanyl, azabicyclohexanyls, azabicycloheptanyl, azabicyclooctanyl, azabycyclononanyl, azaspiroheptanyl, dihydro-1H, 3H, 5H-oxazolo [3, 4-c] oxazolyl, tetrohydro-1’H3’Hspiro [cyclopropane-1, 2’-pyrrolizinyl, hexahydro-1H-pyrralizinyl, hexahydro-1H-pyrrolo [2, 1-c] [1, 4] oxazinyl, octahydroindolizinyl, oxaazaspirononanyls, oxaazspirooctanyls, diazaspirononanyls, oxaazabicycloheptanyls, hexahydropyrrolidinyl 4 (1H0-oxide, tetrohydro-2H-thiopyranyl 1-oxide, tetrohydro-2H-thiopyranyl 1, 1-dioxide, bicycloheptanyl, 2, 3-dihydrofuro (2, 3-b) pyridyl, benzoxazinyl, tetrahydrohydroquinolinyl, tetrahydroisoquinolinyl, hexahydro-1H-pyrrolizine, dihydroindolyl, and the like. The term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2-or 4-pyridones attached through the nitrogen or N-substituted- (1H, 3H) -pyrimidine-2, 4-diones (N-substituted uracils) .
The said alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups referred to in the definitions are unsubstituted or are substituted by at least one substituent selected from the group consisting of substituents.
The substituents are selected from the group consisting of halogen atoms, alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, haloalkyl groups having from 1 to 4 carbon atoms, haloalkoxy groups having from 1 to 4 carbon atoms, cyano groups, alkynyl groups having from 2 to 6 carbon atoms, alkanoyl groups having from 1 to 5 carbon atoms, cycloalkyl groups having from 3 to 7 ring atoms, heteroaryl groups, aryl groups, aralkoxy groups having from 7 to 10 carbon atoms, arylcarbonyl groups, two adjacent-x groups are optionally joined together to form an alkylene or an alkenylene chain having 3 or 4 carbon atoms, aminocarbonyl groups, alkenyl groups having from 2 to 5 carbon atoms, alkylthio groups having from 1 to 4 carbon atoms, aminosulfinyl groups, aminosulfonyl groups, hydroxy groups, -SF
5, -P (O) Me
2, hydroxyalkyl groups having from 1 to 4 carbon atoms, nitro groups, amino groups, carboxy groups, alkoxycarbonyl groups having from 2 to 5 carbon atoms, alkoxyalkyl groups having from 1 to 4 carbon atoms, alkylsulfonyl groups having from 1 to 4 carbon atoms, alkanoylamino groups having from 1 to 4 carbon atoms, alkanoyl (alkyl) amino groups having from 1 to 6 carbon atoms, alkanoylaminoalkyl groups having from 1 to 6 carbon atoms in both the alkanoyl and alkyl part, alkanoyl (alkyl) aminoalkyl groups having from 1 to 6 carbon atoms in both the alkanoyl and each alkyl part, alkylsulfonylamino groups having from 1 to 4 carbon atoms, mono-or di-alkylaminocarbonyl groups having from 1 to 6 carbon atoms, mono-or di-alkylaminosulfinyl groups having from 1 to 6 carbon atoms, mono-or di alkylaminosulfonyl groups having from 1 to 6 carbon atoms, aminoalkyl groups having from 1 to 4 carbon atoms, mono-or di-alkylamino groups having from 1 to 6 carbon atoms, mono-or di-alkylaminoalkyl groups having from 1 to 6 carbon atoms in each alkyl part, aralkyl groups having from 7 to 10 carbon atoms, heteroarylalkyl groups having from 1 to 4 carbon atoms in the alkyl part, heteroarylalkoxy groups having from 1 to 4 carbon atoms in the alkoxy part and alkylsulfonylamino groups having from 1 to 4 carbon atoms.
The terms "halo" or "halogen, " by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl, " or “halogenated alkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo (C
1-C
4) alkyl" is meant to include, but not be limited to, trifluoromethyl, 2, 2, 2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
A "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrugs may also have improved solubility in pharmaceutical compositions over the parent drug. An example, without limitation, of a prodrug would be a compound of any of Formula I, which is administered as an ester (the "prodrug" ) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility, but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial. A further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
Optical Isomers -Diastereomers -Geometric Isomers -Tautomers
Compounds of the present invention may contain one or more asymmetric centers and may thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of the compounds.
Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
Some of the compounds of described herein may contain one or more than one cyclic ring systems and may thus exist in cis-and trans-isomers. The present invention is meant to include all such cis-and trans-isomers.
Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of the present invention.
Compounds described herein may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example MeOH or EtOAc or a mixture thereof. The pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active amine or acid as a resolving agent or on a chiral HPLC column.
Alternatively, any enantiomer of a compound described herein may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
Stable Isotope-Labeled Analogs
One or more than one of the protons (hydrogen atoms) in compounds of the present invention can be replaced with deuterium atom (s) , thus providing deuterated analogs that may have improved pharmacokinetic properties or pharmacological activities.
Salts and Formulations
The compounds described herein can be useful as the free base or as a salt.
The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N, N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydramine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
When the compound of the present invention is alkaline, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
It will be understood that, as used herein, references to the compounds of the present invention are meant to also include the pharmaceutically acceptable salts.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients are mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethyl-cellulose, methylcellulose, hydroxypropylmethy-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene- oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1, 3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomiser (preferably an I atomiser using electrohydrodynamics to produce a fine mist) , or nebuliser, with or without the use of a suitable propellant, such as 1, 1, 1, 2-tetrafluoroethane or 1, 1, 1, 2, 3, 3, 3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
The pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the compound (s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, a propellant (s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns) .
This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.
Capsules (made, for example, from gelatin or HPMC) , blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
A suitable solution formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from l mg to 20 mg of the compound of the invention per actuation and the actuation volume may vary from 1 L to 100 L. A typical formulation may comprise a compound of Formula (A) propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
Suitable flavors, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, poly (DL-lactic-coglycolic acid (PGLA) . Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to administer a metered dose or "puff" containing from 1 pg to 1 mg of the compound of the present invention. The overall daily dose will typically be in the range 1 pg to 1 mg which may be administered in a single dose or, more usually, as divided doses throughout the day.
Compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compound of the present invention are employed. (For purposes of this application, topical application shall include mouth washes and gargles. )
Dosage levels of the order of from about 0.01 mg to about 140 mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5 mg to about 7 g per patient per day. For example, a condition may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day, preferably 2.5 mg to 1 g per patient per day.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
Indications
Compounds of the present invention may be used for treatment of conditions such as cancer.
Combination Therapies
Administration of the SOS1 inhibitors disclosed herein can be combined with other cancer treatments. For example, the SOS1 inhibitors can be administered in combination with surgical treatments, radiation, or other therapeutic agents such as antibodies, other kinase inhibitors (such as RTK inhibitors) , target therapies, inhibitors for RAS signaling pathway (e.g a SHP2 inhibitor, a KRAS inhibitor, a RAF inhibitor, A MEK inhibitor or an ERK inhibitor) , or chemotherapeutics. The inhibitors may also be administered in combination with RNAi therapy, antisense therapy, vaccines, or immunotherapies including adoptive cell transfer therapy such as CAR-T therapy. The SOS1 inhibitors described herein may be combined with one, two, or more other therapeutic agents. In the examples outlined below, it is understood that "second therapeutic agent" also includes more than one therapeutic agent other than the SOS1 inhibitor. For instance, the compounds disclosed herein may be combined with an agent such as a kinase inhibitor, a KRAS inhibitor, a PD-1 antibody, a PD-L1 antibody, a CTLA4 antibody, or any other checkpoint protein antibodies.
Synthesis
The compounds of the present invention can be prepared according to the following synthetic schemes:
Biological Activity Evaluation
HTRF SOS1-KRAS Binding Assay
A homogenous time-resolved fluorescence (HTRF) -based assay was used to screen compounds that inhibit SOS1-KRAS interaction. A low IC
50 number indicates high potency of the inhibitor. Immediately after GST-tagged KRAS protein (AA 1-188) (ProteinTECH, Cat# Ag2700) and His-tagged SOS1 protein (AA 564 -1049) (Cytoskeleton, Inc, Cat# GE02) were mixed in the cold PBS-based assay buffer containing 5 nM GDP (VWR) , 0.1%BSA and 0.05%Tween-20, compounds with varying concentrations were added to this protein mixture. The final concentration of either protein in the assay mixture was 5 nM. After 1 h incubation at 4℃, the anti GST-Tb cryptate donor antibody (PerkinElmer/Cisbio, Cat# 61GSTTLA) and anti 6His-d2 acceptor antibody (PerkinElmer/Cisbio, Cat# 61HISDLA) were added to the assay mixture and incubated for another 1 h at 4℃ before HTRF signals were read using CLARIOstar Microplate Reader (BMG LABTECH) . The HTRF ratio was calculated using the following equation: (emission signal at 665 nm) / (emission signal at 620 nm) x 10,000. IC
50 value was determined as the concentration for 50%inhibition of HTRF ratio compared to DMSO.
IC
50 values of the example compounds determined using the HTRF assay are disclosed in the following table (A
+: IC
50 < 0.01 μM; A: IC
50 between 0.01 μM and 0.1 μM B: IC
50 between 0.1 μM and 1.0 μM; C: IC
50 between 1.0 μM and 10.0 μM; D: IC
50 > 10.0 μM; ND: not determined) .
Abbreviations
The following abbreviations have the meanings indicated. EA means ethyl acetate; CIP means 2-chloro-1, 3-dimethylimidazolidium hexafluorophosphate; DBU means l, 8-diazabicyclo [5.4.0] undec-7-ene; DIBAL means diisobutylaluminum hydride; DCM means dichloromethane; DIEA means diisopropylethylamine; DMAP means N, N-dimethylaminopyridine; DME means 1, 2-dimethoxyethane; DMF means N, N-dimethylformamide; dmpe means l, 2-bis (dimethylρhosphino) ethane; DMSO means dimethylsulfoxide; dppb means l, 4-bis (diphenylphosphino) butane; dppe means 1, 2-bis (diphenylphosphino) ethane; dppf means 1, 1’-bis (diphenylphosphino) ferrocene; dppm means 1, 1’-bis (diphenylphosphino) methane; DIAD means diisopropylazodicarboxylate; EDCI means 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide; HATU means 2- (7-Aza-1H-benzotriazole-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate; HMPA means hexamethylphosphorarnide; IPA means isopropyl alcohol; LDA means lithium diisopropylamide; LHMDS means lithium bis (hexamethyldisilylamide) ; LAH means lithium aluminum hydride; NCS means N-chlorosuccinimide; PE means petroleum ether; PyBOP means benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate; SGC means silica gel chromatography; TDA means tris (2- (2-methoxyethoxy) ethyl) amine; DCM means dichloromethame; TEA means triethylamine; TFA means trifluoroacetic acid; THF means tetrahydrofuran; NCS means N-chlorosuccinimide; NMI means 1-methylimidazole; NMM means N-methylmorpholine; NMP means N-methylpyrrolidine; PPh3 means triphenylphosphine, rt or RT means room temperature; sat. means saturated; T3P means propylphosphonic anhydride; TCFH means N, N, N’, N’-tetramethylchloroformaidinium hexafluorophosphate; MTBE means methyl tert-butyl ether; NBS means N-Bromosuccinimide; DMA means N, N-Dimethylacetamide, *in structures means undetermined R or S chiral center.
Prep HPLC conditions:
Column: GreenODS-A, 21.2 x 250 mm. 10 um
Mobile phase: Gradient of 0.05%TFA and CH
3CN;
Flow rate: 35mL/min.
The present invention will be more readily understood by referring to the following examples which are given to illustrate the invention rather than to limit its scope.
EXAMPLE 1
(±) 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [2, 3-d] pyrimidin-7 (8H) -one
Step 1 3-bromo-2-fluorobenzaldehyde
To a stirred solution of 1-bromo-2-fluorobenzene (50 g, 285.71 mmol) in THF (500 mL) was added lithium diisopropylamide (39.8 g, 371.43 mmol) at -70℃ under Ar. The mixture was stirred for 1 h at -70℃. N, N-Dimethylformamide (31.3 g, 428.56 mmol) was added drop wise. The resulting mixture was stirred at rt for 1 h. The reaction was then quenched with H
2O and extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to get 72.0 g of the title product as brown oil which was used to the next step without further purification.
Step 2 1-bromo-3- (difluoromethyl) -2-fluorobenzene
To a stirred solution of 3-bromo-2-fluorobenzaldehyde (30 g, 147.78 mmol) in DCM (450 mL) was added DAST (47.6 g, 295.55 mmol) drop wise at 0℃. The resulting mixture was stirred for 1 h at rt under Ar. The reaction was then quenched with H
2O and extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to get 46.0 g of the title product as yellow oil which was used to the next step without further purification.
Step 3 1- (3- (difluoromethyl) -2-fluorophenyl) ethanone
The mixture of 1-bromo-3- (difluoromethyl) -2-fluorobenzene (35.0 g , 154.71 mmol) , tributyl (1-ethoxyvinyl) stannane (67.1 g, 185.63 mmol) , triethylamine (39.2 g, 386.72 mmol) and bis (triphenylphosphine) palladium (II) chloride (1.08 g, 1.547 mmol) in 1, 4-dioxane (35 mL) was stirred for 2 h at 100℃. The mixture was then cooled to rt and 1 N HCl (700 mL) was added. The mixture was stirred overnight at rt, and then poured into water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (EA: PE=9: 1) to get 35 g of title product as a white solid.
1H NMR (400 MHz, CDCl
3) δ 8.01 (dddt, J = 8.0, 7.0, 2.0, 1.0 Hz, 1H) , 7.84 –7.70 (m, 1H) , 7.35 (t, J = 7.7 Hz, 1H) , 6.95 (t, J = 54.8 Hz, 1H) , 2.67 (d, J = 5.0 Hz, 3H) .
Step 4 (E) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylidene) -2-methylpropane-2-sulfinamide
To a stirred solution of 1- (3- (difluoromethyl) -2-fluorophenyl) ethanone (5.0 g, 26.57 mmol) in THF (100 mL) was added 2-methylpropane-2-sulfinamide (4.8 g, 39.86 mmol) and titanium ethoxide (18.2 g, 79.59 mmol) at rt. The resulting mixture was stirred for 3 h at 80℃ and then quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to get 7.2 g of the title product as yellow oil which was used to the next step without further purification. MS (ES+) : 292.1 [M+1]
+.
Step 5 N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpropane-2-sulfinamide
To a stirred solution of (E) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylidene) -2-methylpropane-2-sulfinamide (7.2 g, 24.71 mmol) in THF (140 mL) was added NaBH
4 (1.4 g, 37.07 mmol) at 0℃. The resulting mixture was stirred for 2 h at rt, and then quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (PE: EA=1: 1) to get 2.5 g of the title product as a yellow solid. MS (ES+) : 294.1 [M+1]
+.
Step 6 (±) 1- (3- (difluoromethyl) -2-fluorophenyl) ethanamine hydrochloride
To a stirred solution of N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpropane-2-sulfinamide (2.5 g, 8.53 mmol) in EA (25 ml) was added 4 N HCl/EA (25 mL) at rt. The resulting mixture was stirred for 0.5 h at rt, and then evaporated in vacuo. The residue was suspended in MTBE and stirred for 0.5 h, then filtered to get 1.8 g of the title product as a white solid. MS (ES+) : 190.0 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.73 –8.55 (m, 3H) , 7.89 (t, J = 7.4 Hz, 1H) , 7.68 (t, J = 7.1 Hz, 1H) , 7.46 (t, J = 7.8 Hz, 1H) , 7.26 (t, J = 54.0 Hz, 1H) , 4.67 (p, J = 6.3 Hz, 1H) , 1.54 (d, J = 6.8 Hz, 3H) .
Step 7 4, 6-dichloro-2-methylpyrimidine-5-carbaldehyde
To a stirred solution of POCl
3 (18 mL) was added dropwise DMF (6 mL) at 0℃. The resulting mixture was stirred for 1 h. 2-methylpyrimidine-4, 6-diol (5g, 39.68 mmol) was added. The mixture was stirred at rt for 1 h, and then refluxed for 4 h at 120℃. The reaction mixture was poured into ice-water and filtered through a layer of celite. The filtrate was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE: EA=9: 1) to give 758 mg of the title product as a yellow solid.
1H NMR (400 MHz, CDCl
3) δ 10.44 (s, 1H) , 2.77 (s, 3H) .
Step 8 4-amino-6-chloro-2-methylpyrimidine-5-carbaldehyde
To a stirred solution of 4, 6-dichloro-2-methylpyrimidine-5-carbaldehyde (9.8 g, 51.57 mmol) in THF (98 mL) was added NH
3
. H
2O (29.4 mL) at 0-10℃. The resulting mixture was stirred at rt for 4 h, quenched with H
2O and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (EA: PE=1: 3) to get 6.55g of pure product as a yellow solid. MS (ES+) : 172.0 [M+1]
+.
Step 9 (E) -ethyl 3- (4-amino-6-chloro-2-methylpyrimidin-5-yl) acrylate
To a stirred solution of ethyl 2- (diethoxyphosphoryl) acetate (1.05 g, 4.68 mmol) in THF (8 mL) were added NaH (112 mg, 4.68 mmol) and 4-amino-6-chloro-2-methylpyrimidine-5-carbaldehyde (400 mg, 2.34 mmol) at 0℃ under Ar. The resulting mixture was stirred at rt for 2 h, quenched with H
2O and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (EA: PE=1: 1) to get 400 mg of the title product as a yellow solid. MS (ES+) : 242.0 [M+1]
+.
Step 10 2-methyl-4- (methylthio) pyrido [2, 3-d] pyrimidin-7 (8H) -one
To a stirred solution of (E) -ethyl 3- (4-amino-6-chloro-2-methylpyrimidin-5-yl) acrylate (400 mg, 1.66 mmol) in EtOH (8 mL) was added MeSNa (2.31 g, 6.62 mmol) at rt. The resulting mixture was stirred for 2 h at 60℃ under Ar, quenched with H
2O and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to get 340 mg of the title product as a white solid. MS (ES+) : 208.0 [M+1]
+.
Step 11 2-methyl-4- (methylsulfonyl) pyrido [2, 3-d] pyrimidin-7 (8H) -one
To a stirred solution of 2-methyl-4- (methylthio) pyrido [2, 3-d] pyrimidin-7 (8H) -one (240 mg, 1.16 mmol) in DCM (5 ml) was added m-CPBA (851 mg, 3.47 mmol) at 0-10℃. The resulting mixture was stirred for 2 h under Ar, poured into water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (EA: PE=1: 1) to get 90 mg of the title product as a white solid. MS (ES+) : 240.0 [M+1]
+.
Step 12 (±) 4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methylpyrido [2, 3-d] pyrimidin-7 (8H) -one
To a stirred solution of 2-methyl-4- (methylsulfonyl) pyrido [2, 3-d] pyrimidin-7 (8H) -one (90 mg, 0.376 mmol) in DMAc (2.5 mL) were added 1- (3- (difluoromethyl) -2-fluorophenyl) ethanamine hydrochloride (101 mg, 0.451 mmol) and DIPEA (243 mg, 1.88 mmol) at rt. The resulting mixture was stirred for 2 h at 70℃, quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA) to give 58 mg of the title product as a white solid. MS (ES+) : 349.0 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 11.85 (s, 1H) , 8.32 (d, J = 9.7 Hz, 1H) , 8.23 (d, J = 7.4 Hz, 1H) , 7.66 (t, J = 7.4 Hz, 1H) , 7.50 (t, J = 7.1 Hz, 1H) , 7.39 –7.04 (m, 2H) , 6.35 (d, J = 9.7 Hz, 1H) , 5.86 –5.58 (m, 1H) , 2.26 (s, 3H) , 1.54 (d, J = 7.1 Hz, 3H) .
EXAMPLE 2
(±) 6-bromo-4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methylpyrido [2, 3-d] pyrimidin-7 (8H) -one
Route 1:
To a stirred solution of 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [2, 3-d] pyrimidin-7 (8H) -one (20 mg, 0.064 mmol, obtained from Example 1) in DMF (1.0 mL) was added NBS (20 mg, 0.112 mmol) at rt. The resulting mixture was stirred for 2 h at rt, quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (PE: EA=1: 1) to give 12.2 mg of the title product as a white solid. MS (ES+) : 427.0 [M+1]
+.
Route 2:
To a stirred solution of 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid (500 mg, 1.28 mmol, obtained from Example 9) in THF /H
2O (10/1, 10 mL) were added LiOAc (842 mg, 12.76 mmol) and NBS (1362 mg, 7.65 mmol) at 55℃. The mixture was stirred for 5 h at 55℃, treated with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE: EA=1: 1) to give 215 mg of the title product as a yellow solid. MS (ES+) : 427.0 [M+1]
+.
1H NMR (400 MHz, CDCl
3) δ 10.90 (s, 1H) , 8.09 (s, 1H) , 7.51 (q, J = 7.1 Hz, 2H) , 7.20 (d, J = 7.7 Hz, 1H) , 6.92 (t, J = 55.0 Hz, 1H) , 5.86 (s, 1H) , 5.75 (p, J = 7.0 Hz, 1H) , 2.52 (s, 3H) , 1.68 (d, J = 7.0 Hz, 3H) .
EXAMPLE 3
(±) 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrido [2, 3-d] pyrimidin-7 (8H) -one
A mixture of 6-bromo-4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [2, 3-d] pyrimidin-7 (8H) -one (70 mg, 0.164 mmol) , 1-methyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2 (1H) -one (46 mg, 0.197 mmol) , K
3PO
4 (70 mg, 0.329 mmol) and Pd (dppf) Cl
2·DCM (14 mg, 0.016 mol) in THF/H
2O (5/1, 2 mL) was stirred for 1 h under Ar at 70℃ under Ar. The reaction was then quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was recrystallized from DCM to give 18 mg of the title product as an off-white solid. MS (ES+) : 455.9 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 12.12 (s, 1H) , 8.47 (s, 1H) , 8.41 (d, J = 2.6 Hz, 1H) , 8.29 (d, J = 7.3 Hz, 1H) , 7.87 (dd, J = 9.6, 2.6 Hz, 1H) , 7.68 (t, J = 7.3 Hz, 1H) , 7.51 (t, J = 7.2 Hz, 1H) , 7.41 –7.04 (m, 2H) , 6.52 (d, J = 9.4 Hz, 1H) , 5.76 (t, J = 7.3 Hz, 1H) , 3.51 (s, 3H) , 2.28 (s, 3H) , 1.58 (d, J = 7.0 Hz, 3H) .
EXAMPLE 3A
(R) 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrido [2, 3-d] pyrimidin-7 (8H) -one
Step 1 (R, E) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylidene) -2-methylpropane-2-sulfinamide
To a stirred solution of 1- (3- (difluoromethyl) -2-fluorophenyl) ethanone (15.0 g, 79.72 mmol, obtained from Step 3 of EXAMPLE 1) in THF (300 mL) were added (R) -2-methylpropane-2-sulfinamide (14.5 g, 119.58 mmol) and titanium ethoxide (54.6 g, 259.16 mmol) at rt. The resulting mixture was stirred for 16 h at 80℃. The reaction was then quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE: EA=1: 1) to get 16.0 g of the title product as yellow oil. MS (ES+) : 292.1 [M+1]
+.
Step 2 (R) -N- ( (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpropane-2-sulfinamide
To a stirred solution of the product of Step 1 (14.0 g, 48.06 mmol) in THF (150 mL) was added NaBH
4 (2.2 g, 57.67 mmol) at 0℃. The resulting mixture was stirred for 2 h at 0℃, and then quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE: EA=4: 1) to get 10.8 g of the title product as a yellow solid. MS (ES+) : 294.1 [M+1]
+.
Step 3 (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethanamine hydrochloride
To a stirred solution of the product of Step 2 (10.7 g, 36.52 mmol) in EA (100 mL) was added 4 N HCl/EA (100 mL) at rt. The resulting mixture was stirred for 0.5 h at rt, and then evaporated in vacuo. The residue was suspended in MTBE and stirred for 0.5 h, filtered to get 8.2 g of the title product as a white solid. MS (ES+) : 190.0 [M+1]
+.
Step 4 (R) -4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid
Starting with the product of Step 3, the title product of step 4 was prepared by using the same method as described in Step 1 to step 3 of EXAMPLE 9.
Step 5 (R) -6-bromo-4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [2, 3-d] pyrimidin-7 (8H) -one
To a stirred solution of the product of Step 4 (400 mg, 1.02 mmol) in THF/H
2O (10/1, 8 mL) were added LiOAc (337 mg, 5.10 mmol) and NBS (556 mg, 3.06 mmol) at 55℃. The mixture was stirred for 3 h at 55℃and then treated with and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (PE: EA=1: 1) to give 180 mg of the title product as a yellow solid. MS (ES+) : 427.0 [M+1]
+.
Step 6 (R) -4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) pyrido [2, 3-d] pyrimidin-7 (8H) -one
To a stirred solution of the product of Step 5 (55 mg, 0.129 mmol) , 1-methyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2 (1H) -one (49 mg, 0.207 mmol) , K
3PO
4 (74 mg, 0.349 mmol) in THF/H
2O (5/1, 1 mL) was added Pd (dppf) Cl
2·DCM (21 mg, 0.026 mol) at rt under Ar. The mixture was stirred for 2 h at 70℃, then treated with and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA: MeOH=9: 1) and then Prep-HPLC to give 17.2 mg of the title product as a yellow solid. MS (ES+) : 455.9 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 12.11 (s, 1H) , 8.50 (s, 1H) , 8.42 (s, 1H) , 8.30 (s, 1H) , 7.89 (d, J = 9.7 Hz, 1H) , 7.69 (s, 1H) , 7.50 (s, 1H) , 7.40 –7.02 (m, 2H) , 6.51 (d, J = 9.4 Hz, 1H) , 5.76 (s, 1H) , 3.51 (s, 3H) , 2.28 (s, 3H) , 1.58 (d, J = 7.0 Hz, 3H) .
EXAMPLE 4
(±) 6-cyclopropyl-4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [2, 3-d] pyrimidin-7 (8H) -one
To a stirred solution of 6-bromo-4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [2, 3-d] pyrimidin-7 (8H) -one (80 mg, 0.19 mmol) , cyclopropylboronic acid (242 mg, 2.81 mmol) , K
3PO
4 (103 mg, 0.49 mmol) in THF (2 mL) and H
2O (0.4 mL) was added Pd (pddf) Cl
2·DCM (15 mg, 0.02 mmol) . The mixture was stirred for 2 h at 70℃ under Ar, quenched with H
2O and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA) to get 8 mg of the title product as a yellow solid. MS (ES+) : 389.0 [M+1]
+.
1H NMR (400 MHz, CDCl
3) δ 9.93 (s, 1H) , 7.51 (dt, J = 13.7, 7.3 Hz, 2H) , 7.23 –7.11 (m, 2H) , 6.91 (t, J = 55.0 Hz, 1H) , 5.74 (t, J = 7.1 Hz, 1H) , 5.35 (t, J = 4.9 Hz, 1H) , 2.47 (s, 3H) , 1.68 (d, J = 6.9 Hz, 4H) , 1.04 –0.94 (m, 2H) , 0.75 (m, 2H) .
EXAMPLE 5
(±) 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6- (prop-1-en-2-yl) pyrido [2, 3-d] pyrimidin-7 (8H) -one
A mixture of 6-bromo-4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [2, 3-d] pyrimidin-7 (8H) -one (100 mg, 0.235 mmol) , 1- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) ethan-1-one (47 mg, 0.282 mmol) , K
3PO
4 (129 mg, 0.61 mmol) and Pd (dppf) Cl
2·DCM (19 mg, 0.023 mol) in THF/H
2O (5/1, 2 mL) was stirred for 1 h at 70 ℃ under Ar. The reaction was then quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (PE: EA=1: 4) to give 66 mg of the title product as a white solid. MS (ES+) : 389.0 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 11.88 (s, 1H) , 8.31 (d, J = 7.3 Hz, 1H) , 8.25 (s, 1H) , 7.68 (dt, J = 15.5, 7.4 Hz, 1H) , 7.53 (dt, J = 14.6, 7.1 Hz, 1H) , 7.34 (dt, J = 26.3, 7.9 Hz, 1H) , 7.23 (d, J = 5.4 Hz, 1H) , 5.82 –5.69 (m, 2H) , 5.21 (dd, J = 2.9, 1.5 Hz, 1H) , 2.27 (s, 3H) , 2.12 (s, 3H) , 1.57 (d, J = 7.1 Hz, 3H) .
EXAMPLE 6
(±) 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-isopropyl-2-methylpyrido [2, 3-d] pyrimidin-7 (8H) -one
To a stirred solution of 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6- (prop-1-en-2-yl) pyrido [2, 3-d] pyrimidin-7 (8H) -one (30 mg, 0.077 mmol) in MeOH (1 mL) was added 10%Pd/C (15 mg) at room temperature. The reaction vessel was purged three times with H
2 and the resulting mixture was stirred at rt for 1 h. The mixture was then filtered and the filtrate was concentrated to give 18.7 mg of the title product as a brown solid. MS (ES+) : 390.9 [M+1]
+.
1H NMR (400 MHz, CDCl
3) δ 9.60 (s, 1H) , 7.26 (m, 2H) , 7.21 (m, 2H) , 6.91 (d, J = 7.2 Hz, 1H) , 5.75 (d, J = 10.1 Hz, 1H) , 5.55 (d, J = 7.4 Hz, 1H) , 3.23 (s, 1H) , 2.46 (s, 3H) , 1.69 (d, J = 7.0 Hz, 3H) , 1.26 (d, J = 7.0 Hz, 6H) .
EXAMPLE 7
(±) 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6- (1H-pyrazol-4-yl) pyrido [2, 3-d] pyrimidin-7 (8H) -one
Step 1 (±) tert-butyl4- (4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidin-6-yl) -1H-pyrazole-1-carboxylate
A mixture of 6-bromo-4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [2, 3-d] pyrimidin-7 (8H) -one (90 mg, 0.211 mmol) , tert-butyl 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole-1-carboxylate (75 mg, 0.254 mmol) , K
3PO
4 (116 mg, 0.549 mmol) and Pd (dppf) Cl
2·DCM (17 mg, 0.021 mol) in THF/H
2O (5/1, 2 mL) was stirred for 1 h at 70℃ under Ar. The reaction was then quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (PE: EA=1: 4) to give 85 mg of the title product as a yellow solid. MS (ES+) : 515.0 [M+1]
+.
Step 2 (±) 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6- (1H-pyrazol-4-yl) pyrido [2, 3-d] pyrimidin-7 (8H) -one
A mixture of tert-butyl4- (4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidin-6-yl) -1H-pyrazole-1-carboxylate (85 mg, 0.211 mmol) in TFA/DCM (0.5mL/1mL) was stirred for 1 h at rt. The reaction was then quenched with water and mixture was adjusted pH to 8~9 with sat. NaHCO
3 (aq. ) , and then extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA: MeOH=15: 1) to give 9.2 mg of the title product as a yellow solid. MS (ES+) : 415.0 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 12.94 (s, 1H) , 12.03 (s, 1H) , 8.65 (s, 1H) , 8.19 (d, J = 7.4 Hz, 3H) , 7.70 (t, J = 7.5 Hz, 1H) , 7.51 (t, J = 7.0 Hz, 1H) , 7.38 –7.08 (m, 2H) , 5.76 (t, J = 7.1 Hz, 1H) , 2.28 (s, 3H) , 1.60 (d, J = 7.1 Hz, 3H) .
EXAMPLE 8
(±) 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carbonitrile
To a stirred solution of 6-bromo-4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [2, 3-d] pyrimidin-7 (8H) -one (90 mg, 0.211 mmol) , K
4 [Fe (CN)
6]
. 3H
2O (46 mg, 0.197 mmol) , Na
2CO
3 (70 mg, 0.329 mmol) in DMF (2 mL) was added Pd (OAc)
2 (14 mg, 0.062 mmol) at rt under Ar. The mixture was stirred for 1 h at 100℃, quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (PE: EA=1: 4) to give 3.2 mg of the title product as a white solid. MS (ES+) : 374.0 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 12.56 (s, 1H) , 9.17 (s, 1H) , 8.72 (d, J = 7.2 Hz, 1H) , 7.70 (t, J = 7.5 Hz, 1H) , 7.51 (d, J = 7.4 Hz, 1H) , 7.40 –7.10 (m, 2H) , 5.83 –5.63 (m, 1H) , 2.30 (s, 3H) , 1.56 (d, J = 7.0 Hz, 3H) .
EXAMPLE 9
(±) 4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid
Step 1 (±) 4-chloro-6- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methylpyrimidine-5-carbaldehyde
To a stirred solution of 4, 6-dichloro-2-methylpyrimidine-5-carbaldehyde (5 g, 26.316 mmol) in THF (100 ml) was added DIEA (17.5 mL, 105.26 mmol) at 0℃. The resulting mixture was stirred at 0℃ and 1- (3- (difluoromethyl) -2-fluorophenyl) ethanamine hydrochloride (7.1 g, 31.579 mmol) was added in portions. The resulting mixture was stirred at 0℃ for 4 h under Ar, quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE: EA=19: 1-9: 1) to give 8.2 g of the title product as yellow oil. MS (ES+) : 343.9 [M+1]
+.
Step 2 (±) 4-amino-6- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methylpyrimidine-5-carbaldehyde
To a stirred solution of 4-chloro-6- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methylpyrimidine-5-carbaldehyde (9.3 g, 23.724 mmol) in dioxane (180 mL) was added NH
3
. H
2O (90 mL) at rt. The resulting mixture was stirred at 50℃ for 16 h., quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was recrystallized from DCM to give 4.8 g of the title product as a white solid. The filtrate was concentrated, concentrated and the residue was purified by silica gel column chromatography (PE: EA=4: 1-2: 1-1: 1) to give 1.431 g of the title product as a white solid. MS (ES+) : 324.9 [M+1]
+.
Step 3 (±) 4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid
To a stirred solution of 4-amino-6- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methylpyrimidine-5-carbaldehyde (446 mg, 1.377 mmol) in EtOH (32 mL) were added 2, 2-dimethyl-1, 3-dioxane-4, 6-dione (793 mg, 5.507 mmol) and NMM (16 mL) at rt. While the resulting mixture was stirred at 80℃ for 36 h under Ar, additional 2, 2-dimethyl-1, 3-dioxane-4, 6-dione (3.172 g, 22.028 mmol) was added in three batches during the period of time. The reaction was then quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM: MeOH 1%-5%-5%+AcOH) to give 382 mg of the title product as a yellow solid. MS (ES+) : 392.9 [M+1]
+.
EXAMPLE 10
(±) 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 2-trimethyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid (40 mg, 0.102 mmol) in DMF (1.0 ml) were added dimethylamine in THF (2M, 0.76 mL, 1.531 mmol) , DIEA (197 mg, 1.531 mmol) and HATU (582 mg, 1.531 mmol) at rt. The resulting mixture was stirred for 3 h at rt, quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was recrystallized from DCM to give 8.8 mg of the title product as a white solid. MS (ES+) : 420.0 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 12.14 (s, 1H) , 8.40 (d, J = 41.9 Hz, 1H) , 8.33 (s, 1H) , 7.65 (t, J = 7.4 Hz, 1H) , 7.50 (t, J = 7.1 Hz, 1H) , 7.38 –7.02 (m, 2H) , 5.71 (p, J = 7.1 Hz, 1H) , 2.97 (s, 3H) , 2.88 (s, 3H) , 2.29 (s, 3H) , 1.53 (d, J = 7.0 Hz, 3H) .
EXAMPLE 11
(±) 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, 2-dimethyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid (40 mg, 0.102 mmol) in DMF (1.0 mL) were added methylamine hydrochloride (69 mg, 1.02 mmol) , DIEA (132 mg, 1.02 mmol) and HATU (388 mg, 1.02 mmol) at rt. The resulting mixture was stirred for 1 h at rt, quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to give 27 mg of the title product as a white solid. MS (ES+) : 406.0 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 12.50 (s, 1H) , 9.41 (d, J = 5.6 Hz, 1H) , 9.29 (s, 1H) , 8.97 (d, J = 7.3 Hz, 1H) , 7.69 (t, J = 7.5 Hz, 1H) , 7.51 (t, J = 7.2 Hz, 1H) , 7.39 –7.06 (m, 2H) , 5.76 (t, J = 7.2 Hz, 1H) , 2.86 (d, J = 4.8 Hz, 3H) , 2.30 (s, 3H) , 1.57 (d, J = 7.1 Hz, 3H) .
EXAMPLE 12
(±) N-benzyl-4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid (40 mg, 0.102 mmol) in DMF (1.0 mL) were added phenylmethanamine (109 mg, 1.02 mmol) , DIEA (132 mg, 1.02 mmol) and HATU (388 mg, 1.02 mmol) at rt. The resulting mixture was stirred for 1 h at rt, quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (PE: EA=1: 1) to give 4.8 mg of the title product as a white solid. MS (ES+) : 482.0 [M+1]
+.
1H NMR (400 MHz, Chloroform-d) δ 9.84 (s, 1H) , 8.93 (s, 1H) , 7.50 (d, J = 7.8 Hz, 2H) , 7.34 -7.21 (m, 6H) , 6.91 (t, J = 55.0 Hz, 1H) , 6.23 (d, J = 14.7 Hz, 1H) , 5.77 (s, 1H) , 4.66 (d, J = 5.7 Hz, 2H) , 4.39 (d, J = 5.7 Hz, 1H) , 2.47 (s, 3H) .
EXAMPLE 13
(±) 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N- (2, 4-dimethoxybenzyl) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of (2, 4-dimethoxyphenyl) methanamine (25 mg, 0.64 mmol) and 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic (106 mg, 0.63mmol) in DMF (1.5mL) were added DIEA (81 mg, 0.628mmol) and HATU (241 mg, 0.634 mmol) at rt. The mixture was stirred for 0.5 h, treated with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA: PE=2: 1) to give 5 mg of pure product as a white solid. MS (ES+) : 541.9 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 12.51 (s, 1H) , 9.85 (s, 1H) , 9.31 (s, 1H) , 8.97 (d, J = 7.2 Hz, 1H) , 7.68 (d, J = 8.0 Hz, 1H) , 7.50 (s, 1H) , 7.38 –7.07 (m, 3H) , 6.63 –6.56 (m, 1H) , 6.51 –6.40 (m, 1H) , 5.76 (t, J = 7.3 Hz, 1H) , 4.42 (d, J = 5.6 Hz, 2H) , 3.83 (s, 3H) , 3.75 (s, 3H) , 2.30 (s, 3H) , 1.57 (d, J = 7.1 Hz, 3H) .
EXAMPLE 14
(±) 4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-6- (piperidine-1-carbonyl) pyrido [2, 3-d] pyrimidin-7 (8H) -one
To a stirred solution of 4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid (18 mg, 0.046 mmol) in DMF (1 mL) were added piperidine (40 mg, 0.548 mmol) , DIEA (58 mg, 0.548 mmol) and HATU (174 mg, 0.459 mmol) at rt. The resulting mixture was stirred for 30 min at rt, quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (MeOH: EA=2: 98) to give 9.9 mg of the title product as a yellow solid. MS (ES+) : 459.9 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 12.11 (s, 1H) , 8.43 (s, 1H) , 8.33 (d, J = 7.3 Hz, 1H) , 7.65 (t, J = 7.5 Hz, 1H) , 7.51 (t, J = 7.1 Hz, 1H) , 7.38 –7.06 (m, 2H) , 5.78 –5.63 (m, 1H) , 3.57 (m, 2H) , 3.22 (m, 2H) , 2.28 (s, 3H) , 1.51 (m, 9H) .
EXAMPLE 15
4- (±) ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N-diethyl-2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid (20 mg, 0.05 mmol) in DMF (1mL) were added diethylamine (20 mg, 0.27mmol) , N, N’-Diisopropylethylamine (64 mg, 0.51 mmol) and HATU (192 mg, 0.51 mmol) at rt under Ar. The resulting mixture was stirred at rt for 0.5 h, quenched with H
2O and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA) to get 11.8 mg of the title product as a white solid. MS (ES+) : 448.0 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 12.13 (s, 1H) , 8.38 (s, 1H) , 8.33 (d, J = 7.3 Hz, 1H) , 7.64 (t, J = 7.5 Hz, 1H) , 7.50 (t, J = 7.2 Hz, 1H) , 7.40 –7.06 (m, 2H) , 5.71 (p, J = 7.1 Hz, 1H) , 3.43 (t, J = 7.0 Hz, 2H) , 3.19 (q, J = 7.1 Hz, 2H) , 2.28 (s, 3H) , 1.54 (d, J = 7.1 Hz, 3H) , 1.15 (t, J = 7.0 Hz, 3H) , 1.07 (t, J = 7.1 Hz, 3H) .
EXAMPLE 16
(±) Methyl4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylate
To a stirred solution of 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid (60 mg, 0.153 mmol) in CH
3OH (1.0 mL) was added H
2SO
4 (8 drops) at rt. The resulting mixture was stirred for 3 h at 40 ℃, quenched with water. The pH of mixture was adjusted to 8~9 by sat. NaHCO
3 (aq. ) and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA: MeOH=15: 1) to give 28 mg of the title product as a white solid. MS (ES+) : 406.9 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 12.13 (s, 1H) , 9.02 (s, 1H) , 8.78 –8.57 (m, 1H) , 7.67 (s, 1H) , 7.50 (s, 1H) , 7.37 –7.06 (m, 2H) , 5.83 –5.59 (m, 1H) , 3.80 (s, 3H) , 2.27 (s, 3H) , 1.55 (d, J = 6.9 Hz, 3H) .
EXAMPLE 17
(±) 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 8-dimethyl-6- (prop-1-en-2-yl) pyrido [2, 3-d] pyrimidin-7 (8H) -one
To a stirred solution of 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6- (prop-1-en-2-yl) pyrido [2, 3-d] pyrimidin-7 (8H) -one (65 mg, 0.168 mmol) in DMF (1.0 mL) were added Cs
2CO
3 (109 mg, 0.335 mmol) and CH
3I (24 mg, 0.168 mmol) at rt. The resulting mixture was stirred for 1 h at rt, quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (PE: EA=2: 1) to give 21 mg of the title product as a white solid. MS (ES+) : 402.9 [M+1]
+.
1H NMR (400 MHz, CDCl
3) δ 7.50 (t, J = 7.3 Hz, 2H) , 7.46 (s, 1H) , 7.20 (t, J = 7.7 Hz, 1H) , 6.92 (t, J = 55.0 Hz, 1H) , 5.75 (p, J = 7.2 Hz, 1H) , 5.54 (t, J = 5.0 Hz, 2H) , 5.24 (p, J = 1.5 Hz, 1H) , 3.73 (s, 3H) , 2.48 (s, 3H) , 2.18 (s, 3H) , 1.67 (d, J = 7.0 Hz, 3H) .
EXAMPLE 18
(±) 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-isopropyl-2, 8-dimethylpyrido [2, 3-d] pyrimidin-7 (8H) -one
To a stirred solution of 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 8-dimethyl-6- (prop-1-en-2-yl) pyrido [2, 3-d] pyrimidin-7 (8H) -one (12 mg, 0.030 mmol) in MeOH (1 mL) was added 10%Pd/C (10 mg) at room temperature. The reaction vessel was purged three times with H
2 and the resulting mixture was stirred at rt for 1 h. The mixture was then filtered and the filtrate was concentrated to give 6.5 mg the title product as a white solid. MS (ES+) : 405.0 [M+1]
+.
1H NMR (400 MHz, Chloroform-d) δ 7.51 (q, J = 7.0 Hz, 2H) , 7.29 (s, 1H) , 7.20 (t, J = 7.7 Hz, 1H) , 6.85 (d, J = 55.0 Hz, 1H) , 5.74 (p, J = 7.2 Hz, 1H) , 5.51 (t, J = 8.3 Hz, 1H) , 3.73 (s, 3H) , 3.28 (p, J = 6.9 Hz, 1H) , 2.47 (s, 3H) , 1.69 (s, 3H) , 1.28 –1.26 (m, 6H) .
EXAMPLE 19
(±) 6-cyclopropyl-4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 8-dimethylpyrido [2, 3-d] pyrimidin-7 (8H) -one
Step 1 (±) 6-bromo-4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 8-dimethylpyrido [2, 3-d] pyrimidin-7 (8H) -one
To a stirred solution of 6-bromo-4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [2, 3-d] pyrimidin-7 (8H) -one (80 mg, 0.188 mmol) in DMF (1.0 mL) were added Cs
2CO
3 (122 mg, 0.376 mmol) and CH
3I (27 mg, 0.188 mmol) at rt. The resulting mixture was stirred for 1 h at rt, quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (PE: EA=1: 1) to give 56 mg of the title product as a white solid. MS (ES+) : 441.0 [M+1]
+
Step 2 (±) 6-cyclopropyl-4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 8-dimethylpyrido [2, 3-d] pyrimidin-7 (8H) -one
To a stirred solution of 6-bromo-4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 8-dimethylpyrido [2, 3-d] pyrimidin-7 (8H) -one (49 mg, 0.111 mmol) , cyclopropylboronic acid (12 mg, 0.134 mmol) , K
3PO
4 (61 mg, 0.290 mmol) in THF /H
2O (5/1, 2 mL) was added Pd (dppf) Cl
2·DCM (9 mg, 0.011 mol) at rt under Ar. The mixture was stirred for 1 h at 70℃ under Ar, quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (PE: EA=1: 1) to give 12 mg of the title product as a gray solid. MS (ES+) : 403.0 [M+1]
+.
1H NMR (400 MHz, CDCl
3) δ 7.49 (s, 2H) , 7.19 (t, J = 7.7 Hz, 1H) , 7.11 –6.71 (m, 2H) , 5.80 –5.64 (m, 1H) , 5.52 (d, J = 7.5 Hz, 1H) , 3.74 (s, 3H) , 2.46 (s, 3H) , 2.19 (s, 1H) , 1.67 –1.65 (d, 3H) , 1.00 (d, J = 8.4 Hz, 2H) , 0.71 (s, 2H) .
EXAMPLE 20
(±) 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 2, 8-tetramethyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of Example 10 (60 mg, 0.143 mmol) in DMF (1.0 mL) were added Cs
2CO
3 (93 mg, 0.286 mmol) and CH
3I (26 mg, 0.186 mmol) at rt. The resulting mixture was stirred for 1 h at rt, quenched with water. The solid was collected by filtration and dried to give 21.5 mg of the title product as a white solid. MS (ES+) : 434.0 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.48 (s, 1H) , 8.38 (d, J = 7.2 Hz, 1H) , 7.65 (t, J = 7.4 Hz, 1H) , 7.50 (t, J = 7.1 Hz, 1H) , 7.40 –6.99 (m, 2H) , 5.73 (t, J = 7.1 Hz, 1H) , 3.56 (s, 3H) , 2.98 (s, 3H) , 2.86 (s, 3H) , 2.36 (s, 3H) , 1.55 (d, J = 7.1 Hz, 3H) .
EXAMPLE 21
(±) 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid (40 mg, 0.102 mmol) in DMF (1.0 mL) were added NH
4Cl (55 mg, 1.02 mmol) , DIEA (132 mg, 1.02 mmol) and HATU (388 mg, 1.02 mmol) at rt. The resulting mixture was stirred for 1 h at rt, quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to give 21 mg of the title product as a yellow solid. MS (ES+) : 392.0 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 12.54 (s, 1H) , 9.38 (s, 1H) , 9.03 (d, J = 7.3 Hz, 1H) , 8.96 (d, J = 4.3 Hz, 1H) , 7.75 (d, J = 5.6 Hz, 2H) , 7.58 (t, J = 7.1 Hz, 1H) , 7.45 –7.13 (m, 2H) , 5.89 –5.74 (m, 1H) , 2.38 (s, 3H) , 1.64 (d, J = 7.1 Hz, 3H) .
EXAMPLE 22
(±) 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 3-bromo-2-fluorobenzaldehyde
To a stirred solution of 1-bromo-2-fluorobenzene (50 g, 285.71 mmol) in THF (500 mL) was added LDA (39.8 g, 371.43 mmol) at -70℃ under Ar. The mixture was stirred for 1 h at -70℃. N, N-Dimethylformamide (31.3 g, 428.56 mmol) was added dropwise. The resulting mixture was stirred at rt for 1 h and was then quenched with H
2O. The mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to get 72.0 g of the title product as brown oil which was used to the next step without further purification.
Step 2 1-bromo-3- (difluoromethyl) -2-fluorobenzene
To a stirred solution of 3-bromo-2-fluorobenzaldehyde (30 g, 147.78 mmol) in DCM (450 mL) was added DAST (47.6 g, 295.55 mmol) at 0℃. The resulting mixture was stirred for 1 h at rt under Ar. The reaction was then quenched with H
2O and extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to get 46.0 g of the title product as yellow oil which was used to the next step without further purification.
Step 3 1- (3- (difluoromethyl) -2-fluorophenyl) ethanone
A mixture of 1-bromo-3- (difluoromethyl) -2-fluorobenzene (35.0 g , 154.71 mmol) , tributyl (1-ethoxyvinyl) stannane (67.1 g, 185.63 mmol) , TEA (39.2 g, 386.72 mmol) and bis (triphenylphosphine) palladium (II) chloride (1.08 g, 1.547 mmol) in 1, 4-dioxane (35 mL) was stirred for 2 h at 100℃. The mixture was then cooled to rt and 1 N HCl (700 mL) was added. The mixture was stirred overnight at rt, and then poured into water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (EA: PE=9: 1) to get 35 g of the title product as a white solid.
1H NMR (400 MHz, CDCl
3) δ 8.01 (dddt, J = 8.0, 7.0, 2.0, 1.0 Hz, 1H) , 7.84 –7.70 (m, 1H) , 7.35 (t, J = 7.7 Hz, 1H) , 6.95 (t, J = 54.8 Hz, 1H) , 2.67 (d, J = 5.0 Hz, 3H) .
Step 4 (E) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylidene) -2-methylpropane-2-sulfinamide
To a stirred solution of 1- (3- (difluoromethyl) -2-fluorophenyl) ethanone (5.0 g, 26.57 mmol) in THF (100 mL) was added 2-methylpropane-2-sulfinamide (4.8 g, 39.86 mmol) and titanium ethoxide (18.2 g, 79.59 mmol) at rt. The resulting mixture was stirred for 3 h at 80℃ and then quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to get 7.2 g of the title product as yellow oil which was used for the next step without further purification. MS (ES+) : 292.1 [M+1]
+.
Step 5 N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpropane-2-sulfinamide
To a stirred solution of the product of Step 4 (7.2 g, 24.71 mmol) in THF (140 mL) was added NaBH
4 (1.4 g, 37.07 mmol) at 0℃. The resulting mixture was stirred for 2 h at rt, and then quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (PE: EA=1: 1) to get 2.5 g of the title product as a yellow solid. MS (ES+) : 294.1 [M+1]
+.
Step 6 (±) 1- (3- (difluoromethyl) -2-fluorophenyl) ethanamine hydrochloride
To a stirred solution of the product of Step 5 (2.5 g, 8.53 mmol) in EA (25 ml) was added 4 N HCl/EA (25 mL) at rt. The resulting mixture was stirred for 0.5 h at rt, and then evaporated in vacuo. The residue was suspended in MTBE and stirred for 0.5 h, and then filtered to get 1.8 g of the title product as a white solid. MS (ES+) : 190.0 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.73 –8.55 (m, 3H) , 7.89 (t, J = 7.4 Hz, 1H) , 7.68 (t, J = 7.1 Hz, 1H) , 7.46 (t, J = 7.8 Hz, 1H) , 7.26 (t, J = 54.0 Hz, 1H) , 4.67 (p, J = 6.3 Hz, 1H) , 1.54 (d, J = 6.8 Hz, 3H) .
Step 7 4, 6-dichloro-2-methylpyrimidine-5-carbaldehyde
To a stirred solution of POCl
3 (18 mL) was added dropwise DMF (6 mL) at 0℃. The resulting mixture was stirred for 1 h. 2-methylpyrimidine-4, 6-diol (5g, 39.68 mmol) was added. The mixture was stirred at rt for 1 h, and then refluxed for 4 h at 120℃. The reaction mixture was poured into ice-water and filtered through a layer of celite. The filtrate was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE: EA=9: 1) to give 758 mg of the title product as a yellow solid.
1H NMR (400 MHz, CDCl
3) δ 10.44 (s, 1H) , 2.77 (s, 3H) .
Step 8 (±) 4-chloro-6- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methylpyrimidine-5-carbaldehyde
To a stirred solution of the product of Step 7 (5 g, 26.316 mmol) in THF (100 ml) was added DIEA (17.5 mL, 105.26 mmol) at 0℃. The resulting mixture was stirred at 0℃ and 1- (3- (difluoromethyl) -2-fluorophenyl) ethanamine hydrochloride (7.1 g, 31.579 mmol) was added in portions. The resulting mixture was stirred at 0℃ for 4 h under Ar, quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE: EA=19: 1-9: 1) to give 8.2 g of the title product as yellow oil. MS (ES+) : 343.9 [M+1]
+.
Step 9 (±) 4-amino-6- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methylpyrimidine-5-carbaldehyde
To a stirred solution of the product of Step 8 (9.3 g, 23.724 mmol) in dioxane (180 mL) was added NH
3
. H
2O (90 mL) at rt. The resulting mixture was stirred at 50 ℃ for 16 h, quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was recrystallized from DCM to give 4.8 g of the title product as a white solid. The filtrate was concentrated, concentrated and the residue was purified by silica gel column chromatography (PE: EA=4: 1-2: 1-1: 1) to give additional 1.431 g of the title product as a white solid. MS (ES+) : 324.9 [M+1]
+.
Step 10 (±) 4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid
To a stirred solution of the product of Step 9 (446 mg, 1.377 mmol) in EtOH (32 mL) were added 2, 2-dimethyl-1, 3-dioxane-4, 6-dione (793 mg, 5.507 mmol) and NMM (16 mL) at rt. While the resulting mixture was stirred at 80℃ for 36 h under Ar, additional 2, 2-dimethyl-1, 3-dioxane-4, 6-dione (3.172 g, 22.028 mmol) was added in three batches during the period of time. The reaction was then quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM: MeOH 1%-5%-5%+AcOH) to give 382 mg of the title product as a yellow solid. MS (ES+) : 392.9 [M+1]
+.
Step 11 (±) 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 2-trimethyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of the product of Step 10 (40 mg, 0.102 mmol) in DMF (1.0 ml) were added dimethylamine in THF (2M, 0.76 mL, 1.531 mmol) , DIEA (197 mg, 1.531 mmol) and HATU (582 mg, 1.531 mmol) at rt. The resulting mixture was stirred for 3 h at rt, quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was recrystallized from DCM to give 8.8 mg of the title product as a white solid. MS (ES+) : 420.0 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 12.14 (s, 1H) , 8.40 (d, J = 41.9 Hz, 1H) , 8.33 (s, 1H) , 7.65 (t, J = 7.4 Hz, 1H) , 7.50 (t, J = 7.1 Hz, 1H) , 7.38 –7.02 (m, 2H) , 5.71 (p, J = 7.1 Hz, 1H) , 2.97 (s, 3H) , 2.88 (s, 3H) , 2.29 (s, 3H) , 1.53 (d, J = 7.0 Hz, 3H) .
Step 12 (±) 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
A mixture of the product of Step 11 (28 mg, 0.07 mmol) in POCl
3 (1.0 mL) was stirred for 3 h at 100 ℃. After the reaction was completed, MeOH (1.0 mL) was added dropwise at 0-10 ℃. The mixture was heated to 50 ℃, NaOMe (400 mg, 7.41 mmol) was added under Ar. The resulting mixture was stirred overnight, and then quenched with H
2O and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA) to get 2.7 mg of the title product as a white solid. MS (ES+) : 434.0 [M+1]
+
1H NMR (400 MHz, DMSO-d
6) δ 8.76 (s, 1H) , 8.53 (d, J = 7.2 Hz, 1H) , 7.67 (t, J = 7.5 Hz, 1H) , 7.50 (t, J = 7.1 Hz, 1H) , 7.39 –7.06 (m, 2H) , 5.80 –5.67 (m, 1H) , 3.98 (s, 3H) , 3.02 (s, 3H) , 2.83 (s, 3H) , 2.36 (s, 3H) , 1.57 (d, J = 7.1 Hz, 3H) .
EXAMPLE 23
4- ( (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -6- (2, 6-dimethylpiperidine-1-carbonyl) -2-methylpyrido [2, 3-d] pyrimidin-7 (8H) -one
Step 1 (R, E) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylidene) -2-methylpropane-2-sulfinamide
To a stirred solution of 1- (3- (difluoromethyl) -2-fluorophenyl) ethanone (15.0 g, 79.72 mmol) in THF (300 mL) were added (R) -2-methylpropane-2-sulfinamide (14.5 g, 119.58 mmol) and titanium ethoxide (54.6 g, 259.16 mmol) at rt. The resulting mixture was stirred for 16 h at 80℃. The reaction was then quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE: EA=1: 1) to get 16.0 g of the title product as yellow oil. MS (ES+) : 292.1 [M+1]
+.
Step 2 (R) -N- ( (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpropane-2-sulfinamide
To a stirred solution of the product of Step 1 (14.0 g, 48.06 mmol) in THF (150 mL) was added NaBH
4 (2.2 g, 57.67 mmol) at 0℃. The resulting mixture was stirred for 2 h at 0℃, and then quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE: EA=4: 1) to get 10.8 g of the title product as a yellow solid. MS (ES+) : 294.1 [M+1]
+.
Step 3 (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethanamine hydrochloride
To a stirred solution of the product of Step 2 (10.7 g, 36.52 mmol) in EA (100 mL) was added 4 N HCl/EA (100 mL) at rt. The resulting mixture was stirred for 0.5 h at rt, and then evaporated in vacuo. The residue was suspended in MTBE and stirred for 0.5 h, filtered to get 8.2 g of the title product as a white solid. MS (ES+) : 190.0 [M+1]
+.
Step 4 (R) -4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid
Starting with the product of step 3, the title compound was synthesized by using the same procedures as described in Example 22.
Step 5 4- ( (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -6- (2, 6-dimethylpiperidine-1-carbonyl) -2-methylpyrido [2, 3-d] pyrimidin-7 (8H) -one
To a stirred solution of the product of Step 4 (30 mg, 0.077 mmol) in DMF (1 mL) were added 2, 6-dimethylpiperidine (42 mg, 0.385 mmol) , DIEA (49 mg, 0.385 mmol) and HATU (145 mg, 0.385 mmol) . Then the reaction mixture was stirred for 1 h at rt. Water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-HPLC to obtain 4 mg of pure product as a white solid. MS (ES+) : 488.0 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 12.11 (s, 1H) , 8.36 (s, 1H) , 7.65 (1H) , 7.51 (1H) , 7.37 –7.04 (m, 2H) , 5.72 (s, 1H) , 3.64-3.58 (m, 2H) , 2.28 (s, 3H) , 1.66 –1.41 (m, 7H) , 1.24 (m, 8H)
EXAMPLE 24
4- ( (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-6- (2-methylpiperidine-1-carbonyl) pyrido [2, 3-d] pyrimidin-7 (8H) -one
Starting with (R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid (100 mg, 0.255 mmol) and 2-methylpiperidine (126 mg, 2.551 mmol) , the title product was prepared by using the same method described in Step 5 for Example 23. MS (ES+) : 474.0 [M+1]
+.
1H NMR (400 MHz, CDCl
3) δ 8.25 (m, 1H) , 7.43 (m, 2H) , 7.16 –6.66 (m, 3H) , 5.71 (m, 1H) , 4.86 (m, 1H) , 3.30 (m, 1H) , 2.41 (s, 3H) , 1.58 –1.57 (m, 12H) .
EXAMPLE 25
(R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -N-ethyl-N, 2-dimethyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with (R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid and N-methylethanamine, the title product was prepared by using the same method as described in Step 5 for Example 23. MS (ES+) : 434.0 [M+1]
+.
1H NMR (400 MHz, CDCl
3) δ 10.27 (s, 1H) , 8.48 (m, 1H) , 7.66 –7.35 (m, 3H) , 7.09 (m, 1H) , 6.86 (t, J = 55.1 Hz, 1H) , 5.70 (p, J = 7.0 Hz, 1H) , 3.56 (d, J = 6.7 Hz, 1H) , 3.33 (qd, J = 7.1, 4.3 Hz, 1H) , 2.97 (d, J = 8.4 Hz, 3H) , 2.42 (d, J = 1.7 Hz, 3H) , 1.55 (t, J = 6.9 Hz, 3H) , 1.45 –1.38 (m, 3H) .
EXAMPLE 26
(R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -N-ethyl-N-isopropyl-2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with (R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid and N-ethylpropan-2-amine, the title product was prepared by using the same method as described in Step 5 for Example 23. MS (ES+) : 461.9 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 12.17 (d, J = 10.8 Hz, 1H) , 8.46 –8.35 (m, 2H) , 7.70 (t, J = 7.4 Hz, 1H) , 7.56 (t, J = 7.1 Hz, 1H) , 7.46 –7.08 (m, 2H) , 5.82 –5.69 (m, 1H) , 3.85 –3.74 (m, 1H) , 3.22 (d, J = 7.1 Hz, 1H) , 2.34 (s, 3H) , 1.60 (d, J = 7.1 Hz, 3H) , 1.29 (d, J = 6.5 Hz, 3H) , 1.24 (d, J = 7.0 Hz, 3H) , 1.19 (m, 3H) .
EXAMPLE 27
(R) -4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N-isopropyl-N, 2-dimethyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with (R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid and N-methylpropan-2-amine, the title product was prepared by using the same method described in Step 5 for Example 23. MS (ES+) : 448.0 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 12.11 (s, 1H) , 8.40 (d, J = 8.9 Hz, 1H) , 8.32 (m, 1H) , 7.65 (q, J = 7.0 Hz, 1H) , 7.50 (t, J = 7.2 Hz, 1H) , 7.37 –7.06 (m, 2H) , 5.73 –5.65 (m, 1H) , 2.76 (m, 3H) , 2.29 (s, 3H) , 1.59 (s, 3H) , 1.26 –1.10 (m, 6H) .
EXAMPLE 28
(R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -N, N-diisopropyl-2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with (R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid and diisopropylamine, the title product was prepared by using the same method as described in Step 5 for Example 23. MS (ES+) : 475.9 [M+1]
+.
1H NMR (400 MHz, CDCl
3) δ 8.43 (s, 1H) , 7.39 (m, 2H) , 6.77 (d, J = 55.6 Hz, 1H) , 5.68 (m, 1H) , 3.82 –3.77 (m, 1H) , 3.59 –3.52 (m, 1H) , 2.37 (s, 3H) , 1.61 –1.56 (m, 15H) .
EXAMPLE 29
(R) -N-benzyl-4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -N-ethyl-2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with (R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid and N-benzylethanamine, the title product was prepared by using the same method as described in Step 5 for Example 23. MS (ES+) : 509.8 [M+1]
+.
1H NMR (400 MHz, Chloroform-d) δ 8.24 (m, 1H) , 7.44 (m, 3H) , 7.36 (m, 2H) , 7.29 (m, 1H) , 7.23 (s, 1H) , 7.15 –6.70 (m, 2H) , 5.77 –5.58 (m, 1H) , 4.83 (s, 1H) , 4.51 (s, 1H) , 3.52 (m, 1H) , 3.30 (m, 1H) , 2.40 (d, J = 12.4 Hz, 3H) , 1.35 –1.06 (m, 6H) .
EXAMPLE 30
(R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -N-ethyl-2-methyl-7-oxo-N-phenyl-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with (R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid and N-ethylaniline, the title product was prepared by using the same method as described in Step 5 for Example 23. MS (ES+) : 495.6 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 11.80 (s, 1H) , 8.37 (s, 1H) , 8.26 (s, 1H) , 7.62 –7.08 (m, 9H) , 5.67 (s, 1H) , 3.88-3.80 (m, 2H) , 2.18 (d, J = 19.7 Hz, 3H) , 1.54 (d, J = 7.0 Hz, 3H) , 1.11 (m, 3H) .
EXAMPLE 31
(R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7-oxo-N- (pyridin-2-yl) -7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with (R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid and pyridin-2-amine, the title product was prepared by using the same method as described in Step 5 for Example 23. MS (ES+) : 468.9 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 12.78 (s, 1H) , 12.27 (s, 1H) , 9.50 (s, 1H) , 9.10 (d, J = 7.3 Hz, 1H) , 8.37 (d, J = 4.8 Hz, 1H) , 8.32 (d, J = 8.4 Hz, 1H) , 7.87 (t, J = 8.7 Hz, 1H) , 7.78 –7.65 (m, 1H) , 7.52 (t, J = 7.1 Hz, 1H) , 7.39 –7.05 (m, 3H) , 5.78 (t, J = 7.2 Hz, 1H) , 2.33 (s, 3H) , 1.60 (d, J = 7.1 Hz, 3H) .
EXAMPLE 32
(R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7-oxo-N- (thiazol-2-yl) -7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with (R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid and thiazol-2-amine, the title product was prepared by using the same method as described in Step 5 for Example 32. MS (ES+) : 474.4 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 13.07 (s, 1H) , 12.92 (s, 1H) , 9.55 (s, 1H) , 9.11 (d, J = 7.2 Hz, 1H) , 7.70 (t, J = 7.4 Hz, 1H) , 7.58 –7.47 (m, 2H) , 7.40 –7.04 (m, 3H) , 5.81 –5.67 (m, 1H) , 2.34 (s, 3H) , 1.59 (d, J = 7.0 Hz, 3H) .
EXAMPLE 33
4- ( ( (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-7-oxo-N- (1-phenylethyl) -7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with (R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid and 1-phenylethanamine, the title product was prepared by using the same method as described in Step 5 for Example 23. MS (ES+) : 496.0 [M+1]
+.
1H NMR (400 MHz, CDCl
3) δ 11.24 (s, 1H) , 10.03 –9.81 (m, 1H) , 7.41 –6.73 (m, 9H) , 6.40 (dd, J = 7.5, 2.8 Hz, 1H) , 5.75 (p, J = 7.2 Hz, 1H) , 5.27 (m, 1H) , 2.54 (s, 3H) , 1.59 (m, 6H) .
EXAMPLE 34
(R) -N-benzyl-4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -N, 2-dimethyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with (R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid and N-methyl-1-phenylmethanamine, the title product was prepared by using the same method as described in Step 5 for Example 23. MS (ES+) : 495.9 [M+1]
+.
1H NMR (400 MHz, CDCl
3) δ 8.61 (m, 1H) , 7.41 (m, 3H) , 7.34 (m, 2H) , 7.29 (s, 1H) , 7.24 –7.17 (m, 1H) , 7.05 (t, J = 7.7 Hz, 1H) , 6.84 (t, J = 55.1, , 1H) , 5.76 –5.58 (m, 1H) , 4.81 (q, J = 15.1 Hz, 1H) , 4.51 (s, 1H) , 3.01 (d, J = 29.6 Hz, 3H) , 2.42 (d, J = 8.6 Hz, 3H) , 1.53 (d, J = 7.0 Hz, 3H) .
EXAMPLE 35
(R) -4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, 2-dimethyl-7-oxo-N-phenyl-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with (R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid and N-methylaniline, the title product was prepared by using the same method as described in Step 5 for Example 23. MS (ES+) : 481.6 [M+1]
+.
EXAMPLE 36
(R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -N, 2-dimethyl-N- (naphthalen-1-ylmethyl) -7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with (R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid and N-methyl-1- (naphthalen-1-yl) methanamine hydrochloride, the title product was prepared by using the same method as described in Step 5 for Example 23. MS (ES+) : 545.9 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.56 (m, 1H) , 8.36 (m, 1H) , 8.18 (d, J = 8.0 Hz, 1H) , 7.97 (d, J = 7.9 Hz, 1H) , 7.87 (t, J = 9.2 Hz, 1H) , 7.72 –7.44 (m, 6H) , 7.39 –7.03 (m, 2H) , 5.76 –5.61 (m, 1H) , 5.03 (m, 2H) , 2.89 (d, J = 7.4 Hz, 3H) , 2.25 (d, J = 25.4 Hz, 3H) , 1.54 (d, J = 6.9 Hz, 3H) .
EXAMPLE 37
4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6-phenoxypyrido [2, 3-d] pyrimidin-7 (8H) -one
To a stirred solution of 4-amino-6- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrimidine-5-carbaldehyde (40 mg, 0.123 mmol) in NMP (1 mL) were added K
2CO
3 (79 mg, 0.370 mmol) and ethyl 2-phenoxyacetate (44 mg, 0.247 mmol) at rt. The mixture was stirred for 16 h at 100℃. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (PE: EA=1: 1) and Prep-HPLC to give 5.7 mg of the title product as a white solid. MS (ES+) : 440.9 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 12.30 (s, 1H) , 8.29 (s, 1H) , 8.12 (d, J = 7.3 Hz, 1H) , 7.64 (t, J = 7.4 Hz, 1H) , 7.50 (t, J = 7.1 Hz, 1H) , 7.39 –7.19 (m, 4H) , 7.11 –7.03 (m, 1H) , 6.97 (d, J = 8.1 Hz, 2H) , 5.71 (qui, J = 7.1 Hz, 1H) , 2.29 (s, 3H) , 1.52 (d, J = 7.0 Hz, 3H) .
EXAMPLE 38
4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methylpyrido [2, 3-d] pyrimidin-7 (8H) -one
To a stirred solution of LiHMDS (1.0 mL, 1.0 mmol) in THF (1.0 mL) was added methyl 2-methoxyacetate (104 mg, 1.0 mmol) at -70℃. The resulting mixture was stirred for 20 min and 4-amino-6- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methylpyrimidine-5-carbaldehyde (30 mg, 0.08 mmol) was added. The mixture was stirred overnight at rt and then was quenched with H
2O and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-HPLC to get 6.0 mg of the title product as a white solid. MS (ES+) : 379.0 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 12.04 (s, 1H) , 7.99 (d, J = 7.3 Hz, 1H) , 7.66 (t, J = 7.4 Hz, 1H) , 7.59 (s, 1H) , 7.50 (t, J = 7.1 Hz, 1H) , 7.40 –7.02 (m, 2H) , 5.75 (q, J = 7.0 Hz, 1H) , 3.84 (s, 3H) , 2.25 (s, 3H) , 1.58 (d, J = 7.1 Hz, 3H) .
EXAMPLE 39
4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) amino) pyrido [2, 3-d] pyrimidin-7 (8H) -one
Step 1 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -8- (4-methoxybenzyl) -2-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) amino) pyrido [2, 3-d] pyrimidin-7 (8H) -one
To a stirred solution of 6-bromo-4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -8- (4-methoxybenzyl) -2-methylpyrido [2, 3-d] pyrimidin-7 (8H) -one (100 mg, 0.18 mmol) in 1, 4-Dioxane (2.0 mL) were added (S) -tetrahydrofuran-3-amine (100 mg, 1.15 mmol) , sodium tert-butoxide (200 mg, 2.08 mmol) , 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (200 mg , 0.34 mmol) and palladium (II) acetate (50 mg, 0.22 mmol) at rt under Ar. The resulting mixture was stirred at 80℃ for 3 h, and was then quenched with H
2O and extracted with EA. The organic layer was washed with brine, filtered and concentrated. The residue was purified by Prep-TLC (EA) to get 100 mg of pure product as a yellow solid. MS (ES+) : 554.0 [M+1]
+.
Step 2 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) amino) pyrido [2, 3-d] pyrimidin-7 (8H) -one
To a stirred solution of 4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -8- (4-methoxybenzyl) -2-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) amino) pyrido [2, 3-d] pyrimidin-7 (8H) -one (100 mg, 0.18 mmol) in trifluoroacetic acid (0.5 ml) was added trifluoromethanesulfonic acid (0.1 ml) at rt. The resulting mixture was stirred at r, t for 20 min, and was then quenched with H
2O and extracted with EA. The organic layer was washed with brine, filtered and concentrated. The residue was purified by Prep-TLC (EA) to get 15.8 mg of pure product as a yellow solid. MS (ES+) : 433.9 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 12.01 (s, 1H) , 7.74 (d, J = 7.4 Hz, 1H) , 7.64 (t, J = 7.3 Hz, 1H) , 7.49 (t, J = 7.0 Hz, 1H) , 7.30 -7.24 (m, 2H) , 6.95 (d, J = 2.5 Hz, 1H) , 5.75 (t, J = 7.2 Hz, 1H) , 4.12 (s, 1H) , 4.05 (td, J = 8.4, 5.9 Hz, 1H) , 3.92 –3.73 (m, 2H) , 3.56 (m, 1H) , 2.35 –2.26 (m, 1H) , 2.24 (s, 3H) , 1.92 (m, 1H) , 1.58 (d, J = 7.1 Hz, 3H) .
EXAMPLE 40
(R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -N, N, 2-trimethyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of (R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid (100 mg, 0.255 mmol) , diethylamine hydrochloride (281 mg, 2.551 mmol) and DIEA (329 mg, 2.551 mmol) in DMF (2 mL) was added HATU (969 mg, 2.551 mmol) at rt. The resulting mixture was stirred at rt for 4 h, and was then quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA: MeOH= 15: 1) to give 24.5 mg of the title product as a white solid. MS (ES+) : 419.9 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 12.13 (s, 1H) , 8.45 (s, 1H) , 8.33 (d, J = 7.3 Hz, 1H) , 7.65 (t, J = 7.4 Hz, 1H) , 7.50 (t, J = 7.1 Hz, 1H) , 7.40 –7.04 (m, 2H) , 5.71 (p, J = 7.7, 7.0 Hz, 1H) , 2.97 (s, 3H) , 2.88 (s, 3H) , 2.29 (s, 3H) , 1.53 (d, J = 7.1 Hz, 3H) .
EXAMPLE 41
4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6-phenylpyrido [2, 3-d] pyrimidin-7 (8H) -one
To a stirred solution of 4-amino-6- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrimidine-5-carbaldehyde (60 mg, 0.185 mmol) in DMSO (1 mL) were added DBU (183 mg, 1.207 mmol) and ethyl 2-phenylacetate (134 mg, 0.815 mmol) at rt under Ar. The mixture was stirred for 24 h at 150℃, and was then quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-HPLC to give 4.1 mg of the title product as a yellow solid. MS (ES+) : 425.0 [M+1]
+.
1H NMR (400 MHz, CDCl
3) δ 9.21 (s, 1H) , 7.63 –7.58 (m, 2H) , 7.55 (s, 1H) , 7.49 –7.28 (m, 5H) , 7.14 (d, J = 7.7 Hz, 1H) , 6.84 (t, J = 55.0 Hz, 1H) , 5.68 (q, J = 7.0 Hz, 1H) , 5.56 (d, J = 7.5 Hz, 1H) , 2.40 (s, 3H) , 1.61 (d, J = 7.0 Hz, 3H) .
EXAMPLE 42
4- ( ( (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) pyrido [2, 3-d] pyrimidin-7 (8H) -one
Step 1 (S) -methyl 2- (tetrahydrofuran-3-yloxy) acetate
To a stirred solution of (S) -tetrahydrofuran-3-ol (1 g, 11.36 mmol) in THF (10 mL) was added NaH (545 mg, 22.72 mmol) at 0-10
0C. After stirring for 20 min, methyl 2-bromoacetate (1.91 g, 12.5 mmol) was added and the reaction mixture was stirred for 1 h at 0-10
0C. Ice water was added and extracted with DCM/MeOH (9/1) . The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to obtain 1.4 g of pure product as yellow oil. MS (ES+) : 161.0 [M+1]
+.
Step 2 4- ( ( (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) pyrido [2, 3-d] pyrimidin-7 (8H) -one
To a stirred solution of LiHMDS (1.0 mL, 1.0 mmol) in THF (1.0 mL) was added (S) -methyl 2- ( (tetrahydrofuran-3-yl) oxy) acetate (160 mg, 1.0 mmol ) at -70℃. After stirring for 20 min at -70℃, (R) -4-amino-6- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methylpyrimidine-5-carbaldehyde (30 mg, 0.08 mmol) was added. The resulting mixture was stirred over night at rt, was then quenched with H
2O and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-HPLC to get 14.0 mg of the title product as a white solid. MS (ES+) : 435.0 [M+1]
+.
EXAMPLE 43
4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6- (phenylthio) pyrido [2, 3-d] pyrimidin-7 (8H) -one
To a stirred solution of 4-amino-6- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrimidine-5-carbaldehyde (60 mg, 0.185 mmol) in NMP (1 mL) were added K
2CO
3 (118 mg, 0.556 mmol) and ethyl 2- (phenylthio) acetate (54 mg, 0.278 mmol) at rt. The mixture was stirred for 5 h at 160℃, and water was then added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (PE: EA=1: 1) to give 18 mg of the title product as a yellow solid. MS (ES+) : 456.9 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 12.19 (s, 1H) , 8.80 (s, 1H) , 8.39 (1H) , 7.65 (1H) , 7.50 (1H) , 7.30 (3H) , 7.23 (4H) , 5.71 (1H) , 2.29 (s, 3H) , 1.53 (d, 3H) .
EXAMPLE 44
4- ( ( (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6- ( ( (R) -tetrahydrofuran-3-yl) oxy) pyrido [2, 3-d] pyrimidin-7 (8H) -one
Step 1 (R) -methyl 2- (tetrahydrofuran-3-yloxy) acetate
To a stirred solution of (R) -tetrahydrofuran-3-ol (1 g, 11.36 mmol) in THF (10 mL) was added NaH (545 mg, 22.72 mmol) at 0-10
0C. The reaction mixture was stirred for 20 min at 0-10
0C. Then methyl 2-bromoacetate (1.91 g, 12.5 mmol) was added. The reaction mixture was stirred for another 1 h at 0-10
0C, and ice water was then added and extracted with DCM/MeOH (9/1) . The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to obtain 1.5 g of crude product as yellow oil which was used in the next step without further purification. MS (ES+) : 161.0 [M+1]
+.
Step 2 4- ( ( (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6- ( ( (R) -tetrahydrofuran-3-yl) oxy) pyrido [2, 3-d] pyrimidin-7 (8H) -one
Starting with the product of Step 2, the title product was prepared by using the same method as described in Step 2 for Example 42.435.0 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 12.06 (s, 1H) , 7.95 (d, J = 7.5 Hz, 1H) , 7.62 (d, J = 9.6 Hz, 2H) , 7.50 (t, J = 7.0 Hz, 1H) , 7.39 –7.10 (m, 2H) , 5.73 (t, J = 7.1 Hz, 1H) , 5.10 (m, 1H) , 3.95 (dd, J = 10.2, 4.6 Hz, 1H) , 3.91 –3.75 (m, 3H) , 2.25 (m, 4H) , 2.03-1.99 (m, 1H) , 1.58 (d, J = 7.1 Hz, 3H) .
EXAMPLE 45
(R) -4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6- (pyridin-4-yl) pyrido [2, 3-d] pyrimidin-7 (8H) -one
To a stirred solution of LiHMDS (1.0 mL, 1.0 mmol) in THF (1.0 mL) was added ethyl 2- (pyridin-4-yl) acetate (165 mg, 1.0 mmol) in THF (0.1 mL) at -70 ℃. The mixture was stirred for 20 min at -70℃, and (R) -4-amino-6- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrimidine-5-carbaldehyde (30 mg, 0.093 mmol) in THF (0.1 mL) was added at -70 ℃. The resulting mixture was stirred over night at rt, and was then quenched with H
2O and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA) to get 11 mg of the title product as a yellow solid. MS (ES+) : 426.0 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 12.20 (s, 1H) , 8.63 (m 4H) , 7.83 (s, 2H) , 7.60 (m, 2H) , 7.40 –7.08 (m, 2H) , 5.77 (m, 1H) , 2.29 (s, 3H) , 1.58 (d, 3H) .
EXAMPLE 46
(R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -7- (dimethylamino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -7-chloro-4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
A mixture of (R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -N, N, 2-trimethyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxamide (160 mg, 0.382 mmol) in POCl
3 (1 mL) was stirred at 70℃for 3 h under Ar. The reaction was quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to give 120 mg of the title product as a red solid. MS (ES+) : 437.6 [M+1]
+.
Step 2 (R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -7- (dimethylamino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of the product of Step 1 (25 mg, 0.057 mmol) in 1, 4-Dioxane (1 mL) were added dimethylamine hydrochloride (49 mg, 0.57 mmol) and DIEA (75 mg, 0.57 mmol) at rt. The resulting mixture was stirred at rt for 3 h, and was then quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA: MeOH=15: 1) to give 7.7 mg of the title product as a yellow solid. MS (ES+) : 446.9 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.61 (s, 1H) , 8.51 (s, 1H) , 7.68 (s, 1H) , 7.49 (t, J = 7.1 Hz, 1H) , 7.27 (d, J = 7.6 Hz, 1H) , 7.22 (s, 1H) , 3.04 (s, 6H) , 3.02 (s, 3H) , 2.92 –2.86 (m, 3H) , 2.30 (s, 3H) , 1.55 (d, J = 7.1 Hz, 3H) .
EXAMPLE 47
(R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -N, N, 2-trimethyl-7- (methylthio) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of the product of Step 1 of Example 46 (50 mg, 0.114 mmol) in EtOH (2 mL) was added Sodium thiomethoxide (1 mL) at rt. The resulting mixture was stirred at rt overnight, and was then quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA) to give 22.2 mg of the title product as a white solid. MS (ES+) : 450.0 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.62 (m, 2H) , 7.67 (t, J = 7.5 Hz, 1H) , 7.51 (t, J = 7.1 Hz, 1H) , 7.34 –7.21 (m, 2H) , 5.76 (p, J = 7.2 Hz, 1H) , 3.05 (s, 3H) , 2.88 (d, J = 7.4 Hz, 3H) , 2.59 (s, 3H) , 2.38 (s, 3H) , 1.57 (d, J = 7.1 Hz, 3H) .
EXAMPLE 48
(R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -N, N, 2-trimethyl-7- (methylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of the product of Step 1 of Example 46 (40 mg, 0.092 mmol) in dioxane (1 mL) were added methylamine (1 mL) . The reaction mixture was stirred for 1 h at rt, and then treated water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA) to obtain 7 mg of the title product as a yellow solid. MS (ES+) : 433.0 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.41 (s, 1H) , 8.37 (s, 1H) , 7.66 (t, J = 7.4 Hz, 1H) , 7.50 (t, J = 7.0 Hz, 1H) , 7.29 (m, 2H) , 7.00 (s, 1H) , 5.75 (p, J = 7.0 Hz, 1H) , 3.02 (s, 3H) , 2.90 (d, J = 4.6 Hz, 6H) , 2.31 (s, 3H) , 1.55 (d, J = 7.1 Hz, 3H) .
EXAMPLE 49
4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -6-iodo-2-methylpyrido [2, 3-d] pyrimidin-7 (8H) -one
Step 1 4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -6-iodo-8- (4-methoxybenzyl) -2-methylpyrido [2, 3-d] pyrimidin-7 (8H) -one
To a stirred solution of 6-bromo-4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -8- (4-methoxybenzyl) -2-methylpyrido [2, 3-d] pyrimidin-7 (8H) -one (100 mg, 0.183 mmol) in 1, 4-dioxane (1 mL) were added (1R, 2R) -N1, N2-dimethylcyclohexane-1, 2-diamine (200 mg, 1.41 mmol) , NaI (200 mg, 1.33 mmol) and CuI (200 mg, 1.05 mmol) . The reaction mixture was stirred for 16 h at 100 ℃, and then treated water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (PE/EA=3/1) to get 38 mg of the title product as a white solid. MS (ES+) : 594.9 [M+1]
+.
Step 2 4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -6-iodo-2-methylpyrido [2, 3-d] pyrimidin-7 (8H) -one
A mixture of the product of Step 1 (30 mg, 0.051 mmol) in trifluoromethanesulfonic acid (0.2 mL) and TFA (0.1 mL) was stirred for 30 min at rt. The reaction mixture was then treated with ice-water, sat. Na
2CO
3 (aq. ) and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (PE/EA=1/1) to obtain 8 mg of the title product as a yellow solid. MS (ES+) : 474.8 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 12.24 (s, 1H) , 9.06 (s, 1H) , 8.35 (d, J = 7.2 Hz, 1H) , 7.66 (t, J = 7.2 Hz, 1H) , 7.51 (t, J = 7.0 Hz, 1H) , 7.39 –7.27 (m, 2H) , 5.74 –5.66 (m, 1H) , 2.26 (s, 3H) , 1.55 (d, J = 7.0 Hz, 3H) .
EXAMPLE 50
(R) -4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-7-oxo-N-phenyl-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of (R) -4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid (30 mg, 0.077 mmol) in DMF (0.5 mL) were added aniline (14 mg, 0.153 mmol) , DIEA (39 mg, 0.306 mmol) and HATU (87 mg, 0.230 mmol) at rt. The resulting mixture was stirred for 1h at rt, and then diluted with water. The resulting precipitate was filtered and dried to give 15.2 mg of the title product as a white solid. MS (ES+) : 467.8 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 12.77 (s, 1H) , 11.90 (s, 1H) , 9.45 (s, 1H) , 9.07 (d, J = 7.3 Hz, 1H) , 7.72-7.68 (m, 3H) , 7.53-7.49 (m, 1H) , 7.40-7.23 (m, 3H) , 7.14-7.09 (m, 1H) , 5.79-5.75 (m, 1H) , 2.33 (s, 3H) , 1.59 (d, J = 7.1 Hz, 3H) .
EXAMPLE 51
(R) -4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of the product of Step 1 of Example 46 (30 mg, 0.07 mmol) in 1, 4-dioxane (0.5 mL) were added pyrrolidine (49 mg, 0.69 mmol) and DIEA (89 mg, 0.69 mmol) at rt. The mixture was stirred for 1 h at rt, and was then treated with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to give 17.1 mg of the title product as a yellow solid. MS (ES+) : 473.3 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.41 (s, 1H) , 8.23 (d, J = 7.2 Hz, 1H) , 7.65 (d, J = 6.8 Hz, 1H) , 7.48 (d, J = 7.5 Hz, 1H) , 7.33 –7.21 (m, 2H) , 5.73 (m, 1H) , 3.50 (m, 4H) , 3.04 (s, 3H) , 2.90 (d, J = 11.8 Hz, 3H) , 2.28 (s, 3H) , 1.91 (d, J = 6.5 Hz, 4H) , 1.55 (d, J = 7.1 Hz, 3H) .
EXAMPLE 52
(R) -7- (azetidin-1-yl) -4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1 of Example 46 and azetidine, the title product was prepared by using the same method as described for Example 51. MS (ES+) : 459.3 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.42 (s, 1H) , 8.23 (d, J = 7.3 Hz, 1H) , 7.64 (s, 1H) , 7.48 (d, J = 8.0 Hz, 1H) , 7.33 –7.20 (m, 2H) , 5.73 (s, 1H) , 4.02 (m, 4H) , 3.01 (s, 3H) , 2.89 (s, 3H) , 2.32-2.28 (m, 5H) , 1.54 (d, J = 7.0 Hz, 3H) .
EXAMPLE 53
(R) -4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 2-trimethyl-7- (piperidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1 of Example 46 and piperidine, the title product was prepared by using the same method described for Example 51. MS (ES+) : 487.2 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.51 (s, 1H) , 8.38 (d, J = 7.4 Hz, 1H) , 7.66 (m, 1H) , 7.49 (m, 1H) , 7.33 –7.09 (m, 2H) , 5.75 (m, 1H) , 3.47 (m, 4H) , 3.03 (s, 3H) , 2.85 (s, 3H) , 2.29 (s, 3H) , 1.61-1.55 (m, 9H) .
EXAMPLE 54
(R) -4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 2-trimethyl-7- (4-methylpiperazin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1 of Example 46 and methylpiperazine, the title product was prepared by using the same method as described for Example 51. MS (ES+) : 502.2 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.54 (s, 1H) , 8.41 (d, J = 7.3 Hz, 1H) , 7.65 (s, 1H) , 7.50 (t, J = 7.0 Hz, 1H) , 7.33 –7.21 (m, 2H) , 5.74 (m, 1H) , 3.47 (m, 4H) , 3.03 (s, 3H) , 2.84 (s, 3H) , 2.38 (m, 4H) , 2.30 (s, 3H) , 2.21 (s, 3H) , 1.55 (d, J = 7.1 Hz, 3H) .
EXAMPLE 55
(R) -4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 2-trimethyl-7- (piperazin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 tert-butyl (R) -4- (4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6- (dimethylcarbamoyl) -2-methylpyrido [2, 3-d] pyrimidin-7-yl) piperazine-1-carboxylate
Starting with the product of Step 1 of Example 46 and piperazine-1-carboxylate, the title product was prepared by using the same method as described for Example 51.
Step 2 (R) -4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 2-trimethyl-7- (piperazin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
A mixture of the product of Step 1 (25 mg, 0.04 mmol) in TFA/DCM (1: 1, 1.0 mL) was stirred for 2 h at rt. The reaction mixture was adjusted pH>7 with Na
2CO
3 (aq. ) and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to give 15.7 mg of the title product as a white solid. MS (ES+) : 488.3 [M+1]
+
EXAMPLE 56
(R) -4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 2-trimethyl-7-morpholinopyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1 of Example 46 and morpholine, the title product was prepared by using the same method described for Example 51. MS (ES+) : 489.3 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.62 (s, 1H) , 8.49 (d, J = 7.4 Hz, 1H) , 7.71 (s, 1H) , 7.55 (t, J = 7.1 Hz, 1H) , 7.42 –7.14 (m, 2H) , 5.80 (s, 1H) , 3.72 (t, J = 4.8 Hz, 4H) , 3.52 (m, 4H) , 3.08 (s, 3H) , 2.93 (s, 3H) , 2.36 (s, 3H) , 1.61 (d, J = 7.1 Hz, 3H) .
EXAMPLE 57
N4- ( (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -N7, N7, 2-trimethyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) pyrido [2, 3-d] pyrimidine-4, 7-diamine
Step 1 7-chloro-N- ( (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) pyrido [2, 3-d] pyrimidin-4-amine
A mixture of 4- ( ( (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) pyrido [2, 3-d] pyrimidin-7 (8H) -one (680 mg, 1.57 mmol) in PhPOCl
2 (7 mL) was stirred for 2 h at 120 ℃ under Ar. The mixture was then poured into 50 mL H
2O cooled at 0~10℃ and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (EA) to give 560 mg of crude product as a gray solid. MS (ES+) : 453.0 [M+1]
+.
Step 2 N4- ( (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -N7, N7, 2-trimethyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) pyrido [2, 3-d] pyrimidine-4, 7-diamine
To a stirred solution of the product of Step 1 (40 mg, 0.09 mmol) in 1, 4-dioxane (1.0 mL) were added 2M dimethylamine in THF (0.44 ml, 0.88 mmol) and DIEA (114 mg, 0.88 mmol) at rt. The mixture was stirred for 1 h at rt, and then treated with water, and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to give 19.8 mg of the title product as a yellow solid. MS (ES+) : 462.2 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 7.99 (s, 1H) , 7.86 (s, 1H) , 7.64 (s, 1H) , 7.50 (s, 1H) , 7.36 –7.09 (m, 2H) , 5.77 (s, 1H) , 5.19 (s, 1H) , 3.95 –3.82 (m, 4H) , 3.13 (s, 6H) , 2.34 (m, 1H) , 2.27 (s, 3H) , 2.11 (m, 1H) , 1.59 (d, J = 7.1 Hz, 3H) .
EXAMPLE 58
N- ( (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-2-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) pyrido [2, 3-d] pyrimidin-4-amine
To a stirred solution of the product of Step 1 of Example 57 (30 mg, 0.07 mmol) in MeOH (1.0 mL) was added sodium methanolate (100 mg, 1.85 mmol) at rt. The mixture was stirred for 2 h at rt, and then treated with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to obtain 12.6 mg of the title product as a yellow solid. MS (ES+) : 449.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.26 (dd, J = 13.3, 7.2 Hz, 1H) , 8.13 (d, J = 11.0 Hz, 1H) , 7.71 (t, J = 7.3 Hz, 1H) , 7.56 (t, J = 7.1 Hz, 1H) , 7.40 –7.27 (m, 2H) , 5.83 (q, J = 7.0 Hz, 1H) , 5.23 (s, 1H) , 4.12 –3.83 (m, 7H) , 2.48 –2.40 (m, 1H) , 2.38 (s, 3H) , 2.17 –2.03 (m, 1H) , 1.67 (dd, J = 7.1, 2.2 Hz, 3H) .
EXAMPLE 59
N- ( (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-7- (methylthio) -6- ( ( (S) -tetrahydrofuran-3-yl) oxy) pyrido [2, 3-d] pyrimidin-4-amine
To a stirred solution of the product of Step 1 of Example 57 (40 mg, 0.09 mmol) in CH
3CH
2OH (1.5 mL) was added 20%CH
3SNa in H
2O (0.75 mL) at rt. The mixture was stirred for 1 h at rt, and then treated with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (PE: EA=1: 2) to give 11.3 mg of the title product as a white solid. MS (ES+) : 465.1 [M+1]
+.
EXAMPLE 60
N 4- ( (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) pyrido [2, 3-d] pyrimidine-4, 7-diamine
To a stirred solution of the product of Step 1 of Example 57 (30 mg, 0.07 mmol) in 1, 4-dioxane (1.0 mL) were added ammonium hydroxide (1.0 mL) at rt. The mixture was stirred for 36 h at 80 ℃, and then treated with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to obtain 12.1 mg of the title product as a yellow solid. MS (ES+) : 434.1 [M+1]
+.
EXAMPLE 61
N4- ( (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -N7, 2-dimethyl-6- ( (S) -tetrahydrofuran-3-yloxy) pyrido [2, 3-d] pyrimidine-4, 7-diamine
To a stirred solution of the product of Step 1 of Example 57 (40 mg, 0.088 mmol) in 1, 4-dioxane (1 mL) was added methylamine (1 mL) . The reaction mixture was stirred for 1 h at rt, and then treated with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA) to obtain 16.5 mg of the title product as a yellow solid. MS (ES+) : 448.1 [M+1]
+.
EXAMPLE 62
(R) -7-acetamido-4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of (R) -7-chloro-4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide (30 mg, 0.07 mmol) in 1, 4-dioxane (1.0 mL) were added acetamide (30 mg, 0.51 mmol) , Cs
2CO
3 (113 mg, 0.35 mmol) , 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (30 mg, 0.05 mmol) and Pd
2 (dba)
3 (30 mg, 0.05 mmol) at rt. The mixture was purged by Ar three times and stirred for 2 h at 100 ℃. The reaction mixture was then treated water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA: MeOH=15: 1) to obtain 9.5 mg of the title product as a yellow solid. MS (ES+) : 461.0 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 10.94 (s, 1H) , 9.16 (s, 1H) , 7.83 (s, 1H) , 7.55 (d, J = 7.3 Hz, 1H) , 7.39 –7.09 (m, 3H) , 5.91 (t, J = 7.3 Hz, 1H) , 3.04 (s, 3H) , 2.95 (s, 3H) , 2.54 (s, 3H) , 2.13 (s, 3H) , 1.68 (d, J = 7.0 Hz, 3H) .
EXAMPLE 63
(R) -7-benzamido-4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
A mixture of (R) -7-chloro-4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide (30 mg, 0.07 mmol) , benzamide (49 mg, 0.69 mmol) , Cs
2CO
3 (49 mg, 0.69 mmol) , Xant-phos (30 mg, 0.05 mmol) and Pd
2 (dba)
3 (30 mg, 0.03 mmol) in 1, 4-dioxane (0.5 mL) was stirred for 2 h at 100℃ under Ar. The mixture was then treated with water extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA: MeOH=15: 1) and Prep-HPLC to give 7.1 mg of the title product as a yellow solid. MS (ES+) : 523.0 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 11.31 (s, 1H) , 8.99 (s, 1H) , 7.98 (s, 2H) , 7.75-7.53 (m, 5H) , 7.33-7.11 (m, 3H) , 5.87-5.79 (m, 1H) , 3.13 (s, 3H) , 2.92 (s, 3H) , 1.99 (s, 3H) , 1.65 (s, 3H) .
EXAMPLE 64
(R) -4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 2-trimethyl-7- (phenylsulfonamido) pyrido [2, 3-d] pyrimidine-6-carboxamide
A mixture of (R) -7-chloro-4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide (45 mg, 0.10 mmol) , benzenesulfonamide (81 mg, 0.51 mmol) , Cs
2CO
3 (168 mg, 0.51 mmol) , Xant-phos (45 mg, 0.08 mmol) and Pd
2 (dba)
3 (47 mg, 0.05 mmol) in 1, 4-dioxane (1.5 mL) was stirred for 1 h at 100℃. The mixture was then treated with water extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA) to give 23.1 mg of the title product as a yellow solid. MS (ES+) : 559.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 9.24 (s, 1H) , 8.34 (s, 1H) , 7.99 (s, 2H) , 7.67 (m, 1H) , 7.53 (m, 1H) , 7.42 (m, 4H) , 7.33 -7.22 (s, 1H) , 5.79 (s, 1H) , 2.96 (s, 3H) , 2.77 (s, 3H) , 2.46 (s, 3H) , 1.57 –1.56 (d, J= 3.6 Hz, 3H) .
EXAMPLE 65
(R) -4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 2-trimethyl-7- (methylsulfonamido) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of (R) -7-chloro-4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide (40 mg, 0.09 mmol) in 1, 4-dioxane (1.0 mL) were added methanesulfonamide (40 mg, 0.42 mmol) , cesium carbonate (144 mg, 0.44 mmol) , 4, 5- Bis(diphenylphosphino) -9, 9-dimethylxanthene (40 mg, 0.07 mmol) and Pd
2 (dba)
3 (20 mg, 0.03 mmol) at rt. The mixture was purged by Ar three times and stirred for 2 h at 100 ℃. The mixture was then treated with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA: MeOH=15: 1) to obtain 10.3 mg of pure product as a yellow solid. MS (ES+) : 497.2 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.40 (s, 1H) , 7.69 (s, 1H) , 7.55 (s, 1H) , 7.38-7.09 (m, 3H) , 5.81 (s, 1H) , 3.05 (s, 3H) , 2.97 (s, 3H) , 2.86 (s, 3H) , 2.44 (s, 3H) , 1.59 (d, J = 7.0 Hz, 3H) .
EXAMPLE 66
(R) -N4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-N7, N7, 2-trimethylpyrido [2, 3-d] pyrimidine-4, 7-diamine
Step 1 (R) -4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-methoxy-2-methylpyrido [2, 3-d] pyrimidin-7 (8H) -one
To a stirred solution of LiHMDS (1.0 mL, 1.00 mmol) in THF (1.0 mL) was added methyl 2-methoxyacetate (96 mg, 0.93 mmol) at -70 ℃. The mixture was stirred for 20 min and 4- ( ( (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) pyrido [2, 3-d] pyrimidin-7 (8H) -one (100 mg, 0.31 mmol) was added. The resulting mixture was stirred over night at rt. The reaction mixture was then quenched with H
2O and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA) to get 80.0 mg of the title product as a white solid. MS (ES+) : 379.1 [M+1]
+.
Step 2 (R) -7-chloro-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-2-methylpyrido [2, 3-d] pyrimidin-4-amine
A mixture the product of Step 1 (75 mg, 0.20 mmol) in PhPOCl
2 (1.0 mL) was stirred 1 h at 100 ℃. The reaction was quenched with ice water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA) to get 21.0 mg of the title product as a white solid. MS (ES+) : 397.1 [M+1]
+.
Step 3 (R) -N4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-methoxy-N7, N7, 2-trimethylpyrido [2, 3-d] pyrimidine-4, 7-diamine
A mixture of the product of Step 2 (20 mg, 0.05 mmol) in dimethylamine (1.0 mL) was stirred for 1 h at rt. The reaction was quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to get 9.8 mg of pure product as a white solid. MS (ES+) : 406.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.02 (d, J = 7.3 Hz, 1H) , 7.87 (s, 1H) , 7.65 (t, J = 7.5 Hz, 1H) , 7.49 (t, J = 7.1 Hz, 1H) , 7.33 –7.22 (m, 2H) , 5.78 (q, J = 7.1 Hz, 1H) , 3.93 (s, 3H) , 3.13 (s, 6H) , 2.27 (s, 3H) , 1.59 (d, J = 7.1 Hz, 3H) .
EXAMPLE 67
(R) -4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 2-trimethyl-7- (prop-1-en-2-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of (R) -7-chloro-4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide (50 mg, 0.11 mmol) in THF (1.0 mL) were added 4, 4, 5, 5-tetramethyl-2- (prop-1-en-2-yl) -1, 3, 2-dioxaborolane (23 mg, 0.14 mmol) , potassium phosphate tribasic (48 mg, 0.23 mmol) and 1, 1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (10 mg, 0.01 mmol) at rt. The mixture was purged with Ar three times and stirred for 2 h at 70 ℃. The mixture was then treated with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA) to obtain 7.7 mg of pure product as a yellow solid. MS (ES+) : 444.1 [M+1]
+.
1H NMR (400 MHz, Chloroform-d) δ 8.51 (s, 1H) , 7.49 (m, 3H) , 7.18 (s, 1H) , 7.03-6.76 (m, 1H) , 5.86 (m, 1H) , 5.44 (d, J = 6.7 Hz, 2H) , 3.06 (s, 3H) , 2.80 (s, 3H) , 2.64 (s, 3H) , 2.24 (s, 3H) , 1.71 (d, J = 6.9 Hz, 3H) .
EXAMPLE 68
(R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -N, N, 2-trimethyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 1- (3-nitro-5- (trifluoromethyl) phenyl) ethanone
To a stirred solution of 1-bromo-3-nitro-5- (trifluoromethyl) benzene (5.0 g, 18.52 mmol) in 1, 4-dioxane (50 mL) were added tributyl (1-ethoxyvinyl) stannane (8.0 g, 22.22 mmol) , TEA (4.7 g, 46.30 mmol) and bis (triphenylphosphine) palladium (II) chloride (130 mg, 1.85 mmol) . The resulting mixture was stirred for 2 h at 100 ℃. The mixture was the cooled and treated with 1 N HCl (1500 mL) . After stirring for 14 h at rt, the mixture was poured into water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (EA: PE=9: 1) to get 3.5 g of the title product as a yellow solid.
Step 2 (R, E) -2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylidene) propane-2-sulfinamide
To a stirred solution of 1- (3-nitro-5- (trifluoromethyl) phenyl) ethanone (30.0 g, 128.68 mmol) in THF (500 mL) were added (R) -2-methylpropane-2-sulfinamide (23.4 g, 193.02 mmol) and titanium ethoxide (88.1 g, 386.03 mmol) at rt. The resulting mixture was stirred for 16 h at 80 ℃, and then quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to get 41.0 g of the title product as yellow oil. MS (ES+) : 337.1 [M+1]
+.
Step 3 (R) -2-methyl-N- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) propane-2-sulfinamide
To a stirred solution of the product of Step 1 (40.0 g, 119.02 mmol) in THF (400 mL) was added NaBH
4 (5.4 g, 142.82 mmol) at 0℃. The resulting mixture was stirred for 2 h at 0℃, and then quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (EA: PE=4: 1) to get 33.1 g of the title product as a yellow solid. MS (ES+) : 339.1 [M+1]
+.
Step 4 (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethanamine hydrochloride
To a stirred solution of the product of Step 3 (33.0 g, 97.63 mmol) in EA (330 mL) was added 4 N HCl/EA (330 mL) at rt. The resulting mixture was stirred for 0.5 h at rt, and then was evaporated in vacuo. The residue was dissolved in MTBE. The organic layer was filtered and dried to get 17.5 g of the title product as a white solid. MS (ES+) : 235.1 [M+1]
+.
Step 5 (R) -4-chloro-6- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methylpyrimidine-5-carbaldehyde
To a stirred solution of 4, 6-dichloro-2-methylpyrimidine-5-carbaldehyde (2 g, 10.53 mmol) in THF (20 mL) were added DIEA (7 mL, 42.11 mmol) at 0 ℃ and the product of Step 4 (3.4 g, 12.63 mmol) in portions. The resulting mixture was stirred at 0℃ for 4 h under Ar. The reaction mixture was quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE: EA=19: 1-9: 1) to give 4.22 g of the title product. MS (ES+) : 388.7 [M+1]
+.
Step 6 (R) -4-amino-2-methyl-6- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrimidine-5-carbaldehyde
To a stirred solution of the product of Step 5 (4.23 g, 10.90 mmol) in 1, 4-dioxane (120 mL) was added NH
3H
2O (40 mL) at rt. The resulting mixture was stirred at 50 ℃ for 16 h. The reaction mixture was then quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE: EA=4: 1-2: 1-1: 1) to give 2.5 g of the title product. MS (ES+) : 370.0 [M+1]
+.
Step 7 (R) -2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid
To a stirred solution of the product of Step 6 (1.5 g, 4.07 mmol) in EtOH (100 mL) were added 2, 2-dimethyl-1, 3-dioxane-4, 6-dione (2.34 g, 16.26 mmol) and NMM (50 mL) at rt. The resulting mixture was stirred at 80℃ for 36 h under Ar. While stirring, additional 2, 2-dimethyl-1, 3-dioxane-4, 6-dione (7.02 g, 48.78 mmol) was added in three batches. The reaction mixture was then quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM: MeOH 1%-5%-5%+AcOH) to give 1.5 g of the title product.
Step 8 (R) -N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of the product of Step 7 (190 mg, 0.435 mmol) in DMF (2 mL) were added dimethylamine (2M in THF, 2.2 mL, 4.35 mmol) , DIEA (0.72 mL, 4.35 mmol) and HATU (1.65 g, 4.35 mmol) at rt. The resulting mixture was stirred at rt for 4 h, and then quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (eluted with EA: PE= 2: 1-4: 1-8: 1) to give 120 mg of the title product as a yellow solid. MS (ES+) : 465.1 [M+1]
+.
Step 9 (R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -N, N, 2-trimethyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of the product of Step 8 (25 mg, 0.054 mmol) in MeOH (1 mL) was added 10%Pd/C (25 mg) . The reaction mixture was stirred for 1 h at rt under H
2, and then filtered and concentrated. The residue was purified by Prep-HPLC to obtain 4 mg of the title product as a white solid. MS (ES+) : 435.0 [M+1]
+.
1H NMR (400 MHz, Chloroform-d) δ 8.48 (s, 1H) , 7.04 (s, 1H) , 6.77 (s, 1H) , 6.71 (s, 1H) , 5.39 (t, J = 7.2 Hz, 1H) , 3.12 (s, 3H) , 3.02 (s, 3H) , 2.45 (s, 3H) , 1.54 (d, J = 7.0 Hz, 3H) .
EXAMPLE 69
(R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (dimethylamino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
A mixture of the product of Step 8 of Example 68 (100 mg, 0.22 mmol) in POCl
3 (1 mL) was stirred at 70℃ for 3 h under Ar. The mixture was then quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to give 80 mg of the title product as a yellow solid. MS (ES+) : 483.0 [M+1]
+.
Step 2 (R) -7- (dimethylamino) -N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of the product of Step 1 (75 mg, 0.16 mmol) in 1, 4-dioxane (1.5 mL) were added dimethylamine hydrochloride (130 mg, 1.6 mmol) and DIEA (207 mg, 1.6 mmol) at rt. The resulting mixture was stirred at rt for 20 h, and then quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA: MeOH=9: 1) to give 41 mg of the title product as a yellow solid. MS (ES+) : 492.1 [M+1]
+.
1H NMR (400 MHz, chloroform-d) δ 8.58-8.35 (m, 3H) , 8.17-8.11 (m, 1H) , 5.66 (m, 1H) , 3.08 (d, J = 3.7 Hz, 9H) , 2.96 (s, 3H) , 2.55 (s, 3H) , 1.73 (d, J = 7.1 Hz, 3H) .
Step 3 (R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (dimethylamino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution the product of Step 2 (25 mg, 0.051 mmol) in MeOH (1 mL) was added 10%Pd/C (25 mg) at rt under H
2. The resulting mixture was stirred for 30 min at rt. The reaction mixture was filtered through a layer of celite. The filtrate was evaporated to dryness to obtain 15.3 mg of the title product as an off-white solid. MS (ES+) : 462.0 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.43 (s, 1H) , 8.24 (d, J = 8.0 Hz, 1H) , 6.83 (m, 2H) , 6.69 (s, 1H) , 5.55-5.46 (m, 3H) , 3.03 (m, 9H) , 2.88 (s, 3H) , 2.34 (s, 3H) , 1.49 (d, J = 7.1 Hz, 3H) .
EXAMPLE 70
(R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of the product of Step 1 of Example 69 (40 mg, 0.083 mmol) in 1, 4-dioxane (1 mL) were added pyrrolidine (40 mg) and DIEA (40 mg) . The reaction mixture was stirred for 1 h at rt, and was then treated with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to obtain 30 mg of crude product as a yellow solid. MS (ES+) : 518.1 [M+1]
+. Step 2 (R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of the product of Step 1 (30 mg, 0.058 mmol) in MeOH (1 mL) were added 10%Pd/C (30 mg) . The reaction mixture was stirred for 1 h at rt under H
2, and was then filtered through a pad of celite. The filtrate was concentrated and the residue was purified by Prep-HPLC to obtain 5 mg of pure product as a yellow solid. MS (ES+) : 488.3 [M+1]
+.
EXAMPLE 71
(R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (azetidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamid
Step 1 (R) -7- (azetidin-1-yl) -N, N, 2-trimethyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of the product of Step 1 of Example 69 (40 mg, 0.08 mmol) in 1, 4-dioxane (1.0 mL) were added azetidine (47 mg, 0.83 mmol) and DIEA (107 mg, 0.83 mmol) at rt. The mixture was stirred for 1 h at rt, and was then treated with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to give 37 mg of pure product as a yellow solid. MS (ES+) : 504.1 [M+1]
+.
Step 2 (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (azetidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamid
To a stirred solution of the product of Step 1 (35 mg, 0.07 mmol) in CH
3OH (1.0 mL) was added 10%Pd/C (35 mg) at rt. The mixture was stirred for 0.5 h at rt (15℃) under H
2, then filtered through a pad of celite. The filtrate was concentrated and the residue was purified by Prep-TLC (EA: MeOH=15: 1 + 1%NH
3 H
2O) to give 11.1 mg of the title product as a yellow solid. MS (ES+) : 474.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.45 (s, 1H) , 6.84 (2H) , 6.72 (s, 1H) , 5.58–5.47 (m, 3H) , 4.08 (m, 4H) , 3.02 (s, 3H) , 2.91 (s, 3H) , 2.42 (s, 3H) , 2.36 (m, 2H) , 1.52 (d, J = 7.0 Hz, 3H) .
EXAMPLE 72
(R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -N, N, 2-trimethyl-7- (piperidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -N, N, 2-trimethyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (piperidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of the product of Step 1 of Example 48 (40 mg, 0.08 mmol) in 1, 4-dioxane (1.0 mL) were added piperidine (71 mg, 0.83 mmol) and DIEA (107 mg, 0.83 mmol) at rt. The mixture was stirred for 1 h at rt, and was then treated with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to give 40 mg of pure product as a yellow solid. MS (ES+) : 532.2 [M+1]
+.
Step 2 (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -N, N, 2-trimethyl-7- (piperidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of the product of Step 1 (35 mg, 0.07 mmol) in EA (1.0 mL) was added 10%Pd/C (35 mg) at rt. The mixture was stirred for 1 h at rt (15℃) under H
2, and was then filtered through a pad of celite. The filtrate was concentrated and the residue was purified by Prep-TLC (EA: MeOH=15: 1 + 1%NH
3 H
2O) to give 10.7 mg of the title product as a yellow solid. MS (ES+) : 502.3 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 9.23 (s, 1H) , 8.56 (s, 1H) , 6.84 (m , 2H) , 6.72 (s, 1H) , 5.60 (m, 3H) , 3.57 (m, 4H) , 3.03 (s, 3H) , 2.89 (s, 3H) , 2.46 (s, 3H) , 1.64 -1.53 (m, 9H) .
EXAMPLE 73
(R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -N, N, 2-trimethyl-7-morpholinopyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -N, N, 2-trimethyl-7-morpholino-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of the product of Step 1 of Example 69 (30 mg, 0.06 mmol) in 1, 4-dioxane (1.0 mL) were added morpholine (59 mg, 0.68 mmol) and N, N-Diisopropylethylamine (88 mg, 0.68 mmol) at rt. The mixture was stirred for 2 h at rt, and was then treated with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to obtain 30 mg of pure product as a yellow solid. MS (ES+) : 534.2 [M+1]
+.
Step 2 ( (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -N, N, 2-trimethyl-7-morpholinopyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of the product of Step 1 (30 mg, 0.05 mmol) in ethanol (2.0 mL) was added 10%Pd/C (30 mg, 0.28 mmol) at rt. The mixture was stirred under H
2 for 0.5 h at rt, and was then filtered through a layer of diatomite. The filtrate was concentrated and the residue was purified by Prep-HPLC to obtain 6.0 mg of pure product as a yellow solid. MS (ES+) : 504.0 [M+1]
+.
1H NMR (400 MHz, Chloroform-d) δ 9.37 (s, 1H) , 8.50 (s, 1H) , 7.05 (s, 1H) , 6.99 (s, 1H) , 6.78 (s, 1H) , 5.54 (s, 1H) , 3.64 (m, 8H) , 3.09 (s, 3H) , 2.98 (s, 3H) , 2.58 (s, 3H) , 1.75-1.70 (m, 3H) .
EXAMPLE 74
(R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -N, N, 2-trimethyl-7- (4-methylpiperazin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -N, N, 2-trimethyl-7- (4-methylpiperazin-1-yl) -4- ( (1- (3-nitro-5 (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of the product of Step 1 of Example 69 (30 mg, 0.06 mmol) in 1, 4-dioxane (1.0 mL) was added 1-methylpiperazine (68 mg, 0.68 mmol) at rt. The mixture was stirred for 2 h at rt, and was then treated with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to obtain 30 mg of pure product as a yellow solid. MS (ES+) : 547.2 [M+1]
+. Step 2 (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -N, N, 2-trimethyl-7- (4-methylpiperazin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of the product of Step 1 (30 mg, 0.05 mmol) in MeOH (2.0 mL) was added 10%Pd/C (30 mg, 0.28 mmol) at rt. The mixture was stirred under H
2 for 0.5 h at rt, and was filtered through a layer of diatomite. The filtrate was concentrated to obtain 12.5 mg of the title product as a yellow solid. MS (ES+) : 517.2 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.51 (s, 1H) , 8.31 (s, 1H) , 7.02-6.70 (m, 3H) , 5.48 (s, 1H) , 3.47 (s, 4H) , 3.02 (s, 3H) , 2.84 (s, 3H) , 2.35 (m, 7H) , 2.21 (s, 3H) , 1.50 (m, 3H) .
EXAMPLE 75
(R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (4, 4-difluoropiperidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -7- (4, 4-difluoropiperidin-1-yl) -N, N, 2-trimethyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1 of Example 69 and 4, 4-difluoropiperidine, the title product was prepared by using the same method as described in Step 2 for Example 69.
MS (ES+) : 568.1 [M+1]
+.
Step 2 (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (4, 4-difluoropiperidin-1-yl) -N, N, 2-trimethyl pyrid o [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 3 for Example 69. MS (ES+) : 538.1 [M+1]
+.
1H NMR (400 MHz, DMSO) δ 8.97 (s, 1H) , 8.62 (s, 1H) , 6.87 –5.83 (m, 2H) , 6.71 (1H) , 5.70 –5.41 (m, 3H) , 3.67 –3.63 (m, 4H) , 3.04 (s, 3H) , 2.90 (s, 3H) , 2.43 (s, 3H) , 2.12 –2.00 (m, 4H) , 1.53 (d, J = 6.9 Hz, 3H) .
EXAMPLE 76
(R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (3, 3-difluoroazetidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -7- (3, 3-difluoroazetidin-1-yl) -N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1 of Example 69 and 3, 3-difluoroazetidine, the title product was prepared by using the same method as described in Step 2 for Example 69.
MS (ES+) : 540.0 [M+1]
+.
Step 2 (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (3, 3-difluoroazetidin-1-yl) -N, N, 2-trimethylpyrid o [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 3 for Example 69. MS (ES+) : 510.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.86 –8.65 (m, 1H) , 8.60 (d, J = 4.3 Hz, 1H) , 7.02 –6.63 (m, 3H) , 5.73 –5.40 (m, 2H) , 4.46 (m, 4H) , 3.04 (s, 3H) , 2.93 (s, 3H) , 2.40 (s, 3H) , 1.58 –1.46 (m, 3H) .
EXAMPLE 77
(R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -N, N, 2-trimethyl-7- (N-methylacetamido) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of the product of Example 64 (27 mg, 0.059 mmol) in DMF (1 mL) were added CH
3I (33 mg, 0.234 mmol) and Cs
2CO
3 (38 mg, 0.118 mmol) . Then the reaction mixture was stirred for 2 h at rt. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA/MeOH=9/1) to obtain 8 mg of pure product as a white solid. MS (ES+) : 474.9 [M+1]
+
1H NMR (400 MHz, Chloroform-d) δ 8.10 (s, 1H) , 7.55 –7.46 (m, 2H) , 7.21 (d, J = 7.1 Hz, 1H) , 6.91 (t, J = 54.9 Hz, 1H) , 6.21 (s, 1H) , 5.81 (t, J = 7.1 Hz, 1H) , 3.48 (s, 3H) , 3.09 (s, 3H) , 3.02 (s, 3H) , 2.61 (s, 3H) , 2.21 (s, 3H) , 1.71 (d, J = 7.0 Hz, 3H) .
EXAMPLE 78
(R) -7- (dimethylamino) -N, N, 2-trimethyl-4- (1- (3- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of the product of Step 3 of Example 69 (20 mg, 0.043 mmol) in THF (1 mL) and DMF (0.25 mL) was added tert-Butyl nitrite (10 mg) at 60℃. Then the reaction mixture was stirred for 1 h at 60℃ under Ar protection. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA/MeOH=9/1) to obtain 5 mg of pure product as a yellow solid. MS (ES+) : 446.9 [M+1] .
1H NMR (400 MHz, Chloroform-d) δ 8.55 (s, 1H) , 7.79 (d, J = 7.7 Hz, 1H) , 7.73 (s, 1H) , 7.52-7.44 (m, 2H) , 5.67 (m, 1H) , 3.01-2.94 (m, 12H) , 2.59 (s, 3H) , 1.76 (d, J = 6.8 Hz, 3H) .
EXAMPLE 79
(R) -7- (dimethylamino) -4- (1- (3-hydroxy-5- (trifluoromethyl) phenyl) ethylamino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -4- (1- (3-bromo-5- (trifluoromethyl) phenyl) ethylamino) -7- (dimethylamino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of (R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (dimethylamino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide (100 mg, 0.217 mmol) in acetonitrile (1 mL) were added CuBr
2 (200 mg, 0.823 mmol) and tert-butyl nitrite (200 mg, 1.942 mmol) at 0-10℃. After the reaction mixture was stirred for 1 h at rt, water was added and the mixture was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA/MeOH=9/1) to obtain 55 mg of the title product as a yellow solid. MS (ES+) : 525.2 [M+1]
+.
Step 2 (R) -7- (dimethylamino) -N, N, 2-trimethyl-4- (1- (3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of the product od Step 1 (55 mg, 0.096 mmol) in 1, 4-dioxane (1 mL) were added 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (55 mg, 0.217 mmol) , KOAc (110 mg, 1.122 mmol) and Pd (dppf) Cl
2 (55 mg, 0.075 mmol) at rt. After the reaction mixture was stirred for 1 h at 100℃ under Ar, water was added and the mixture was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to obtain 140 mg of crude product as brown oil. MS (ES+) : 491.0 [M-82] .
Step 3 (R) -7- (dimethylamino) -4- (1- (3-hydroxy-5- (trifluoromethyl) phenyl) ethylamino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of the product of Step 2 (140 mg, 0.286 mmol) in THF (1 mL) were added NaOH (200 mg, 5 mmol) , H
2O
2 (200 mg, 5.882 mmol) at 0-10℃. After the reaction mixture was stirred for 1 h at rt, water was added and the mixture was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA/MeOH=9/1) to obtain 14 mg of the title product as a yellow solid. MS (ES+) : 463.1 [M+1] .
1H NMR (400 MHz, Chloroform-d) δ 10.16 (s, 1H) , 9.12 (s, 1H) , 8.51 (s, 1H) , 7.21 (s, 1H) , 7.10 (s, 1H) , 6.92 (s, 1H) , 5.59 (t, J = 7.3 Hz, 1H) , 3.10 (s, 6H) , 3.03 (s, 3H) , 2.92 (s, 3H) , 2.44 (s, 3H) , 1.56 (d, J = 7.0 Hz, 3H) .
EXAMPLE 80
(R) - (4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (dimethylamino) -2-methylpyrido [2, 3-d] pyrimidin-6-yl) (morpholino) methanone
Step 1 (R) -methyl 2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine -6-carboxylate
To a stirred solution of (R) -2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid (1 g, 2.29 mmol) in MeOH (10 mL) was added conc. H
2SO
4 (449 mg, 4.58 mmol) at rt. The resulting mixture was stirred at 70℃ for 20 h. After the reaction was completed, the reaction was quenched with sat. NaHCO
3 (aq. ) to pH=8 and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to give 794 mg of the crude product as a yellow solid. MS (ES+) : 452.0 [M+1]
+.
Step 2 (R) -methyl 7-chloro-2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxylate
A mixture of the product of Step 1 (794 mg, 1.76 mmol) in POCl
3 (5 mL) was stirred for 20 h at 100℃under Ar. The reaction was quenched with ice water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to give 270 mg of the title product as a yellow solid. MS (ES+) : 470.0 [M+1]
+.
Step 3 (R) -methyl 7- (dimethylamino) -2-methyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxylate
A mixture of the product of Step 2 (130 mg, 0.277 mmol) in dimethylamine (2.0 mL) was stirred at rt for 1 h. The reaction was quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to give 120 mg of the crude product as a yellow solid. MS (ES+) : 479.0 [M+1]
+.
Step 4 (R) -7- (dimethylamino) -2-methyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxylic acid
To a stirred solution of (R) -methyl7- (dimethylamino) -2-methyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxylate (120 mg, 0.256 mmol) in THF/H
2O (1 mL/1 mL) was added LiOH (53 mg, 1.26 mmol) at rt. The resulting mixture was stirred at 50℃ for 2 h, and then 1N NaOH (2 mL) and MeOH (4 mL) were added. The resulting mixture was stirred overnight at 50℃. After the reaction was completed, the reaction was adjusted with 1N HCl to pH=6 and filtered to give 90 mg of the title product as a yellow solid. MS (ES+) : 465.1 [M+1]
+.
Step 5 (R) - (7- (dimethylamino) -2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidin-6-yl) (morpholino) methanone
To a stirred solution of (R) -7- (dimethylamino) -2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxylic acid (23 mg, 0.053 mmol) in DMF (1 mL) were added morpholine (55 mg, 0.53 mmol) , DIEA (69 mg, 0.53 mmol) and HATU (201 mg , 0.53 mmol ) at rt. The resulting mixture was stirred at rt for 20 h. After the reaction was completed, the reaction was quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA) to give 16 mg of the title product as a yellow solid. MS (ES+) : 534.0 [M+1]
+.
Step 6 (R) - (4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (dimethylamino) -2-methylpyrido [2, 3-d] pyrimidin-6-yl) (morpholino) methanone
To a stirred solution of (R) - (7- (dimethylamino) -2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidin-6-yl) (morpholino) methanone (16 mg, 0.037 mmol) and MeOH (1 mL) was added 10%Pd/C (16 mg) at rt under H
2. The resulting mixture was stirred for 1 h at rt. After the reaction was completed, the reaction solution was filtered through a layer of Celite. The filtrate was evaporated to dryness to obtain 11.6 mg of the title product as a yellow solid. MS (ES+) : 504.1 [M+1]
+.
1H NMR (400 MHz, Chloroform-d) δ 7.92 (m, 1H) , 7.03 (m, 1H) , 6.91 –6.70 (m, 2H) , 5.78 (m, , 1H) , 5.54 (m, 1H) , 3.92 –3.46 (m, 8H) , 3.15 (d, J = 6.1 Hz, 6H) , 2.57 (m, 3H) , 1.60 (m, 3H) .
EXAMPLE 81
(R) - (4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (dimethylamino) -2-methylpyrido [2, 3-d] pyrimidin-6-yl) (piperidin-1-yl) methanone
Step 1 (R) - (7- (dimethylamino) -2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidin-6-yl) (piperidin-1-yl) methanone
Starting with the product of Step 4 of EXAMPLE 80 and piperidine, the title product was prepared by using the same method described in Step 5 of EXAMPLE 80. MS (ES+) : 532.1 [M+1] .
Step 2 (R) - (4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (dimethylamino) -2-methylpyrido [2, 3-d] pyrimidin-6-yl) (piperidin-1-yl) methanone
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 6 of EXAMPLE 80. MS (ES+) : 502.1 [M+1]
+.
1H NMR (400 MHz, Chloroform-d) δ 8.69 (s, 1H) , 7.21 (s, 1H) , 7.02 (d, J = 11.8 Hz, 1H) , 6.74 (d, J = 10.9 Hz, 1H) , 5.54 (m, 1H) , 3.89 (m, 1H) , 3.55 (m, 2H) , 3.42 (m, 1H) , 2.97 (m, 6H) , 2.63 (d, J = 9.5 Hz, 3H) , 1.76-1.64 (m, 4H) , 1.52-1.42 (m, 4H) .
EXAMPLE 82
(R) - (4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (dimethylamino) -2-methylpyrido [2, 3-d] pyrimidin-6-yl) (pyrrolidin-1-yl) methanone
Step 1 (R) - (7- (dimethylamino) -2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidin-6-yl) (pyrrolidin-1-yl) methanone
Starting with the product of Step 4 of EXAMPLE 80 and Pyrrolidine, the title product was prepared by using the same method as described in Step 5 of EXAMPLE 80. MS (ES+) : 518.1 [M+1]
+.
Step 2 (R) - (4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (dimethylamino) -2-methylpyrido [2, 3-d] pyrimidin-6-yl) (pyrrolidin-1-yl) methanone
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 6 of EXAMPLE 80. MS (ES+) : 488.1 [M+1]
+.
1H NMR (400 MHz, Chloroform-d) δ 8.27 (s, 1H) , 6.99 (m, 2H) , 6.77 (s, 1H) , 5.54 (m, 1H) , 3.59 (m, 2H) , 3.26 (m, 2H) , 3.03 (m, 6H) , 2.59 (s, 3H) , 1.96 –1.83 (m, 4H) , 1.66 (d, 3H)
EXAMPLE 83
(R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (3, 3-difluoropyrrolidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -7- (3, 3-difluoropyrrolidin-1-yl) -N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the mixture of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and 3, 3-difluoropyrrolidine hydrochloride, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 554.0 [M+1]
+.
Step 2 (R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (3, 3-difluoropyrrolidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of (R) -7- (3, 3-difluoropyrrolidin-1-yl) -N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide (39 mg, 0.071 mmol) in EtOH (1 mL) were added Fe (20 mg, 0.35 mmol) and NH
4Cl (39 mg, 0.71 mmol) at rt. The resulting mixture was stirred for 3 h at 70℃. After the reaction was completed, the reaction was quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA: MeOH=15: 1) to give 20 mg of the title product as a yellow solid. MS (ES+) : 524.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.49 (d, J = 4.0 Hz, 1H) , 8.25 (s, 1H) , 6.90 –6.78 (m, 2H) , 6.69 (s, 1H) , 5.61 –5.42 (m, 3H) , 3.93 –3.68 (m, 4H) , 3.05 (s, 3H) , 2.92 (s, 3H) , 2.34 (s, 3H) , 1.50 (d, J = 7.1 Hz, 3H) .
EXAMPLE 84
(R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (4-fluoropiperidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -7- (4-fluoropiperidin-1-yl) -N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the mixture of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and 4-fluoropiperidine hydrochloride, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 550.0 [M+1]
+.
Step 2 (R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (4-fluoropiperidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 520.0 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.52 (s, 1H) , 8.34 (d, J = 7.7 Hz, 1H) , 6.84 (d, J = 14.3 Hz, 2H) , 6.70 (s, 1H) , 5.58 –5.41 (m, 3H) , 4.90 (ddd, J = 48.9, 7.2, 3.8 Hz, 1H) , 3.54 (m, 4H) , 3.03 (s, 3H) , 2.86 (s, 3H) , 2.36 (s, 3H) , 2.01 –1.87 (m, 2H) , 1.84 –1.70 (m, 2H) , 1.50 (d, J = 7.0 Hz, 3H) .
EXAMPLE 85
(R) - (4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) (piperidin-1-yl) methanone
Step 1 (R) -methyl2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine -6-carboxylate
Starting with (R) -methyl 7-chloro-2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3d] pyrimidine-6-carboxylate and pyrrolidine, the title product was prepared by using the same method described in Step 3 of EXAMPLE 80. MS (ES+) : 505.0 [M+1]
+.
Step 2 (R) -2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxylic acid
Starting with the product of step 1, the title product was prepared by using the same method described in Step 4 of EXAMPLE 80. MS (ES+) : 491.3 [M+1]
+.
Step 3 (R) - (2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) (piperidin-1-yl) methanone
Starting with the product of step 2 and piperidine, the title product was prepared by using the same method as described in Step 5 of EXAMPLE 80. MS (ES+) : 558.2 [M+1]
+.
Step 4 (R) - (4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) (piperidin-1-yl) methanone
Starting with the product of step 3, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 528.2 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.94 (s, 1H) , 8.45 (d, J = 7.3 Hz, 1H) , 6.85 (m, 2H) , 6.72 (s, 1H) , 5.56 (m, 3H) , 3.76 (m, 2H) , 3.55 (m, 6H) , 2.43 (s, 3H) , 1.93 (m, 4H) , 1.68 –1.41 (m, 9H) .
EXAMPLE 86
(R) - (4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) (morpholino) methanone
Step 1 (R) - (2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) (morpholino) methanone
Starting with the product of step 2 of EXAMPLE 85, the title product was prepared by using the same method as described in Step 4 of EXAMPLE 80. MS (ES+) : 560.2 [M+1]
+.
Step 2 (R) - (4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) (morpholino) methanone
Starting with the product of step 2, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 530.2 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 9.07 (s, 1H) , 8.53 (d, J = 12.1 Hz, 1H) , 6.86 (t, J = 15.2 Hz, 2H) , 6.73 (s, 1H) , 5.67 –5.47 (m, 3H) , 3.69 (m, 4H) , 3.60 –3.43 (m, 8H) , 2.44 (d, J = 6.8 Hz, 3H) , 1.95 (m, 4H) , 1.56 (d, J = 7.1 Hz, 3H) .
EXAMPLE 87
(R) -N
4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -N
7, N
7, 2-trimethyl-6- (pyridin-4-yl) pyrido [2, 3-d] pyrimidine-4, 7-diamine
Step 1 (R) -6-bromo-2-methyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidin-7 (8H) -one
To a stirred solution of (R) -2-methyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid (550 mg, 1.26 mmol) in THF/H
2O (5: 1, 11 mL) were added LiOAc (831 mg, 12.59 mmol) and NBS (1344 mg, 7.55 mmol) at rt. The mixture was stirred for 2.5 h at 55℃. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE: EA=1: 2) to give 578 mg of pure product as a yellow solid. MS (ES+) : 471.8 [M+1]
+.
Step 2 (R) -6-bromo-7-chloro-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) pyrido [2, 3-d] pyrimidin-4-amine
The mixture of (R) -6-bromo-2-methyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidin-7 (8H) -one (460 mg, 0.98 mmol) in Phenylphosphonic dichloride (4.5 mL) was stirred for 6 h at 100℃ under Ar. After the reaction was completed, the mixture was poured into ice-H
2O and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM: MeOH=9: 1) to give 1.36 g (23%wt) of crude product as a gray solid. MS (ES+) : 489.9 [M+1]
+.
Step 3 (R) -6-bromo-N
7, N
7, 2-trimethyl-N
4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) pyrido [2, 3-d] pyrimidine-4, 7-diamine
To a stirred solution of (R) -6-bromo-7-chloro-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) pyrido [2, 3-d] pyrimidin-4-amine (650 mg, 1.33 mmol) in 1, 4-Dioxane (13 mL) were added 2M dimethylamine in THF (13 mL, 26.58 mmol) and DIEA (3429 mg, 26.58 mmol) at rt. The mixture was stirred for 0.5 h at rt. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to give 150 mg of crude product as a gray solid. MS (ES+) : 498.9 [M+1]
+.
Step 4 (R) -N
7, N
7, 2-trimethyl-N
4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -6- (pyridin-4-yl) pyrido [2, 3-d] pyrimidine-4, 7-diamine
To a stirred solution of (R) -6-bromo-N
7, N
7, 2-trimethyl-N
4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) pyrido [2, 3-d] pyrimidine-4, 7-diamine (50 mg, 0.10 mmol) in 1, 4-Dioxane/H
2O (5: 1, 2.0 mL) were added pyridin-4-ylboronic acid (50 mg, 0.40 mmol) , K
2CO
3 (50 mg, 0.36 mmol) , x-phos (50 mg, 0.10 mmol) and x-phosPdG
2 (30 mg, 0.04 mmol) at rt. The mixture was stirred for 1 h at 100 ℃ under Ar. After the reaction was completed, then quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA + 1%NH
3H
2O) to give 35 mg of the title product as a yellow solid. MS (ES+) : 498.0 [M+1]
+.
Step 5 (R) -N
4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -N
7, N
7, 2-trimethyl-6- (pyridin-4-yl) pyrido [2, 3-d] pyrimidine-4, 7-diamine
Starting with the product of step 4, the title product was prepared by using the same method as described in Step 12 of EXAMPLE 78. MS (ES+) : 468.1 [M+1]
+.
1H NMR (400 MHz, Chloroform-d) δ 8.57 (m, 3H) , 7.44 (d, J = 5.0 Hz, 2H) , 7.15 (s, 1H) , 7.06 (s, 1H) , 6.74 (s, 1H) , 5.60 (s, 1H) , 2.81 (s, 6H) , 2.64 (s, 3H) , 1.74 (d, J = 7.1 Hz, 3H) .
EXAMPLE 88
(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (pyridin-4-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Step 1 (R) -6-bromo-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of step 2 of EXAMPLE 87 and pyrrolidine, the title product was prepared by using the same method as described in Step 3 of EXAMPLE 87. MS (ES+) : 525.0 [M+1]
+.
Step 2 (R) -2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -6- (pyridin-4-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of step 1 and pyridin-4-ylboronic acid, the title product was prepared by using the same method as described in Step 4 of EXAMPLE 87. MS (ES+) : 524.0 [M+1]
+.
Step 3 (R) -6-bromo-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of Step 2, the title product was prepared by using the same method as described in Step 12 of EXAMPLE 79. MS (ES+) : 494.1 [M+1]
+.
1H NMR (400 MHz, Chloroform-d) δ 8.55 (s, 2H) , 7.89 –7.76 (m, 1H) , 7.05 (s, 1H) , 6.93 (s, 1H) , 6.77 (s, 1H) , 6.46 (s, 1H) , 5.62 (s, 1H) , 3.22 (m, 4H) , 2.58 (s, 3H) , 2.08 (m, 4H) , 1.32 (d, 3H) .
EXAMPLE 89
N- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-7- (pyrrolidin-1-yl) -6- ( ( (S) -tetrahydrofuran-3-yl) oxy) pyrido [2, 3-d] pyrimidin-4-amine
Step 1 2-methyl-4- ( ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -6- ( ( (S) -tetrahydrofuran-3-yl) oxy) pyrido [2, 3-d] pyrimidin-7 (8H) -one
To a stirred solution of LiHMDS (5.8 mL, 5.85 mmol, 1N in THF) in THF (7.0 mL) was added methyl (S) -2- ( (tetrahydrofuran-3-yl) oxy) acetate (937 mg, 5.85 mmol ) in THF (1.0 mL) at -70℃ under Ar. The reaction mixture was stirred for 20 min at -70℃, then was added (R) -4-amino-2-methyl-6- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrimidine-5-carbaldehyde (720 mg, 1.95 mmol) in THF (1.0 mL) at -70℃. The resulting mixture was stirred overnight at rt. After the reaction was completed, then quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (EA) to give 330 mg of pure product as a yellow solid. Yield: 35.3%. MS (ES+) : 480.1 [M+1]
+.
Step 2 7-chloro-2-methyl-N- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -6- ( ( (S) -tetrahydrofuran-3-yl) oxy) pyrido [2, 3-d] pyrimidin-4-amine
The mixture of 2-methyl-4- ( ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -6- ( ( (S) -tetrahydrofuran-3-yl) oxy) pyrido [2, 3-d] pyrimidin-7 (8H) -one (400 mg, 0.84 mmol) in Phenylphosphonic dichloride (4.0 mL) was stirred for 1.5 h at 120℃ under Ar. After the reaction was completed, the mixture was poured into ice-water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM: MeOH=9: 1) , then by Prep-TLC (EA) to give 180 mg of pure product as a yellow solid. Yield: 43.4%. MS (ES+) : 498.0 [M+1]
+.
Step 3 2-methyl-N- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) -6- ( ( (S) -tetrahydrofuran-3-yl) oxy) pyrido [2, 3-d] pyrimidin-4-amine
To a stirred solution of 7-chloro-2-methyl-N- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -6- ( ( (S) -tetrahydrofuran-3-yl) oxy) pyrido [2, 3-d] pyrimidin-4-amine (60 mg, 0.12 mmol) in 1, 4-Dioxane (1.0 mL) were added pyrrolidine (86 mg, 1.21 mmol) and DIEA (156 mg, 1.21 mmol) at rt. The mixture was stirred for 1 h at rt. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to give 58 mg of crude product as a yellow solid. Yield: 90.6%. MS (ES+) : 533.0 [M+1]
+.
Step 4 N- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-7- (pyrrolidin-1-yl) -6- ( ( (S) -tetrahydrofuran-3-yl) oxy) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of Step 3, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 503.1 [M+1]
+.
1 H NMR (400 MHz, DMSO-d
6) δ 9.65 (d, J = 7.8 Hz, 1H) , 8.22 (s, 1H) , 6.95 (m, 1H) , 6.88 (m, 1H) , 6.73 (m, 1H) , 5.59 (m, 2H) , 5.30 (d, J = 5.3 Hz, 1H) , 4.00 (m, 1H) , 3.92 –3.72 (m, 8H) , 2.48 (s, 3H) , 2.39 –2.33 (m, 1H) , 2.08 (m, 1H) , 1.90 (m, 4H) , 1.63 (d, J = 7.1 Hz, 3H) .
EXAMPLE 90
4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (3-fluoropyrrolidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7-chloro-N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with (R) -7-chloro-N, N, 2 -trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide, the title product was prepared by using the same methods as described in Step 2 of EXAMPLE 83. MS (ES+) : 453.1 [M+1]
+.
Step 2 4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (3-fluoropyrrolidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 506.1 [M+1]
+.
1H NMR (400 MHz, Chloroform-d) δ 7.87 (s, 1H) , 7.05 (s, 1H) , 6.90 (s, 1H) , 6.81 (s, 1H) , 5.68 (s, 1H) , 5.32 (m, 1H) , 3.88 (m, 4H) , 3.12 (s, 3H) , 2.79 (s, 3H) , 2.58 (s, 3H) , 2.34 (m, 2H) , 1.59 (d, J = 6.8 Hz, 3H) .
EXAMPLE 91
N
4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -N
7, N
7, 2-trimethyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) pyrido [2, 3-d] pyrimidine-4, 7-diamine
Step 1 N
7, N
7, 2-trimethyl-N
4- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -6- ( ( (S) -tetrahydrofuran-3-yl) oxy) pyrido [2, 3-d] pyrimidine-4, 7-diamine
Starting with the product of Step 2 of EXAMPLE 89, the title product was prepared by using the same method as described in Step 3 of EXAMPLE 89. MS (ES+) : 507.2 [M+1]
+.
Step 2 N
4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -N
7, N
7, 2-trimethyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) pyrido [2, 3-d] pyrimidine-4, 7-diamine
Starting with the product of Step 2, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 477.0 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 9.43 (s, 1H) , 8.14 (s, 1H) , 6.91 (s, 1H) , 6.87 (s, 1H) , 6.74 (s, 1H) , 5.61 (s, 2H) , 5.26 (s, 1H) , 3.98 (m, 1H) , 3.88 (m, 4H) , 3.27 (s, 6H) , 2.48 (s, 3H) , 2.36 (m, 1H) , 2.10 (m, 1H) , 1.62 (d, J = 7.0 Hz, 3H) .
EXAMPLE 92
(R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (3, 3-dimethylazetidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -7- (3, 3-dimethylazetidin-1-yl) -N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the mixture of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and 3, 3-dimethylazetidine hydrochloride, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69 MS (ES+) : 532.1 [M+1]
+.
Step 2 (R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (3, 3-dimethylazetidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 6. MS (ES+) : 502.2 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 9.38 (s, 1H) , 8.63 (s, 1H) , 6.92 –6.80 (m, 2H) , 6.73 (t, J = 1.9 Hz, 1H) , 5.54 (m, 3H) , 3.78 (m, 4H) , 3.02 (s, 3H) , 2.93 (s, 3H) , 2.46 (s, 3H) , 1.55 (d, J = 7.0 Hz, 3H) , 1.28 (s, 6H) .
EXAMPLE 93
(R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -N, N, 2-trimethyl-7- (3- (trifluoromethyl) azetidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -N, N, 2-trimethyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (3- (trifluoromethyl) azetidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the mixture of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and 3, 3-dimethylazetidine hydrochloride, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 532.1 [M+1]
+.
Step 2 (R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -N, N, 2-trimethyl-7- (3- (trifluoromethyl) azetidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 542.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.50 (s, 1H) , 8.24 (s, 1H) , 6.84 (d, 2H) , 6.70 (s, 1H) , 5.47 (s, 1H) , 4.27 (m, 2H) , 3.97 (m, 2H) , 3.04 (s, 3H) , 2.90 (s, 3H) , 2.35 (s, 3H) , 1.49 (d, J = 6.9 Hz, 3H) .
EXAMPLE 94
4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- ( (S) -3-fluoropyrrolidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 7- ( (S) -3-fluoropyrrolidin-1-yl) -N, N, 2-trimethyl-4- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the mixture of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and (S) -3-fluoropyrrolidine hydrochloride, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 536.1 [M+1]
+.
Step 2 4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- ( (S) -3-fluoropyrrolidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 506.3 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.99 (s, 1H) , 8.55 (m, 1H) , 6.85 (m, 2H) , 6.72 (s, 1H) , 5.67 –5.34 (m, 4H) , 3.86 –3.58 (m, 4H) , 3.05 (m, 4H) , 2.83 (s, 3H) , 2.44 (d, J = 5.1 Hz, 3H) , 2.30 –2.19 (m, 2H) , 1.54 (t, J = 7.9 Hz, 3H) .
EXAMPLE 95
(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (pyridin-3-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Step 1 (R) -2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -6- (pyrimidin-5-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of step 1 of EXAMPLE 88 and 3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine, the title product was prepared by using the same method as described in Step 4 of EXAMPLE 10. MS (ES+) : 524.0 [M+1]
+.
Step 2 (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (pyridin-3-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 494.0 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.69 (d, J = 2.3 Hz, 1H) , 8.58 (d, J = 4.9 Hz, 1H) , 8.41 (d, J = 7.0 Hz, 1H) , 8.12 (d, J = 7.9 Hz, 1H) , 7.83 (d, J = 8.0 Hz, 1H) , 7.49 (dd, J = 7.8, 4.9 Hz, 1H) , 6.83 (d, J = 9.2 Hz, 2H) , 6.69 (s, 1H) , 5.51 (m, 3H) , 3.15 (m, 4H) , 2.35 (s, 3H) , 1.74 (m, 4H) , 1.49 (d, J = 7.1 Hz, 3H) .
EXAMPLE 96
(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (pyridin-2-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Step 1 (R) -2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -6- (pyridin-2-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
To a stirred solution of (R) -6-bromo-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine (100 mg, 0.19 mmol) in 1, 4-Dioxane/H
2O (5: 1, 3.0 ml) were added 2- (tributylstannyl) pyridine (141 mg, 0.38 mmol) , K
2CO
3 (79 mg, 0.57 mmol) , x-phos (91 mg, 0.19 mmol) and x-phosPdG
2 (75 mg, 0.10 mmol) at rt. The mixture was stirred for 1 h at 100 ℃ under N
2. After the reaction was completed, then quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA + 1%NH
3H
2O) to give 32 mg of the title product as a yellow solid. MS (ES+) : 524.0 [M+1]
+.
Step 2 (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (pyridin-2-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 494.1 [M+1]
+
.
EXAMPLE 97
(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (pyrimidin-5-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Step 1 (R) -2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -6- (pyrimidin-5-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of step 1 of EXAMPLE 88 and 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine, the title product was prepared by using the same method as described in Step 4 of EXAMPLE 87. MS (ES+) : 525.1 [M+1]
+.
Step 2 (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (pyrimidin-5-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of Step 1 , the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 495.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 9.30 (s, 1H) , 9.21 (s, 1H) , 8.93 (s, 2H) , 8.53 (s, 1H) , 8.48 (s, 1H) , 6.84 (d, J = 7.4 Hz, 2H) , 6.71 (s, 1H) , 5.53 (m, 3H) , 3.18 (m, 4H) , 2.41 (s, 3H) , 1.78 (m, 4H) , 1.51 (d, J = 7.0 Hz, 3H) .
EXAMPLE 98
(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (1-methyl-1H-pyrazol-4-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Step 1 (R) -2-methyl-6- (1-methyl-1H-pyrazol-4-yl) -N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of step 1 of EXAMPLE 88 and 1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole, the title product was prepared by using the same method as described in Step 4 of EXAMPLE 87. MS (ES+) : 527.0 [M+1]
+.
Step 2 (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (1-methyl-1H-pyrazol-4-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 6. MS (ES+) : 497.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.32 (s, 1H) , 8.06 (s, 1H) , 7.83 (s, 1H) , 7.55 (d, J = 5.2 Hz, 1H) , 6.83 (m, 2H) , 6.69 (s, 1H) , 5.51 (m, 3H) , 3.89 (s, 3H) , 3.26 (m, 4H) , 2.34 (s, 3H) , 1.78 (m, 4H) , 1.49 (d, J = 7.0 Hz, 3H) .
EXAMPLE 99
(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (1H-pyrazol-4-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Step 1 tert-butyl (R) -4- (2-methyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) -1H-pyrazole-1-carboxylate
To a stirred solution of (R) -6-bromo-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine (100 mg, 0.19 mmol) in DMF/H
2O (5: 1, 2.0 mL) were added tert-butyl 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole-1-carboxylate (112 mg, 0.38 mmol) , Cs
2CO
3 (187 mg, 0.57 mmol) and Pd (Ph
3P)
2Cl
2 (67 mg, 0.10 mmol) at rt. The mixture was stirred for 1 h at 70 ℃ under Ar. After the reaction was completed, then quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by prep-TLC (EA: MeOH=15: 1 + 1%NH
3H
2O) to give 120 mg (35%wt) of the title product as a red solid. MS (ES+) : 557.2 [M-56+1]
+.
Step 2 (R) -2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -6- (1H-pyrazol-4-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
The mixture of tert-butyl (R) -4- (2-methyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) -1H-pyrazole-1-carboxylate (120 mg, 35%wt) in TFA/DCM (1: 1, 2.0 mL) was stirred for 3 h at rt. After the reaction was completed, the reaction was quenched with water, adjusted pH to 8~9 by sat. Na
2CO
3 (aq. ) and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by prep-TLC (EA+1%NH
3H
2O) to give 22 mg of the title product as a yellow solid. MS (ES+) : 513.2 [M+1]
+.
Step 3 (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (1H-pyrazol-4-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 483.3 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.32 (s, 1H) , 7.98 (m, 1H) , 6.84 (s, 1H) , 6.81 (s, 1H) , 6.68 (s, 1H) , 5.50 (m, 3H) , 3.23 (m, 4H) , 2.33 (s, 3H) , 1.76 (m, 4H) , 1.48 (d, J = 7.0 Hz, 3H) .
EXAMPLE 100
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (pyridin-4-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Step 1 (R) -6-bromo-7-chloro-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of Step 5 of EXAMPLE 3A, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 87. MS (ES+) : 427.0 [M+1]
+. MS (ES+) : 445.2 [M+1]
+.
Step 2 (R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3- d] pyrimidin-4-amine
Starting with the product of Step 1 and pyrrolidine, the title product was prepared by using the same method as described in Step 3 of EXAMPLE 87. MS (ES+) : 480.2 [M+1]
+
Step 3 (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (pyridin-4-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of Step 3 and 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine, the title product was prepared by using the same method as described in Step 4 of EXAMPLE 87. MS (ES+) : 479.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 9.30 (s, 1H) , 8.72 (d, J = 2.3 Hz, 1H) , 8.64 (dd, J = 4.8, 1.6 Hz, 1H) , 8.57 (s, 1H) , 7.88 (dd, J = 8.0, 2.1 Hz, 1H) , 7.71 (t, J = 7.5 Hz, 1H) , 7.54 (m, 2H) , 7.40 –7.05 (m, 2H) , 5.85 (q, J = 7.0 Hz, 1H) , 3.20 (m, 4H) , 2.46 (s, 3H) , 1.79 (m, 4H) , 1.60 (d, J = 7.1 Hz, 3H) .
EXAMPLE 101
4- ( (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -7- ( (S) -3-fluoropyrrolidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -N, N, 2-trimethyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine -6-carboxamide
Starting with the product of Step 5 of EXAMPLE 3A, the title product was prepared by using the same method as described in Step 8 of EXAMPLE 1. MS (ES+) : 419.9 [M+1]
+.
Step 2 (R) -7-chloro-4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 1 of EXAMPLE 69. MS (ES+) : 437.6 [M+1]
+.
Step 3 4- ( (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -7- ( (S) -3-fluoropyrrolidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 2 and (S) -3-fluoropyrrolidine hydrochloride, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 491.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.88 (s, 1H) , 8.58 (s, 1H) , 7.71 (m, 1H) , 7.52 (t, J = 7.2 Hz, 1H) , 7.38 –7.05 (m, 2H) , 5.79 (m, 1H) , 5.53 –5.34 (m, 1H) , 3.75 (m, 4H) , 3.06 (d, J = 5.2 Hz, 4H) , 2.83 (s, 2H) , 2.37 (m, 3H) , 2.24 (m, 2H) , 1.59 (t, J = 6.7 Hz, 3H) .
EXAMPLE 102
(R) - (4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) (4-methylpiperazin-1-yl) methanone
Step1 (R) - (2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) (4-methylpiperazin-1-yl) methanone
Starting with the product of step 2 of EXAMPLE 85 and 1-methylpiperazine, the title product was prepared by using the same method as described in Step 5 of EXAMPLE 80. MS (ES+) : 573.3 [M+1]
+.
Step 2 (R) - (4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) (4-methylpiperazin-1-yl) methanone
Starting with the product of step 2, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 543.3 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.73 (s, 1H) , 7.00 –6.81 (m, 2H) , 6.71 (s, 1H) , 5.56 (m, 3H) , 3.82 (m, 12H) , 3.17 (d, J = 3.3 Hz, 3H) , 2.45 (d, J = 6.9 Hz, 3H) , 1.93 (m, 4H) , 1.58 (d, J = 7.0 Hz, 3H) .
EXAMPLE 103
(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -6- (cyclopentyloxy) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Step 1 (R) -6-methoxy-2-methyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidin-7 (8H) -one
To a stirred solution of LiHMDS (1M in THF, 4.5 mL, 4.47 mmol) in THF (11.0 mL) was added methyl 2-methoxyacetate (465 mg, 4.47 mmol ) in THF (1.0 mL) at -70℃. The mixture was stirred for 20 min at -70℃. Then (R) -4-amino-2-methyl-6- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrimidine-5-carbaldehyde (550 mg, 1.49 mmol) in THF (1.0 mL) was added at -70℃. The resulting mixture was stirring overnight at rt. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (EA) to give 200 mg of the title product as a yellow solid. MS (ES+) : 424.1 [M+1]
+.
Step 2 (R) -7-chloro-6-methoxy-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) pyrido [2, 3-d] pyrimidin-4-amine
The mixture of (R) -6-methoxy-2-methyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidin-7 (8H) -one (190 mg, 0.45 mmol) in phenylphosphonic dichloride (2.0 mL) was stirred for 2 h at 120℃ under Ar. After the reaction was completed, the mixture was poured into ice-water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. DCM was added to the residue and stirred for 30 min, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM: MeOH=9: 1) to give 385 mg (50.5%wt) of crude product as a gray solid. MS (ES+) : 442.0 [M+1]
+.
Step 3 (R) -6-methoxy-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
To a stirred solution of (R) -7-chloro-6-methoxy-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) pyrido [2, 3-d] pyrimidin-4-amine (380 mg, 0.86 mmol) in 1, 4-Dioxane (4.0 mL) were added pyrrolidine (612 mg, 8.62 mmol) and DIEA (1112 mg, 8.62 mmol) at rt. The mixture was stirred for 1 h at rt. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to give 160 mg of crude product as a brown solid. MS (ES+) : 477.3 [M+1]
+.
Step 4 (R) -2-methyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-ol
To a stirred solution of (R) -6-methoxy-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine (65 mg, 0.14 mmol) in DCE (1.0 mL) was added BBr
3 (1 M in DCM, 2.0 mL) at rt. The mixture was stirred for 3 h at 70 ℃ under Ar. After the reaction was completed, water was added at 0~10 ℃and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to give 70 mg of crude product as a brown solid. MS (ES+) : 463.1 [M+1]
+.
Step 5 (R) -6- (cyclopentyloxy) -2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
To a stirred solution of (R) -2-methyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-ol (28 mg, 0.06 mmol) in DMF (1.0 mL) were added iodocyclopentane (71 mg, 0.36 mmol) and K
2CO
3 (50 mg, 0.36 mmol) at rt. The mixture was stirred for 5 h at rt. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (PE: EA=1: 1+1%NH
3H
2O) to give 12 mg of crude product as a yellow solid. MS (ES+) : 531.2 [M+1]
+.
Step 6 (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -6- (cyclopentyloxy) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of step 5, the title product was prepared by using the same method described in Step 2 of EXAMPLE 83. MS (ES+) : 501.3 [M+1]
+.
1H NMR (400 MHz, Methanol-d
4) δ 7.62 (s, 1H) , 6.99 –6.90 (m, 2H) , 6.81 (d, J = 2.1 Hz, 1H) , 5.63 (q, J = 7.0 Hz, 1H) , 4.98 (t, J = 2.9 Hz, 1H) , 3.86 (m, 4H) , 2.46 (s, 3H) , 2.02 (m, 4H) , 1.94 (m, 4H) , 1.84 –1.73 (m, 4H) , 1.64 (d, J = 7.0 Hz, 3H) .
EXAMPLE 104
(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (prop-1-en-2-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyri`midin-4-amine
Step 1 (R) -2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -6- (prop-1-en-2-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
To a stirred solution of (R) -6-bromo-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine (190 mg, 0.362 mmol) in THF/H
2O (2/0.4 mL) were added 4, 4, 5, 5-tetramethyl-2- (prop-1-en-2-yl) -1, 3, 2-dioxaborolane (160 mg, 0.952 mmol) , K
3PO
4 (260 mg, 1.226 mmol) and Pd (dppf) Cl
2·DCM (160 mg, 0.196 mmol) . Then the reaction mixture was stirred for 1 h at 70℃ over Ar. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA/MeOH=9/1) to obtain 85 mg of pure product as a brown solid. MS (ES+) : 487.0 [M+1]
+.
Step 2 (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (prop-1-en-2-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 6. MS (ES+) : 457.2 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 9.51 (s, 1H) , 8.46 (s, 1H) , 6.86 (m, 2H) , 6.74 (s, 1H) , 5.61 (m, 3H) , 5.36 (s, 1H) , 5.00 (s, 1H) , 3.57 (m, 4H) , 2.11 (s, 3H) , 1.91 (m, 4H) , 1.58 (d, J = 7.0 Hz, 3H) .
EXAMPLE 105
(R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (3-hydroxy-3-methylazetidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with (R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7-chloro-N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide and 3-methylazetidin-3-ol hydrochloride, the title product was prepared by using the same method described in Step 11 of EXAMPLE 79. MS (ES+) : 504.3 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.49 (s, 1H) , 6.84 (m, 2H) , 6.71 (s, 1H) , 5.76 (s, 1H) , 5.55 (m, 3H) , 3.94 (m, 4H) , 3.02 (s, 3H) , 2.90 (s, 3H) , 2.42 (s, 3H) , 1.52 (d, J = 6.9 Hz, 3H) , 1.42 (s, 3H) .
EXAMPLE 106
(R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (3-fluoroazetidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with (R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7-chloro-N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide and 3-fluoroazetidine hydrochloride, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 492.2 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.48 (s, 1H) , 6.83 (m, 2H) , 6.69 (s, 1H) , 5.51 (m, 4H) , 4.36 (m, 2H) , 4.04 (m, 2H) , 3.03 (s, 3H) , 2.90 (s, 3H) , 2.36 (s, 3H) , 1.50 (d, J = 7.1 Hz, 3H) .
EXAMPLE 107
4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- ( (3S, 4R) -3, 4-difluoropyrrolidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 7- ( (3S, 4R) -3, 4-difluoropyrrolidin-1-yl) -N, N, 2-trimethyl-4- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with The mixture of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and (3S, 4R) -3, 4-difluoropyrrolidine hydrochloride, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 554.0 [M+1]
+.
Step 2 4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- ( (3S, 4R) -3, 4-difluoropyrrolidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 524.2 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.54 (s, 1H) , 6.86 (m, 2H) , 6.70 (s, 1H) , 5.65 –5.29 (m, 5H) , 3.82 (m, 4H) , 3.06 (s, 3H) , 2.93 (s, 3H) , 2.39 (s, 3H) , 1.52 (d, J = 7.0 Hz, 3H) .
EXAMPLE 108
4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (3-azabicyclo [3.1.0] hexan-3-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 7- (3-azabicyclo [3.1.0] hexan-3-yl) -N, N, 2-trimethyl-4- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with The mixture of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and 3-azabicyclo [3.1.0] hexane hydrochloride, the title product was prepared by using the same method as described in Step 11 of EXAMPLE 79. MS (ES+) : 530.2 [M+1]
+.
Step 2 4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (3-azabicyclo [3.1.0] hexan-3-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 500.3 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.69 (s, 1H) , 8.37 (m, 1H) , 6.77 (m, 2H) , 6.64 (s, 1H) , 5.46 (m, 3H) , 3.76 (m, 1H) , 3.52 (m, 2H) , 3.41 (m, 1H) , 2.97 (s, 3H) , 2.81 (d, J = 3.7 Hz, 3H) , 2.34 (d, J = 3.8 Hz, 3H) , 1.63 (dt, J = 7.7, 3.4 Hz, 2H) , 1.45 (d, J = 7.0 Hz, 3H) , 0.67 (m, 1H) , 0.01-0.00 (m, 1H) .
EXAMPLE 109
(R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (3-fluoro-3-methylazetidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -7- (3-fluoro-3-methylazetidin-1-yl) -N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the mixture of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and 3-fluoro-3-methylazetidine hydrochloride, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 536.3 [M+1]
+.
Step 2 (R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (3-fluoro-3-methylazetidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 506.3 [M+1]
+.
EXAMPLE 110
4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (6, 6-dimethyl-3-azabicyclo [3.1.0] hexan-3-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 7- (6, 6-dimethyl-3-azabicyclo [3.1.0] hexan-3-yl) -N, N, 2-trimethyl-4- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with The mixture of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 558.3 [M+1]
+.
Step 2 4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (6, 6-dimethyl-3-azabicyclo [3.1.0] hexan-3-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 528.2 [M+1]
+.
EXAMPLE 111
(R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7-isopropyl-N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (prop-1-en-2-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
The mixture of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide (150 mg, 0.311 mmol) , 4, 4, 5, 5-tetramethyl-2- (prop-1-en-2-yl) -1, 3, 2-dioxaborolane (15 d) , K
3PO
4 (210 mg, 0.99 mmol) and Pd (dppf) Cl
2·DCM (135 mg, 0.165 mmol) in THF/H
2O (5/1, 4.8 mL) was stirred at 70℃ for 2 h under Ar. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA: PE=7: 3) to give 28 mg of the title product as a yellow solid. MS (ES+) : 489.0 [M+1]
+.
Step 2 (R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -N, N, 2-trimethyl-7- (prop-1-en-2-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1, the title product was prepared by using the same method described in Step 2 of EXAMPLE 83. MS (ES+) : 459.2 [M+1]
+.
Step 3 (R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7-isopropyl-N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of (R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -N, N, 2-trimethyl-7- (prop-1-en-2-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide (32 mg, 0.0699 mmol) in EA (6 mL) was added Pd/C (32 mg) at rt under H
2. The mixture was stirred at rt for 6 h. After the reaction was completed, the mixture was filtered through a layer of celite and the filtrate was concentrated. The residue was purified by Prep-TLC (EA) to give 7 mg of the title product as a yellow solid. MS (ES+) : 461.2 [M+1]
+.
EXAMPLE 112
(R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-cyclopropyl-N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 methyl (R) -7-cyclopropyl-2-methyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxylate
To a stirred solution of (R) -4-amino-2-methyl-6- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrimidine-5-carbaldehyde (50 mg, 0.14 mmol) in (CH
3)
2CHOH (1.0 mL) were added methyl 3-cyclopropyl-3-oxopropanoate (57 mg, 0.41 mmol) and piperidine (34 mg, 0.41 mmol) at rt. The mixture was stirred for 2 h at 80℃. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA: MeOH=15: 1) to give 58 mg of the crude product as a yellow solid which was used in the next step without further purification. MS (ES+) : 476.2 [M+1]
+.
Step 2 (R) -7-cyclopropyl-2-methyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxylic acid
To a stirred solution of methyl (R) -7-cyclopropyl-2-methyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxylate (55 mg, 0.12 mmol) in MeOH/H
2O (5: 1, 1.0 mL) was added LiOH
. H
2O (15 mg, 0.35 mmol) at rt. The mixture was stirred for 2 h at rt. After the reaction was completed, water was added, adjust pH to 4~5 by 1N HCl (aq. ) and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA: MeOH=15: 1) to give 27 mg of the title product as a yellow solid. MS (ES+) : 462.1 [M+1]
+.
Step 3 (R) -7-cyclopropyl-N, N, 2-trimethyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of (R) -7-cyclopropyl-2-methyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxylic acid (27 mg, 0.06 mmol) in DMF (1.0 mL) were added dimethylamine (2M in THF, 0.3 ml, 0.59 mmol) , DIEA (76 mg, 0.59 mmol) and HATU (223 mg, 0.59 mmol) at rt. The mixture was stirred for 1 h at rt. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA) to give 58 mg of the crude product as yellow oil which was used in the next step without further purification. MS (ES+) : 489.2 [M+1]
+.
Step 4 (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-cyclopropyl-N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 3, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 459.4 [M+1]
+.
EXAMPLE 113
(R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-cyclobutyl-N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -methyl 7-cyclobutyl-2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxylate
Starting with (R) -4-amino-2-methyl-6- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrimidine-5-carbaldehyde and methyl 3-cyclobutyl-3-oxopropanoate, the title product was prepared by using the same method as described in Step 1 of EXAMPLE 112. MS (ES+) : 490.3 [M+1]
+.
Step 2 (R) -7-cyclobutyl-2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxylic acid
Starting with the product of Step 1 , the title product was prepared by using the same method as described in Step 2 of EXAMPLE 112. MS (ES+) : 476.2 [M+1]
+.
Step 3 (R) -7-cyclobutyl-N, N, 2-trimethyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 2 , the title product was prepared by using the same method as described in Step 3 of EXAMPLE 112. MS (ES+) : 503.2 [M+1]
+.
Step 4 (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-cyclobutyl-N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 3 , the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 473.3 [M+1]
+.
EXAMPLE 114
(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (1, 3, 4-oxadiazol-2-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Step 1 (R) -2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -6- (1, 3, 4-oxadiazol-2-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
To a stirred solution of (R) -2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxylic acid (160 mg, 0.327 mmol) in DCE (4.5 mL) was added (isocyanoimino) triphenylphosphorane (198 mg, 0.654 mmol) at rt. The resulting mixture was stirred at 80℃for 20 h. After the reaction was completed, the reaction was quenched with water and extracted with EA. The organic layer was washed with brine and dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA) to give 40 mg of the title product as a yellow solid. MS (ES+) : 515.2 [M+1]
+. Step 2 (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (1, 3, 4-oxadiazol-2-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of Step 1 , the title product was prepared by using the same method as described in Step 1 of EXAMPLE 83. MS (ES+) : 485.3 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 9.47 (s, 1H) , 8.93 (s, 2H) , 6.84 (d, J = 11.3 Hz, 2H) , 6.71 (s, 1H) , 5.53 (m, 3H) , 3.28 (m, 4H) , 2.42 (s, 3H) , 1.87 –1.82 (m, 4H) , 1.52 (d, J = 7.0 Hz, 3H) .
EXAMPLE 115
4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (3, 8-diazabicyclo [3.2.1] octan-3-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 tert-butyl 3- (4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -6- (dimethylcarbamoyl) -2-methylpyrido [2, 3-d] pyrimidin-7-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
Starting with The mixture of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and tert-butyl 3, 8-diazabicyclo [3.2.1] octane-8-carboxylate, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 659.0 [M+1]
+.
Step 2 tert-butyl 3- (4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -6- (dimethylcarbamoyl) -2-methylpyrido [2, 3-d] pyrimidin-7-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
Starting with the product of Step 3, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 629.3 [M+1]
+.
Step 3 4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (3, 8-diazabicyclo [3.2.1] octan-3-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of tert-butyl3- (4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -6- (dimethylcarbamoyl) -2-methylpyrido [2, 3-d] pyrimidin-7-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (69 mg, 0.110 mmol) in DCM (4 mL) was added TFA (2 mL) at rt under Ar. The mixture was stirred at rt for 2 h. After the reaction was completed, sat. Na
2CO
3 (aq. ) was added and extracted with 10%MeOH/DCM. The organic layer was dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by Prep-HPLC (Column: Green ODS-A, 21.2*250mm, 10um; Mobile A: water with 0.05%TFA, Mobile B: CH
3CN; Gradient: 45%B over 2 min, 60%B over 15 min; Flow: 35 mL/min) to give 35.9 mg of the title product as a yellow solid. MS (ES+) : 529.3 [M+1]
+.
EXAMPLE 116
(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (3-methylpyridin-4-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Step 1 3-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine
To a stirred solution of 4-bromo-3-methylpyridine (200 mg, 1.16 mmol) in 1, 4-Dioxane (5.0 mL) were added 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (295 mg, 1.16 mmol) , KOAc (456 mg, 4.65 mmol) and Pd (dppf) Cl
2 (85 mg, 0.116 mmol) at rt. The mixture was evacuated by Ar three times and stirred for 1 h at 110℃ under Ar. After the reaction was completed, the mixture was filtered through a pad of celite. The filter cake was washed with DCM and the filtrate was concentrated to give 835 mg of crude product as brown oil which was used in the next step without further purification.
Step 2 (R) -2-methyl-6- (3-methylpyridin-4-yl) -N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
To a stirred solution of (R) -6-bromo-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine (80 mg, 0.152 mmol) , 3-methyl -4 - (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (228 mg, 0.304 mmol) , K
2CO
3 (65 mg, 0.457 mmol) , X-phos (73 mg, 0.152 mmol) in 1, 4-Dioxane /H
2O (5: 1, 1.5 mL) was added x-phosPdG2 (62 mg, 0.076 mmol) at rt. The mixture was evacuated by Ar three times and stirred for 1 h at 100℃. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (5%MeOH: DCM) to give 57 mg of the title product as a brown solid. MS (ES+) : 538.3 [M+1]
+.
Step 3 (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (3-methylpyridin-4-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of Step 2, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 508.3 [M+1]
+.
EXAMPLE 117
7- ( ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -9-methyl-1, 2, 3, 3a-tetrahydropyrrolo [1”, 2”: 4', 5'] pyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-4 (5H) -one
Step 1 (R) -2-methyl-6-nitro-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidin-7 (8H) -one
To a stirred solution of (R) -4-amino-2-methyl-6- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrimidine-5-carbaldehyde (1.9 g, 5.1 mmol) in Isopropyl alcohol (19 mL) were added ethyl 2-nitroacetate (1.5 g, 11.3 mmol) and Piperidine (1.3 g, 15.4 mmol) at rt. The mixture was stirred for 16 h at 80℃ under Ar. After cooling, water was added and extracted with EA. The water layer was adjusted pH=6 by 1N HCl and then extracted with EA. The organic layer was dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (EA: PE=1: 1) to give 1.935 g of the title product as a yellow solid. MS (ES+) : 439.2 [M+1]
+.
Step 2 (R) -7-chloro-2-methyl-6-nitro-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) pyrido [2, 3-d] pyrimidin-4-amine
The solution of (R) -2-methyl-6-nitro-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidin-7 (8H) -one (1.935 g, 4.41 mmol) in Phenylphosphonic Dichloride (23 mL) was stirred for 2 h at 120℃ under Ar. After cooling, it was dropped into ice-water and extracted with EA. The organic layer was dried over anhydrous Na
2SO
4, filtered and concentrated. DCM was added to the residue and stirred, filtered. The filtrate was concentrated and purified by silica gel column chromatography (10%MeOH: DCM) to give 3.7 g of crude product as brown oil which was used in the next step without further purification. MS (ES+) : 456.9 [M+1]
+.
Step 3 methyl 1- (2-methyl-6-nitro-4- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidin-7-yl) pyrrolidine-2-carboxylate
Starting with the product of Step 2 and methyl pyrrolidine-2-carboxylate hydrochloride, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 550.2 [M+1]
+. Step 4 7- ( ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -9-methyl-1, 2, 3, 3a-tetrahydropyrrolo [1”, 2”: 4', 5'] pyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-4 (5H) -one
Starting with the product of Step 3, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 458.3 [M+1]
+.
EXAMPLE 118
7- ( ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -5, 9-dimethyl-1, 2, 3, 3atetrahydropyrrolo [1”, 2”: 4', 5'] pyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-4 (5H) -one
To a stirred solution of 7- ( ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -9-methyl-1, 2, 3, 3a-tetrahydropyrrolo [1”, 2”: 4', 5'] pyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-4 (5H) -one (20 mg, 0.044 mmol) and Cs
2CO
3 (28.5 mg, 0.087 mmol) in DMF (1 mL) was added iodomethane (9.2 mg, 0.065 mmol) at 0℃. The mixture was stirred for 2 h at 0℃ under Ar. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (10%MeOH: DCM) to give 3 mg of the title product as a yellow solid. MS (ES+) : 472.1 [M+1]
+.
EXAMPLE 119
(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -6-isopropyl-2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
To a stirred solution of (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (prop-1-en-2-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine (35 mg, 0.08 mmol) in EA (2.0 mL) was added 10%wt Pd/C three times (120 mg) at rt. The mixture was stirred for 7 h at rt under H
2. After the reaction was completed, the mixture was filtered and concentrated. The residue was purified by Prep-HPLC (Column: Green ODS-A, 21.2*250mm, 10um; Mobile A: water with 0.05%TFA, Mobile B: CH
3CN; Gradient: 45%B over 2 min, 60%B over 15 min; Flow: 35 mL/min) to give 8.8 mg of pure product as a white solid. MS (ES+) : 459.2 [M+1]
+.
EXAMPLE 120
(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-7- (pyrrolidin-1-yl) -6- (3, 3, 3-trifluoroprop-1-en-2-yl) pyrido [2, 3-d] pyrimidin-4-amine
Step 1 (R) -2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) -6- (3, 3, 3-trifluoroprop-1-en-2-yl) pyrido [2, 3-d] pyrimidin-4-amine
To a stirred solution of (R) -6-bromo-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine (200 mg, 0.38 mmol) in THF/H
2O (5: 1, 3.0mL) were added 4, 4, 6-trimethyl-2- (3, 3, 3-trifluoroprop-1-en-2-yl) -1, 3, 2-dioxaborinane (169 mg, 0.76 mmol) , K
3PO
4 (243 mg, 1.15 mmol) and Pd (dppf) Cl
2·DCM (62 mg, 0.08 mmol) at rt. The mixture was stirred for 1 h at 70℃ under Ar. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (PE: EA=1: 1+1%NH
3
. H
2O) to give 170 mg of the title product as yellow oil. MS (ES+) : 541.2 [M+1]
+.
Step 2 (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-7- (pyrrolidin-1-yl) -6- (3, 3, 3-trifluoroprop-1-en-2-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of Step 3, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 511.2 [M+1]
+.
EXAMPLE 121
4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (6, 6-difluoro-3-azabicyclo [3.1.0] hexan-3-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 7- (6, 6-difluoro-3-azabicyclo [3.1.0] hexan-3-yl) -N, N, 2-trimethyl-4- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the mixture of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and 6, 6-difluoro-3-azabicyclo [3.1.0] hexaneheMioxalate, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 566.2 [M+1]
+.
Step 2 4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (6, 6-difluoro-3-azabicyclo [3.1.0] hexan-3-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 536.2 [M+1]
+.
EXAMPLE 122
(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6-phenyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Step 1 (R) -2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -6-phenyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with R) -6-bromo-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine and phenylboronic acid, the title product was prepared by using the same method described in Step 1 of EXAMPLE 96. MS (ES+) : 523.2 [M+1]
+.
Step 2 (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6-phenyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 493.3 [M+1]
+.
EXAMPLE 123
(R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -N, N, 2-trimethyl-7-phenylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7-phenylpyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide (60 mg, 0.124 mmol) , phenylboronic acid (35 mg, 0.248 mmol) , K
2CO
3 (53 mg, 0.373 mmol) , x-phos (60 mg, 0.124 mmol) in 1, 4-Dioxane/H
2O (5: 1, 3mL) was added x-phosPdG2 (51 mg, 0.062 mmol) at rt. The mixture was stirred for 2 h at 100℃ under Ar. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA) to give 22 mg of the title product as a yellow solid. MS (ES+) : 525.2 [M+1]
+.
Step 2 (R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -N, N, 2-trimethyl-7-phenylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 495.2 [M+1]
+.
EXAMPLE 124
(R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyla mino) -N, N, 2-trimethyl-7- (2-oxopyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (2-oxopyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide (80 mg, 0.166 mmol) in 1, 4-dioxane (4 mL) were added Pd
2 (dba)
3 (80 mg, 0.087 mmol ) , Xant-phos (80 mg, 0.138 mmol) , Cs
2CO
3 (112 mg, 0.344 mmol) and pyrrolidin-2-one (144 mg, 1.694 mmol) at rt under Ar. The mixture was stirred at 100 ℃ for 2 h. After the reaction was completed, the mixture was filtered through a layer of celite and the filtrate was concentrated. The residue was purified by Prep-TLC (EA) to give 49 mg of the title product as a yellow solid. MS (ES+) : 532.2 [M+1]
+.
Step 2 (R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -N, N, 2-trimethyl-7- (2-oxopyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 502.2 [M+1]
+.
EXAMPLE 125
4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (3- (hydroxymethyl) pyrrolidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 7- (3- (hydroxymethyl) pyrrolidin-1-yl) -N, N, 2-trimethyl-4- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with The mixture of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and pyrrolidin-3-ylmethanol, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 548.3 [M+1]
+.
Step 2 4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (3- (hydroxymethyl) pyrrolidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 518.2 [M+1]
+.
EXAMPLE 126
(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -6- (isopropylsulfonyl) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Step 1 (R) -6- (isopropylsulfonyl) -2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
To a stirred solution of (R) -6- (isopropylthio) -2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine (35 mg, 0.067 mmol) in MeOH (1 mL) was added MMPP (210 mg, 0.67 mmol) at 0℃. The mixture was stirred at rt for 16 hours. After the reaction was completed, water was added and extracted with EA. The organic layer was dried over anhydrous Na
2SO
4, filtered and concentrated under vacuum. The residue was purified by Prep-TLC (EA) to give 11 mg of pure product as a white solid. MS (ES+) : 553.0 [M+1]
+.
Step 2 (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -6- (isopropylsulfonyl) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of Step 1, the title product was prepared by using the same method described in Step 2 of EXAMPLE 83. MS (ES+) : 523.0 [M+1]
+.
EXAMPLE 127
(R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-sulfonamide
Step 1 ethyl 2- (N, N-dimethylsulfamoyl) acetate
To a stirred solution of ethyl 2- (chlorosulfonyl) acetate (4.5 g, 24.2 mmol) in DCM (45 mL) was added 2M Dimethylamine (36.3 mL, 72.58 mmol) at 0℃. The mixture was stirred for 1 h at rt under Ar. After the reaction was completed, water was added and extracted with DCM twice. The organic layer was washed by brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (EA: PE=1: 5) to give 2 g of the title product as yellow oil. MS (ES+) : 196.0 [M+1]
+.
Step 2 (R) -N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-sulfonamide
To a stirred solution of (R) -4-amino-2-methyl-6- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrimidine-5-carbaldehyde (200 mg, 0.342 mmol) in Isopropyl alcohol (2 mL) were added ethyl2- (N, N-dimethylsulfamoyl) acetate (317 mg, 1.025 mmol) and Piperidine (138 mg, 1.025 mmol) . The mixture was stirred for 16 h at 85℃ under Ar. After cooling, water was added and extracted with EA. The water layer was adjusted pH=6 by 1N HCl and then extracted with EA. The organic layer was dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (EA: PE=1: 3) to give 273 mg of the title product as yellow oil. MS (ES+) : 501.0 [M+1]
+.
Step 3 (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-sulfonamide
Starting with the product of Step 2 , the title product was prepared by using the same method as described in Step 2 of EXAMPLE 103. MS (ES+) : 518.9 [M+1]
+.
Step 4 (R) -N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-sulfonamide
Starting with the product of step 3 and Pyrrolidine, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 554.0 [M+1]
+.
Step 5 (R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-sulfonamide
Starting with the product of Step 4, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 524.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ9.01 (s, 1H) , 8.78 (s, 1H) , 6.86 (s, 1H) , 6.82 (s, 1H) , 6.72 (s, 1H) , 5.55 (m, 3H) , 3.72 (m, 4H) , 2.80 (s, 6H) , 2.39 (s, 3H) , 1.89 (m, 4H) , 1.55 (d, J = 7.0 Hz, 3H) .
EXAMPLE 128
Methyl 1- (4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -6- (dimethylcarbamoyl) -2-methylpyrido [2, 3-d] pyrimidin-7-yl) pyrrolidine-2-carboxylate
Step 1 methyl 1- (6- (dimethylcarbamoyl) -2-methyl-4- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidin-7-yl) pyrrolidine-2-carboxylate
Starting with The mixture of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and methyl pyrrolidine-2-carboxylate, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 576.3 [M+1]
+.
Step 2 methyl 1- (4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -6- (dimethylcarbamoyl) -2-methylpyrido [2, 3-d] pyrimidin-7-yl) pyrrolidine-2-carboxylate
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 546.3 [M+1]
+.
EXAMPLE 129
1- (4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -6- (dimethylcarbamoyl) -2-methylpyrido [2, 3-d] pyrimidin-7-yl) pyrrolidine-2-carboxylic acid
To a stirred solution of methyl1- (4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -6- (dimethylcarbamoyl) -2-methylpyrido [2, 3-d] pyrimidin-7-yl) pyrrolidine-2-carboxylate (70 mg, 0.128 mmol) in EtOH/H
2O (5: 1, 4 mL) was added LiOH
. H
2O (20 mg, 0.476 mmol ) at rt. The mixture was stirred at rt for 2.5 h. After the reaction was completed, the mixture was adjusted pH= 6-7 with 1N HCl and concentrated. Then MeOH: DCM=1: 9 was added and the organic layer was dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-HPLC (Column: Green ODS-A, 21.2 x 250mm, 10um; Mobile A: water with 0.05%TFA, Mobile B: CH
3CN; Gradient: 45%B over 2 min, 60%B over 15 min; Flow: 35 mL/min) to give 5.2 mg of the title product as a yellow solid. MS (ES+) : 532.3 [M+1]
+.
EXAMPLE 130
(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-7- (pyrrolidin-1-yl) -6- (2- (trifluoromethyl) pyridin-4-yl) pyrido [2, 3-d] pyrimidin-4-amine
Step 1 (R) -2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) -6- (2- (trifluoromethyl) pyridin-4-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of step 1 of EXAMPLE 88 and 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2- (trifluoromethyl) pyridine, the title product was prepared by using the same method as described in Step 4 of EXAMPLE 87. MS (ES+) : 592.2 [M+1]
+.
Step 2 (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-7- (pyrrolidin-1-yl) -6- (2- (trifluoromethyl) pyridin-4-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 562.3 [M+1]
+.
EXAMPLE 131
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (1, 3, 4-oxadiazol-2-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Step 1 (R) -methyl4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylate
To a stirred solution of (R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid (1 g, 2.55 mmol) in MeOH (10 mL) was added H
2SO
4 (500 mg, 5.1 mmol) at rt. The resulting mixture was stirred at 70℃ for 20 h. After the reaction was completed, the reaction was quenched with sat. NaHCO
3 (aq. ) and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA) to obtain 850 mg of the title product as a yellow solid. MS (ES+) : 407.2 [M+1]
+.
Step 2 (R) -methyl7-chloro-4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methylpyrido [2, 3-d] pyrimidine-6-carboxylate
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 1 of EXAMPLE 46. MS (ES+) : 425.2 [M+1]
+.
Step 3 (R) -methyl4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxylate
Starting with the product of Step 2 and methyl pyrrolidine, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 460.2 [M+1]
+.
Step 4 (R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxylic acid
Starting with the product of Step 3, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 112. MS (ES+) : 446.2 [M+1]
+.
Step 5 (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (1, 3, 4-oxadiazol-2-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
To a stirred solution of (R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxylic acid (110 mg, 0.245 mmol) in DCE (2 mL) was added (isocyanoimino) triphenylphosphorane (155 mg, 0.49 mmol) . Then the reaction mixture was stirred for 2 h at 80℃. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-HPLC (Column: Green ODS-A, 21.2 x 250mm, 10um; Mobile A: water with 0.05%TFA, Mobile B: CH
3CN; Gradient: 45%B over 2 min, 60%B over 15 min; Flow: 35 mL/min) to obtain 7 mg of pure product as a white solid. MS (ES+) : 470.0 [M+1]
+.
EXAMPLE 132
4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -N, N, 2-trimethyl-7- (3-methyl-3, 8-diazabicyclo [3.2.1] octan-8-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 N, N, 2-trimethyl-7- (3-methyl-3, 8-diazabicyclo [3.2.1] octan-8-yl) -4- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the mixture of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and 3-methyl -3, 8-diazabicyclo [3.2.1] octane
. 2HCl, the title product was prepared by using the same method described in Step 2 of EXAMPLE 69. MS (ES+) : 573.2 [M+1]
+.
Step 2 4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -N, N, 2-trimethyl-7- (3-methyl-3, 8-diazabicyclo [3.2.1] octan-8-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1 , the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 543.3 [M+1]
+.
EXAMPLE 133
4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (8-azabicyclo [3.2.1] octan-8-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 7- (8-azabicyclo [3.2.1] octan-8-yl) -N, N, 2-trimethyl-4- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the mixture of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and 8-azabicyclo [3.2.1] octane hydrochloride, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 558.0 [M+1]
+.
Step 2 4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (8-azabicyclo [3.2.1] octan-8-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1 , the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 528.2 [M+1]
+.
EXAMPLE 134
4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (3-hydroxypyrrolidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 7- (3-hydroxypyrrolidin-1-yl) -N, N, 2-trimethyl-4- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the mixture of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and pyrrolidin-3-ol, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 534.5 [M+1]
+.
Step 2 4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (3-hydroxypyrrolidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1 , the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 504.1 [M+1]
+.
EXAMPLE 135
N- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -9-methyl-1, 2, 3, 3a, 4, 5-hexahydropyrrolo [1”, 2”: 4', 5'] pyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-7-amine
To a solution of 4- { [ (1R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl] amino} -6-methyl-5, 7, 9, 11, 17-pentaazatetracyclo [8.7.0.0^ {3, 8} . 0^ {11, 15} ] heptadeca-1, 3 (8) , 4, 6, 9-pentaen-16-one (40 mg, 0.088 mmol) in THF (4 mL) was added diborane (1M in THF, 102 mg, 4 mmol) . The mixture was stirred at rt for 16 hours. After the reaction was completed, water was added and extracted with EA. The organic layer was dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-HPLC (Column: Green ODS-A, 21.2*250mm, 10um; Mobile A: water with 0.05%TFA, Mobile B: CH
3CN; Gradient: 45%B over 2 min, 60%B over 15 min; Flow: 35 mL/min) to give 4.8 mg of pure product as a yellow solid. MS (ES+) : 444.2 [M+1]
+.
EXAMPLE 136
(R) -tert-butyl4- (4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -6- (dimethylcarbamoyl) -2-methylpyrido [2, 3-d] pyrimidin-7-yl) piperidine-1-carboxylate
Step 1 (R) -ethyl7- (1- (tert-butoxycarbonyl) piperidin-4-yl) -2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxylate
Starting with (R) -4-amino-2-methyl-6- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrimidine-5-carbaldehyde and tert-butyl 4- (3-methoxy -3-oxopropanoyl) piperidine-1-carboxylate, the title product was prepared by using the same method described in Step 1 of EXAMPLE 112. To a stirred solution of (R) -4-amino-2-methyl-6- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrimidine-5-carbaldehyde (90 mg, 0.244 mmol) in i-PrOH (1 mL) were added tert-butyl 4- (3-methoxy-3-oxopropanoyl) piperidine-1-carboxylate (214 mg, 0.716 mmol) and Piperidine (70 mg, 0.716 mmol) at rt. The resulting mixture was stirred at 80℃ for 16 h. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (PE/EA=2/1) to obtain 100 mg of pure product as a yellow solid. MS (ES+) : 633.0 [M+1]
+.
Step 2 (R) -7- (1- (tert-butoxycarbonyl) piperidin-4-yl) -2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxylic acid
Starting with the product of Step 1 , the title product was prepared by using the same method as described in Step 2 of EXAMPLE 112. MS (ES+) : 605.0 [M+1]
+.
Step 3 (R) -tert-butyl4- (6- (dimethylcarbamoyl) -2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidin-7-yl) piperidine-1-carboxylate
Starting with the product of Step 2, the title product was prepared by using the same method as described in EXAMPLE 10. MS (ES+) : 632.0 [M+1]
+.
Step 4 (R) -tert-butyl4- (4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -6- (dimethylcarbamoyl) -2-methylpyrido [2, 3-d] pyrimidin-7-yl) piperidine-1-carboxylate
Starting with the product of Step 3, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 602.3 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.71 (s, 1H) , 8.64 (s, 1H) , 6.87 (s, 1H) , 6.82 (s, 1H) , 6.70 (s, 1H) , 5.62 –5.44 (m, 3H) , 4.07 –4.02 (m, 2H) , 3.09 (s, 3H) , 2.86 (m, 6H) , 2.43 (s, 3H) , 1.72 (m, 4H) , 1.53 (d, J = 7.0 Hz, 3H) , 1.43 (s, 9H) .
EXAMPLE 137
(R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -N, N, 2-trimethyl-7- (piperidin-4-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of (R) -tert-butyl 4- (4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -6- (dimethylcarbamoyl) -2-methyl pyrido [2, 3-d] pyrimidin-7-yl) piperidine-1-carboxylate (25 mg, 0.041 mmol) in DCM (0.5 mL) was added TFA (0.25 mL) at rt. The resulting mixture was stirred at rt for 1 h. After the reaction was completed, the reaction was quenched with sat. Na
2CO
3 (aq. ) and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA/MeOH=9/1) to obtain 6 mg of the title product as a yellow solid. MS (ES+) : 502.3 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.74 (s, 1H) , 8.62 (d, J = 8.1 Hz, 1H) , 6.88 (s, 1H) , 6.83 (s, 1H) , 6.70 (s, 1H) , 5.54 (s, 2H) , 5.50 (d, J = 7.3 Hz, 1H) , 3.09 (s, 3H) , 3.08-2.94 (m, 4H) , 2.86 (s, 3H) , 2.44 (s, 3H) , 2.18 (t, J = 7.4 Hz, 1H) , 1.87 (m, 2H) , 1.55 –1.47 (m, 4H) , 0.85 (t, J = 6.7 Hz, 2H) .
EXAMPLE 138
(R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -N, N, 2-trimethyl-7- (1-methylpiperidin-4-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (piperidin-4-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of (R) -tert-butyl 4- (6- (dimethylcarbamoyl) -2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidin-7-yl) piperidine-1-carboxylate (120 mg, 0.190 mmol) in DCM (1 mL) was added TFA (0.5 mL) at rt. The resulting mixture was stirred at rt for 1 h. After the reaction was completed, the reaction was quenched with sat. Na
2CO
3 (aq. ) and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA/MeOH=9/1) to obtain 64 mg of pure product as a yellow solid. MS (ES+) : 532.0 [M+1]
+.
Step 2 (R) -N, N, 2-trimethyl-7- (1-methylpiperidin-4-yl) -4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of (R) -N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (piperidin-4-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide (65 mg, 0.122 mmol) in DCM (2 mL) were added formaldehyde (120 mg) , AcOH (120 mg) and STAB (120 mg) at 0-10℃. The resulting mixture was stirred at 0-10 ℃ for 1 h. After the reaction was completed, the reaction was quenched with sat. Na
2CO
3 (aq. ) and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to obtain 60 mg of crude product as a yellow solid which was used in the next step without further purification. MS (ES+) : 546.0 [M+1]
+.
Step 3 (R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -N, N, 2-trimethyl-7- (1-methylpiperidin-4-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 2, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 516.0 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.75 (s, 1H) , 8.65 (d, J = 7.6 Hz, 1H) , 6.88 (s, 1H) , 6.83 (s, 1H) , 6.70 (s, 1H) , 5.56 (s, 2H) , 5.50 (d, J = 7.2 Hz, 1H) , 3.09 (m, 5H) , 2.86 (m, 5H) , 2.44 (m, 7H) , 1.81 (m, 4H) , 1.53 (d, J = 7.0 Hz, 3H) .
EXAMPLE 139
4- ( ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (2-carbamoylpyrrolidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 7- (2-carbamoylpyrrolidin-1-yl) -N, N, 2-trimethyl-4- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the mixture of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and DL-prolineamide hydrochloride, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 561.3 [M+1]
+.
Step 2 4- ( ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (2-carbamoylpyrrolidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 531.3 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.49 (s, 1H) , 7.37 (d, J = 25.0 Hz, 1H) , 6.99 (d, J = 31.1 Hz, 1H) , 6.83 (d, J = 12.6 Hz, 2H) , 6.71 (s, 1H) , 5.58 (m, 3H) , 4.69 (d, J = 7.8 Hz, 1H) , 3.70 (m, 2H) , 3.03 (d, J = 7.6 Hz, 3H) , 2.97 –2.87 (m, 3H) , 2.43 (s, 3H) , 1.94 (m, 4H) , 1.53 (d, J = 7.0 Hz, 3H) .
EXAMPLE 140
4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -N, N, 2-trimethyl-7- (2- (methylcarbamoyl) pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 tert-butyl 2- (methylcarbamoyl) pyrrolidine-1-carboxylate
The mixture of 1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid (1.2 g, 5.581 mmol) , methylamine hydrochloride (754 mg, 11.170 mmol ) , triethylamine (2.276 g, 22.534 mmol) and HOBT (904 mg, 6.696 mmol) in DCM (12mL) was stirred at room temperature for 4 h. After the reaction was completed, water was added and extracted with DCM. The organic layer was dried over anhydrous Na
2SO
4, filtered and concentrated to obtain 204 mg of the title product as a white solid.
Step 2 N-methylpyrrolidine-2-carboxamide hydrochloride
The mixture of tert-butyl 2- (methylcarbamoyl) pyrrolidine-1-carboxylate (1.07 g, 4.692 mmol) in 4N HCl/EA (10mL) was stirred at room temperature for 1 h. After the reaction was completed, the mixture was concentrated to obtain 630 mg of the title product as a white solid.
Step 3 N, N, 2-trimethyl-7- (2- (methylcarbamoyl) pyrrolidin-1-yl) -4- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the mixture of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and N-methylpyrrolidine-2-carboxamide hydrochloride, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 575.1 [M+1]
+.
Step 4 4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -N, N, 2-trimethyl-7- (2- (methylcarbamoyl) pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 3, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 545.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.67 (s, 1H) , 8.46 (m, 1H) , 7.86 (d, J = 38.8 Hz, 1H) , 6.91 –6.75 (m, 2H) , 6.71 (s, 1H) , 5.72 –5.41 (m, 3H) , 4.79 –4.61 (m, 1H) , 3.03 (d, J = 7.4 Hz, 3H) , 2.91 (d, J = 13.4 Hz, 3H) , 2.63 –2.55 (m, 3H) , 2.40 (d, J = 7.6 Hz, 3H) , 2.24 –1.78 (m, 4H) , 1.51 (t, J = 7.3 Hz, 3H) .
EXAMPLE 141
4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (2- (dimethylcarbamoyl) pyrrolidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 7- (2- (dimethylcarbamoyl) pyrrolidin-1-yl) -N, N, 2-trimethyl-4- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the mixture of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and N, N-dimethylpyrrolidine- 2-carboxamide hydrochloride, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 589.3 [M+1]
+.
Step 2 4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (2- (dimethylcarbamoyl) pyrrolidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 559.3 [M+1]
+.
EXAMPLE 142
4- ( ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (3-methoxypyrrolidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 7- (3-methoxypyrrolidin-1-yl) -N, N, 2-trimethyl-4- ( ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the mixture of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and 3-methoxypyrrolidine, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 548.3 [M+1]
+.
Step 2 4- ( ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (3-methoxypyrrolidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1 , the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 518.3 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.40 (dd, J = 14.2, 8.0 Hz, 1H) , 8.15 (dt, J = 19.4, 9.9 Hz, 1H) , 6.84 (t, J = 12.2 Hz, 2H) , 6.69 (s, 1H) , 5.54 (s, 2H) , 5.47 (t, J = 7.0 Hz, 1H) , 4.04 (qd, J = 4.5, 2.8, 2.2 Hz, 1H) , 3.67 –3.42 (m, 4H) , 3.25 (s, 3H) , 3.04 (d, J = 3.7 Hz, 3H) , 2.89 (m, 3H) , 2.33 (s, 3H) , 2.11 –1.93 (m, 2H) , 1.50 (d, J = 6.9 Hz, 3H) .
EXAMPLE 143
(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -6- (isopropylthio) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Step 1 (R) -6- (isopropylthio) -2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
The mixture of (R) -6-bromo-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine (150 mg, 0.286 mmol) , 15 drops of propane-2-thiol, 30 drops of DIEA, Xant-phos (150 mg, 0.259 mmol) and Pd
2 (dba)
3 (150 mg, 0.164 mmol) in 1, 4-Dioxane (5 mL) was stirred at 90℃ for 4.5 h. After the reaction was completed, water was added and extracted with EA. The organic layer was dried over anhydrous Na
2SO
4, filtered and concentrated. The filtrate was concentrated and purified by silica gel column chromatography (EA: PE=2: 3) to give 103 mg of the title product as a yellow solid. MS (ES+) : 521.2 [M+1]
+.
Step 2 (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -6- (isopropylthio) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 491.1 [M+1]
+.
EXAMPLE 144
4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -N, N, 2-trimethyl-7- (3-methylpyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 N, N, 2-trimethyl-7- (3-methylpyrrolidin-1-yl) -4- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the mixture of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and 3-methylpyrrolidine hydrochloride, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 532.1 [M+1]
+.
Step 2 4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -N, N, 2-trimethyl-7- (3-methylpyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1 , the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83.. MS (ES+) : 502.1 [M+1]
+.
EXAMPLE 145
4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (3- (fluoromethyl) pyrrolidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 tert-butyl 3- ( (methylsulfonyloxy) methyl) pyrrolidine-1-carboxylate
To a stirred solution of tert-butyl3- (hydroxymethyl) pyrrolidine-1-carboxylate (2.2 g, 10.89 mmol) and TEA (3.34 g, 29.9 mmol) in DCM (22 mL) was added methanesulfonyl chloride (1.49 g, 12.06 mmol) at 0-10℃. The mixture was stirred at rt for 1 h and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE: EA=3: 1) to give 2.86 g of pure product as yellow oil. MS (ES+) : 224.0 [M-56+1]
+.
Step 2 tert-butyl 3- (fluoromethyl) pyrrolidine-1-carboxylate
To a stirred solution of tert-butyl3- (fluoromethyl) pyrrolidine-1-carboxylate (2.86 g, 9.91 mmol) in THF (28 mL) was add tetrabutylammonium fluoride (1M in THF, 51.2 mL) . The mixture was stirred at 75℃ for 1 h. After the reaction was completed, water was added and extracted with EA. The organic layer was dried over anhydrous Na
2SO
4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE: EA=6: 1) to give1.118 g of pure product as yellow oil. MS (ES+) : 148.0 [M-56+1]
+.
Step 3 3- (fluoromethyl) pyrrolidine hydrochloride
The mixture of tert-butyl3- (fluoromethyl) pyrrolidine-1-carboxylate (1.1 g, 5.41 mmol) in 4N HCl (in EA, 10 mL) was stirred at rt for 1 h. The mixture was concentrated under vacuum to give 820 mg of pure product as yellow oil. MS (ES+) : 104.1 [M+1]
+.
Step 4 7- (3- (fluoromethyl) pyrrolidin-1-yl) -N, N, 2-trimethyl-4- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the mixture of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and 3- (fluoromethyl) pyrrolidine hydrochloride, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 550.1 [M+1]
+.
Step 5 4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (3- (fluoromethyl) pyrrolidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 4 , the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 520.1 [M+1]
+.
EXAMPLE 146
N- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -6- (isopropylsulfinyl) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Step 1 6- (isopropylsulfinyl) -2-methyl-N- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
To a stirred solution of (R) -6- (isopropylthio) -2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine (60 mg, 0.115 mmol) in MeOH (1.5 mL) was added MMPP (72 mg, 0.23 mmol) at 0℃ under Ar. The mixture was stirred for 1 h at 0℃ under Ar. After the reaction was completed, water was added and extracted with EA. The organic layer was dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA) to give 39 mg of the title product as a yellow solid. MS (ES+) : 537.0 [M+1]
+.
Step 2 N- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -6- (isopropylsulfinyl) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of Step 1, the title product was prepared by using the same method described in Step 2 of EXAMPLE 83. MS (ES+) : 507.1 [M+1]
+.
EXAMPLE 147
7- (8-azabicyclo [3.2.1] octan-8-yl) -4- ( ( (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the mixture of (R) -7-chloro-4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide and 8-azabicyclo [3.2.1] octane hydrochloride, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 513.1 [M+1]
+.
EXAMPLE 148
4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (3-carbamoylpyrrolidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 7- (3-carbamoylpyrrolidin-1-yl) -N, N, 2-trimethyl-4- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the mixture of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and pyrrolidine-3-carboxamide hydrochloride, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 561.1 [M+1]
+.
Step 2 4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (3-carbamoylpyrrolidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 531.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.48 (d, J = 8.5 Hz, 1H) , 7.54 (s, 1H) , 6.99 (s, 1H) , 6.84 (t, J = 12.1 Hz, 2H) , 6.72 (s, 1H) , 5.58 (s, 2H) , 5.53 (s, 1H) , 3.65 (m, 4H) , 3.03 (m, 4H) , 2.95 –2.82 (m, 3H) , 2.43 (s, 3H) , 2.16 (m, 1H) , 2.10 –1.99 (m, 1H) , 1.53 (d, J = 7.0 Hz, 3H) .
EXAMPLE 149
(tran/cis) 4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (3-hydroxy-8-azabicyclo [3.2.1] octan-8-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (tran/cis) 7- (3-hydroxy-8-azabicyclo [3.2.1] octan-8-yl) -N, N, 2-trimethyl-4- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the mixture of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and 8-azabicyclo [3.2.1] octan-3-ol, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 574.0 [M+1]
+.
Step 2 (tran/cis) 4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (3-hydroxy-8-azabicyclo [3.2.1] octan-8-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 544.1 [M+1]
+.
EXAMPLE 150
4- ( ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (3, 3-difluoro-8-azabicyclo [3.2.1] octan-8-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 7- (3, 3-difluoro-8-azabicyclo [3.2.1] octan-8-yl) -N, N, 2-trimethyl-4- ( ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the mixture of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and 3-difluoro-8-azabicyclo [3.2.1] octane hydrochloride, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 594.3 [M+1]
+.
Step 2 4- ( ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (3, 3-difluoro-8-azabicyclo [3.2.1] octan-8-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1 , the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 564.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.53 (s, 1H) , 8.33 (s, 1H) , 6.92 –6.77 (m, 2H) , 6.70 (d, J = 1.9 Hz, 1H) , 5.55 (s, 2H) , 5.48 (t, J = 7.3 Hz, 1H) , 4.59 (m, 2H) , 3.05 (s, 3H) , 2.89 (s, 3H) , 2.37 (s, 3H) , 1.91 (m, 4H) , 1.50 (d, J = 7.0 Hz, 3H) .
EXAMPLE 151
(R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (3, 3-dimethylpyrrolidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -7- (3, 3-dimethylpyrrolidin-1-yl) -N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the mixture of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and 3, 3-dimethylpyrrolidine hydrochloride, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 546.1 [M+1]
+.
Step 2 (R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (3, 3-dimethylpyrrolidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 516.1 [M+1]
+
1H NMR (400 MHz, DMSO-d
6) δ 8.42 (m, 2H) , 6.84 (t, J = 12.9 Hz, 2H) , 6.70 (s, 1H) , 5.56 (s, 2H) , 5.48 (d, J = 7.6 Hz, 1H) , 3.03 (s, 3H) , 2.88 (d, J = 3.7 Hz, 3H) , 2.36 (s, 3H) , 1.74 (t, J = 7.2 Hz, 2H) , 1.50 (d, J = 7.1 Hz, 3H) , 1.07 (s, 6H) .
EXAMPLE 152
(R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -N, N, 2-trimethyl-7- (5-azaspiro [2.4] heptan-5-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step1 (R) -N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (5-azaspiro [2.4] heptan-5-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the mixture of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and 5-azaspiro [2.4] heptane hydrochloride, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 544.1 [M+1]
+.
Step 2 (R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -N, N, 2-trimethyl-7- (5-azaspiro [2.4] heptan-5-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 514.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.42 (m, 2H) , 6.84 (t, J = 12.1 Hz, 2H) , 6.70 (s, 1H) , 5.56 (s, 2H) , 5.49 (t, J = 7.4 Hz, 1H) , 3.66 (m, 2H) , 3.02 (s, 3H) , 2.91 (d, J = 5.9 Hz, 3H) , 2.37 (s, 3H) , 1.87 (t, J = 7.0 Hz, 2H) , 1.51 (d, J = 7.1 Hz, 3H) , 0.62 (d, J = 2.9 Hz, 4H) .
EXAMPLE 153
1- (4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -6- (dimethylcarbamoyl) -2-methylpyrido [2, 3-d] pyrimidin-7-yl) pyrrolidine-3-carboxylic acid
Step 1 methyl 1- (6- (dimethylcarbamoyl) -2-methyl-4- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidin-7-yl) pyrrolidine-3-carboxylate
Starting with the mixture of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and methyl pyrrolidine-3-carboxylate hydrochloride, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 576.1 [M+1]
+.
Step 2 methyl 1- (4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -6- (dimethylcarbamoyl) -2-methylpyrido [2, 3-d] pyrimidin-7-yl) pyrrolidine-3-carboxylate
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 546.1 [M+1]
+.
Step 3 1- (4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -6- (dimethylcarbamoyl) -2-methylpyrido [2, 3-d] pyrimidin-7-yl) pyrrolidine-3-carboxylic acid
Starting with the product of Step 2 , the title product was prepared by using the same method as described in Step 2 of EXAMPLE 112. MS (ES+) : 532.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 9.17 (s, 1H) , 8.58 –8.46 (m, 1H) , 6.85 (m, 2H) , 6.73 (s, 1H) , 5.68 –5.36 (m, 3H) , 3.03 (s, 3H) , 2.96 –2.87 (m, 3H) , 2.46 (s, 3H) , 2.17 (m, 2H) , 1.55 (d, J = 7.0 Hz, 3H) .
EXAMPLE 154
N- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -7- (8-azabicyclo [3.2.1] octan-8-yl) -2-methyl-6- (1, 3, 4-oxadiazol-2-yl) pyrido [2, 3-d] pyrimidin-4-amine
Step 1 methyl7- (8-azabicyclo [3.2.1] octan-8-yl) -2-methyl-4- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxylate
Starting with the mixture of (R) -methyl 7-chloro-2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxylate and 8-azabicyclo [3.2.1] octane hydrochloride, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 80. MS (ES+) : 545.0 [M+1]
+.
Step 2 7- (8-azabicyclo [3.2.1] octan-8-yl) -2-methyl-4- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxylic acid
The mixture of methyl 7- (8-azabicyclo [3.2.1] octan-8-yl) -2-methyl-4- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxylate (350 mg, 0.643 mmol) and 2 N NaOH (2 mL) in MeOH (4 mL) was stirred at 50℃ overnight. After the reaction was completed, the reaction was quenched with 1N HCl and extracted with DCM/MeOH (9/1) . The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to obtain 290 mg of the title product as a yellow solid. MS (ES+) : 531.0 [M+1]
+.
Step 3 7- (8-azabicyclo [3.2.1] octan-8-yl) -2-methyl-N- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -6- (1, 3, 4-oxadiazol-2-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of Step 2 , the title product was prepared by using the same method as described in Step 1 of EXAMPLE 114. MS (ES+) : 555.1 [M+1]
+.
Step 4 N- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -7- (8-azabicyclo [3.2.1] octan-8-yl) -2-methyl-6- (1, 3, 4-oxadiazol-2-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of Step 3, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 525.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 9.46 (s, 1H) , 8.94 (d, J = 12.1 Hz, 1H) , 8.63 (s, 1H) , 6.86 (s, 1H) , 6.83 (s, 1H) , 6.70 (s, 1H) , 5.67 –5.41 (m, 3H) , 4.04 (m, 4H) , 2.38 (d, J = 7.3 Hz, 3H) , 1.94 –1.80 (m, 4H) , 1.78 –1.62 (m, 4H) , 1.50 (d, J = 7.0 Hz, 3H) .
EXAMPLE 155
(tran/cis) 4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (3-fluoro-8-azabicyclo [3.2.1] octan-8-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (tran/cis) 7- (3-fluoro-8-azabicyclo [3.2.1] octan-8-yl) -N, N, 2-trimethyl-4- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of 7- (3-hydroxy-8-azabicyclo [3.2.1] octan-8-yl) -N, N, 2-trimethyl-4- ( (R) -1- (3-nitro- 5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide (30 mg, 0.052 mmol) in DCM (10 mL) was added DAST (30 mg, 5.1 mmol) at 0-10℃. The resulting mixture was stirred at 0-10℃ for 1 h. After the reaction was completed, the reaction was quenched with ice water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to obtain 26 mg of crude product as a yellow solid. MS (ES+) : 576.1 [M+1]
+.
Step 2 (tran/cis) 4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (3-fluoro-8-azabicyclo [3.2.1] octan-8-yl) -N, N, 2 -trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 546.1 [M+1]
+.
EXAMPLE 156
(R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (7-azabicyclo [2.2.1] heptan-7-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -7- (7-azabicyclo [2.2.1] heptan-7-yl) -N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the mixture of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and 7-azabicyclo [2.2.1] heptane hydrochloride, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 544.1 [M+1]
+.
Step 2 (R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (7-azabicyclo [2.2.1] heptan-7-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1, the title product was prepared by using the same method asdescribed in Step 2 of EXAMPLE 83. MS (ES+) : 514.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.57 (t, J = 7.2 Hz, 1H) , 8.52 (d, J = 4.0 Hz, 1H) , 6.85 (m, 2H) , 6.71 (s, 1H) , 5.67 –5.23 (m, 3H) , 4.43 (t, J = 4.7 Hz, 2H) , 3.04 (s, 3H) , 2.87 (s, 3H) , 2.39 (s, 3H) , 1.77 (m, 2H) , 1.59 (m, 2H) , 1.54 –1.39 (m, 7H) .
EXAMPLE 157
4- ( ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -N, N, 2-trimethyl-7- (2-methylpyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 N, N, 2-trimethyl-7- (2-methylpyrrolidin-1-yl) -4- ( ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the mixture of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and 2-methylpyrrolidine hydrochloride, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 532.1 [M+1]
+.
Step 2 4- ( ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -N, N, 2-trimethyl-7- (2-methylpyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 502.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.72 (s, 1H) , 8.49 (m, 1H) , 6.85 (m, 2H) , 6.71 (s, 1H) , 5.68-5.38 (m, 3H) , 4.43 (m, 1H) , 3.02 (s, 4H) , 2.77 (d, J=5.5 Hz, 2H) , 2.40 (s, 3H) , 2.04 (m, 2H) , 1.87-1.73 (m, 1H) , 1.62 (m, 1H) , 1.52 (m, 3H) , 1.26 (m, 3H) .
EXAMPLE 158
(R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (2, 2-dimethylpyrrolidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -7- (2, 2-dimethylpyrrolidin-1-yl) -N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the mixture of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and 2, 2-dimethylpyrrolidine hydrochloride, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 546.1 [M+1]
+.
Step 2 (R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (2, 2-dimethylpyrrolidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 516.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.87 (t, J = 7.9 Hz, 1H) , 8.46 (d, J = 7.5 Hz, 1H) , 6.85 (m, 2H) , 6.72 (s, 1H) , 5.65 –5.39 (m, 3H) , 3.13 (m, 2H) , 3.00 (s, 3H) , 2.85 (d, J = 8.7 Hz, 3H) , 2.44 (d, J = 2.9 Hz, 3H) , 1.84 (m, 4H) , 1.60 –1.46 (m, 7H) .
EXAMPLE 159
(R) -1- (4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -6- (dimethylcarbamoyl) -2-methylpyrido [2, 3-d] pyrimidin-7-yl) azetidine-2-carboxylic acid
Step 1 (R) -methyl 1- (6- (dimethylcarbamoyl) -2-methyl-4- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidin-7-yl) azetidine-2-carboxylate
Starting with the mixture of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and (R) -methyl azetidine-2-carboxylate hydrochloride, the title product was prepared by using the same method described in Step 2 of EXAMPLE 69. MS (ES+) : 562.1 [M+1]
+.
Step 2 (R) -methyl 1- (4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -6- (dimethylcarbamoyl) -2-methylpyrido [2, 3-d] pyrimidin-7-yl) azetidine-2-carboxylate
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 532.1 [M+1]
+.
Step 3 (R) -1- (4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -6- (dimethylcarbamoyl) -2-methylpyrido [2, 3-d] pyrimidin-7-yl) azetidine-2-carboxylic acid
Starting with the product of Step 1, the title product was prepared by using the same method as described in EXAMPLE 129. MS (ES+) : 518.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.47 (s, 1H) , 8.33 (s, 1H) , 6.85 (s, 1H) , 6.81 (s, 1H) , 6.70 (s, 1H) , 5.64 -5.32 (m, 3H) , 4.81 (s, 1H) , 4.04 (m, 2H) , 2.99 (s, 3H) , 2.89 (s, 3H) , 2.74 –2.61 (m, 1H) , 2.35 (s, 3H) , 2.21 (m, 1H) , 1.49 (d, J = 7.1 Hz, 3H) .
EXAMPLE 160
4- ( ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (3-cyanopyrrolidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 7- (3-cyanopyrrolidin-1-yl) -N, N, 2-trimethyl-4- ( ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the mixture of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and pyrrolidine-3-carbonitrile hydrochloride, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 543.1 [M+1]
+.
Step 2 4- ( ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (3-cyanopyrrolidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 513.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.47 (s, 1H) , 8.23 (s, 1H) , 6.84 (m, 2H) , 6.70 (s, 1H) , 5.54 (s, 2H) , 5.47 (t, J = 7.3 Hz, 1H) , 3.86 –3.52 (m, 5H) , 3.04 (s, 3H) , 2.90 (s, 3H) , 2.40 –2.16 (m, 5H) , 1.50 (d, J = 7.0 Hz, 3H) .
EXAMPLE 161
(R) - (4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) dimethylphosphine oxide
Step 1 (R) -dimethyl (2-methyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) phosphine oxide
To a stirred solution of (R) -6-bromo-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine (150 mg, 0.29 mmol) in 1, 4-Dioxane (3.0 mL) were added dimethylphosphine oxide (67 mg, 0.86 mmol) , DIEA (148 mg, 1.15 mmol) , xant-phos (83 mg, 0.14 mmol) and Pd
2 (dba)
3 (70 mg, 0.07 mmol) at rt. The mixture was stirred for 3 h at 100℃ under Ar. After the reaction was completed, the reaction was quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by prep-TLC (PE: EA=1: 2 and DCM: MeOH=9: 1) to give 148 mg of crude product as a yellow solid which was used in the next step without further purification. MS (ES+) : 523.0 [M+1]
+.
Step 2 (R) - (4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) dimethylphosphine oxide
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 493.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 9.31 (s, 1H) , 8.88 (d, 1H) , 6.88 (s, 1H) , 6.84 (s, 1H) , 6.73 (s, 1H) , 5.59 (m, 3H) , 3.78 (m, 4H) , 2.43 (s, 3H) , 1.95 –1.76 (m, 10H) , 1.58 (d, J = 7.0 Hz, 3H) .
EXAMPLE 162
(R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carbonitrile
Step 1 (R) -2-methyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carbonitrile
To a stirred solution of (R) -6-bromo-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine (280 mg, 0.53 mmol) in NMP (2.0 mL) was added CuCN (143 mg, 1.60 mmol) at rt. The mixture was stirred for 3 h at 160℃. After the reaction was completed, the reaction was quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (EA) to give 129 mg of the title product as a brown solid. MS (ES+) : 472.0 [M+1]
+.
Step 2 (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carbonitrile
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 442.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 9.19 (s, 1H) , 9.11 (s, 1H) , 6.87 (s, 1H) , 6.84 (s, 1H) , 6.73 (s, 1H) , 5.74 –5.40 (m, 3H) , 3.78 (m, 4H) , 2.41 (s, 3H) , 1.98 (m, 4H) , 1.54 (d, J = 7.1 Hz, 3H) .
EXAMPLE 163
7- ( ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -9-methyl-5- (tetrahydrofuran-3-yl) -1, 2, 3, 3a-tetrahydropyrrolo [1”, 2”: 4', 5'] pyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-4 (5H) -one
Step 1 tert-butyl 2- (tetrahydrofuran-3-ylcarbamoyl) pyrrolidine-1-carboxylate
To a stirred solution of 1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid (500 mg, 2.32 mmol) in DMF (5 mL) were added tetrahydrofuran-3-amine hydrochloride (243 mg, 2.78 mmol) , DIEA (1.2 g, 9.28 mmol) and HATU (1.06 g, 2.78 mmol) at rt. The mixture was stirred for 1 h at rt. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (EA) to give 644 mg of the title product as a white solid. MS (ES+) : 229.0 [M-55]
+.
Step 2 N- (tetrahydrofuran-3-yl) pyrrolidine-2-carboxamide hydrochloride
The mixture of tert-butyl 2- (tetrahydrofuran-3-ylcarbamoyl) pyrrolidine-1-carboxylate (644 mg, 2.26 mmol) in 4 N HCl/EA (4 mL) was stirred for 0.5 h at rt under Ar. After the reaction was completed, the mixture was concentrated to give the crude product as a white solid which was used in the next step without further purification. MS (ES+) : 185.1 [M+1]
+.
Step 3 1- (6-bromo-2-methyl-4- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidin-7-yl) -N- (tetrahydrofuran-3-yl) pyrrolidine-2-carboxamide
To a stirred solution of (R) -6-bromo-7-chloro-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) pyrido [2, 3-d] pyrimidin-4-amine (110 mg, 0.224 mmol) in 1.4-dioxane (2 mL) were added N- (tetrahydrofuran-3-yl) pyrrolidine-2-carboxamide hydrochloride (493 mg, 2.24 mmol) and DIEA (587 mg, 4.48 mmol) at rt. The mixture was stirred for 1.5 h at 50℃ under Ar. After cooling, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA) to give 119 mg of the title product as yellow oil. MS (ES+) : 640.0 [M+1]
+.
Step 4 9-methyl-7- ( ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -5- (tetrahydrofuran-3-yl) -1, 2, 3, 3a-tetrahydropyrrolo [1”, 2”: 4', 5'] pyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-4 (5H) -one
To a stirred solution of methyl1- (6-bromo-2-methyl-4- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidin-7-yl) -N- (tetrahydrofuran-3-yl) pyrrolidine-2-carboxamide (99 mg, 0.155 mmol) in 1.4-dioxane (29 mL) were added Cs
2CO
3 (152 mg, 0.465 mmol) , Xant-phos (99 mg, 0.171 mmol) and Pd
2 (dba)
3 (99 mg, 0.108 mmol) at rt. The mixture was evacuated by Ar three times and stirred for 2 h at 80℃ under Ar. After cooling, water was added and extracted with EA. The organic layer was dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (5%MeOH: EA) to give 22 mg of P1 and 27 mg of P2 as a yellow solid. MS (ES+) : 558.1 [M+1]
+.
Step 5 7- ( ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -9-methyl-5- (tetrahydrofuran-3-yl) -1, 2, 3, 3a-tetrahydropyrrolo [1”, 2”: 4', 5'] pyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-4 (5H) -one
P1: To a stirred solution of 9-methyl-7- ( ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -5- (tetrahydrofuran-3-yl) -1, 2, 3, 3a-tetrahydropyrrolo [1”, 2”: 4', 5'] pyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-4 (5H) -one (P1, 22 mg, 0.039 mmol) in EtOH/H
2O (5: 1, 1 mL) were added NH
4Cl (88 mg, 1.645 mmol) and Fe (88 mg, 1.571 mmol) at rt. The mixture was stirred for 2 h at 70℃. After the reaction was completed, water was added and extracted with EA. The organic layer was dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (5%MeOH: EA) to give 8.2 mg of the title product as a white solid. MS (ES+) : 528.1 [M+1]
+.
P2: To a stirred solution of 9-methyl-7- ( ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -5- (tetrahydrofuran-3-yl) -1, 2, 3, 3a-tetrahydropyrrolo [1”, 2”: 4', 5'] pyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-4 (5H) -one (P2, 27 mg, 0.048 mmol) in EtOH/H
2O (5: 1, 1 mL) were added NH
4Cl (88 mg, 1.645 mmol) and Fe (88 mg, 1.571 mmol) at rt. The mixture was stirred for 2 h at 70℃. After the reaction was completed, water was added and extracted with EA. The organic layer was dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (5%MeOH: EA) to give 4.8 mg of the title product as a white solid. MS (ES+) : 528.1 [M+1]
+.
EXAMPLE 164
(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -6- (cyclopropylsulfonyl) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Step 1 (R) -6- (cyclopropylsulfonyl) -2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
To a stirred solution of (R) -6-bromo-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine (100 mg, 0.190 mmol) in DMSO (3 mL) were added sodium cyclopropanesulfinate (200 mg, 1.56 mmol) , K
2CO
3 (200 mg, 1.45 mmol) , CuI (200 mg, 1.05 mmol) and N, N'-Dimethyl-1, 2-ethanediamine (200 mg, 2.27 mmol) at rt. The resulting mixture was stirred at 100℃ for 2 h. After the reaction was completed, the reaction was quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA) to obtain 15 mg of pure product as a yellow solid. MS (ES+) : 551.1 [M+1]
+.
Step 2 (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -6- (cyclopropylsulfonyl) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 521.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 9.03 (s, 1H) , 8.64 (d, J = 7.5 Hz, 1H) , 6.84 (s, 1H) , 6.82 (s, 1H) , 6.71 (s, 1H) , 5.63 –5.43 (m, 3H) , 3.74 (m, 4H) , 2.35 (s, 3H) , 1.90 (m, 5H) , 1.53 (d, J = 7.0 Hz, 3H) , 1.14 (m, 4H) .
EXAMPLE 165
(R) -4- ( (1- (3- (1, 1-difluoroethyl) phenyl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 4-amino-6-chloro-2-methylpyrimidine-5-carbaldehyde
To a stirred solution of 4, 6-dichloro-2-methylpyrimidine-5-carbaldehyde (24 g, 132.60 mmol) in THF (240 mL) was added NH
3·H
2O (72 mL) at 0℃. The mixture was allowed to warm up to room temperature and stirred for 4 h. The precipitate was collected by filtration and dried in vacuum to give product (4 g, 23.31 mmol, 17.7%yield) as a yellow solid. The filtrate was concentrated and purified by silica gel column to give the title product of step 1 (8 g) as a yellow solid, total 53.1%yield. MS (ES+) : 172.0 [M+1]
+, 174.0 [M+1]
+.
Step 2 4-amino-2-methyl-6- (methylthio) pyrimidine-5-carbaldehyde
To a stirred solution of 4-amino-6-chloro-2-methylpyrimidine-5-carbaldehyde (12 g, 70 mmol) in THF (120 mL) was added MeSNa (20.4 g, 280 mmol) . The mixture was stirred at 60 ℃ for 4 h. The mixture was filtered and the filter cake was washed with DCM (100 mL X 3) . The filtrate was concentrated in vacuum and purified by chromatography silica gel column (PE : EA = 6 : 1 ~ 4 : 1) to give the title product of step 2 (2.7 g) as a yellow solid. MS (ES+) : 184.0 [M+1]
+.
Step 3 methyl 2-methyl-4- (methylthio) -7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylate
A mixture of 4-amino-2-methyl-6- (methylthio) pyrimidine-5-carbaldehyde (2.7 g, 14.7 mmol) in diethyl malonate (20 mL) was stirred at 140℃ for 3 days. The mixture was concentrated and purified by chromatography silica gel column (PE : EA = 4 : 1 ~ EA) to give the title product of step 3 (1.6 g) as a yellow solid. MS (ES+) : 266.0 [M+1]
+.
Step 4 2-methyl-4- (methylthio) -7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid
To a stirred solution of methyl 2-methyl-4- (methylthio) -7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylate (1.6 g, 6.0 mmol) in THF (10 mL) and H
2O (10 mL) was added LiOH·H
2O (1.2 g, 30 mmol) . The reaction mixture was stirred at room temperature for 3 h. The THF was removed by concentration in vacuum. The pH of the mixture was adjusted to 4~5 with 1N HCl. The precipitate was collected by filtration and dried with toluene for several times to give the title product (1 g) as a white solid. MS (ES+) : 252.0 [M+1]
+.
Step 5 N, N, 2-trimethyl-4- (methylthio) -7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of 2-methyl-4- (methylthio) -7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboxylic acid (1 g, 3.98 mmol) in DMF (10 mL) was added dimethylamine hydrochloride (360 mg, 4.38 mmol) , HATU (2.3 g, 5.97 mmol) and DIEA (1.55g, 11.94 mmol) . The mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with H
2O (50 mL) . The precipitate was collected by filtration and dried with toluene to give the title product of step 5 (800 mg) as a yellow solid. MS (ES+) : 279.0 [M+1]
+.
Step 6 7-chloro-N, N, 2-trimethyl-4- (methylthio) pyrido [2, 3-d] pyrimidine-6-carboxamide
The mixture of N, N, 2-trimethyl-4- (methylthio) -7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6 -carboxamide (580 mg, 2.1 mmol) in phenylphosphonic dichloride (5 mL) was stirred at 100 ℃ for 1 h. After the reaction was completed, the reaction was quenched with ice water. The pH of the mixture was adjusted to 8 with 20%of NaHCO
3 (aq. ) and extracted with DCM (50 mL X 3) . The organic layer was washed with brine (50 mL X 3) , dried over anhydrous Na
2SO
4, filtered and concentrated in vacuum. The residue was purified by chromatography silica gel column (PE : EA = 4 : 1 to EA, then to DCM : MeOH = 10 : 1) to give the title product of step 6 (300 mg) as an orange oil. MS (ES+) : 297.0 [M+1]
+ , 299.0 [M+1]
+.
Step 7 N, N, 2-trimethyl-4- (methylthio) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of 7-chloro-N, N, 2-trimethyl-4- (methylthio) pyrido [2, 3-d] pyrimidine-6-carboxamide (300 mg, 1 mmol) in dioxane (5 ml) was added pyrrolidine (142 mg, 2 mmol) and DIEA (387 mg, 3 mmol) . The mixture was stirred at room temperature for 12 h. The mixture was diluted with water (10 mL) and extracted with DCM (20 mL X 3) . The combined organic layer was washed with brine (20 mL X 3) , dried over Na
2SO
4 and concentrated in vacuum to give the product. The residue was purified by silica gel column to give the title product of step 7 (250 mg) as a white solid. MS (ES+) : 332.0 [M+1]
+.
Step 8 4-hydroxy-N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of N, N, 2-trimethyl-4- (methylthio) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrim-idine-6-carboxamide (160 mg, 0.53 mmol) in DCM (10 ml) was added m-CPBA (274.2 mg, 1.59 mmol) at 0 ℃. The mixture solution was stirred at rt for 3 h. After the reaction was completed, NaHCO
3 (aq, 20 ml) was added, extracted with DCM (20 ml X 5) , combined with the DCM layer, dried over Na
2SO
4, concentrated in vacuum and the residue was purified by chromatography silica gel column (DCM : MeOH = 20 : 1) to give the title product of step 8 (100 mg) as a red solid. MS (ES+) : 302.0 [M+1]
+.
Step 9 3- (1, 1-difluoroethyl) benzonitrile
To a stirred solution of 3-acetylbenzonitrile (5 g, 34.44 mmol) in DCM (80 mL) was added DAST (39.00 g, 24.11 mmol) at 0℃. The mixture was stirred at 50℃ for 16 h. After the reaction was completed, the mixture was poured into ice/10%K
2CO
3 (600 mL) slowly. Then the mixture was extracted with EA (3 x 240 mL) . The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated in vacuum to give the title product of step 9 (6 g, crude) as a yellow oil.
1H NMR (400 MHz, CDCl
3) 7.81 (s, 1H) , 7.74 (t, J = 7.2 Hz, 2H) , 7.57 (t, J = 8.0 Hz, 1H) , 1.94 (t, J = 18.0 Hz, 3H)
Step 10 3- (1, 1-difluoroethyl) benzaldehyde
3- (1, 1-difluoroethyl) benzonitrile (6 g, 35.92 mmol) was dissolved in toluene (60 mL) under N
2 atmosphere. The reaction was cooled to -78℃, DIBAL-H (1M, 72 mL, 71.83 mmol) was added dropwise to the mixture at -78℃ over 30 minutes. After stirring for another 30 minutes, HOAc (10 mL) was added dropwise at -78℃, followed by H
2O (10 mL) dropwise at -78℃. Then, the mixture was stirred at 25℃ for 16 h. After the reaction was completed, the mixture was extracted with EA (3 x 80 mL) . The organic layer was washed with brine (80 mL) , dried over anhydrous Na
2SO
4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (PE : EA = 50 : 1 to 10 : 1) to give 3- (1, 1-difluoroethyl) benzaldehyde (4.46 g) as a yellow liquid.
1H NMR (400 MHz, CDCl
3) δ 10.06 (s, 1H) , 8.03 (s, 1H) , 7.95 (d, J = 7.6 Hz, 1H) , 7.79 (d, J = 7.8 Hz, 1H) , 7.62 (t, J = 7.7 Hz, 1H) , 1.96 (t, J = 18.2 Hz, 3H) .
Step 11 1- (3- (1, 1-difluoroethyl) phenyl) ethan-1-ol
To a stirred solution of 3- (1, 1-difluoroethyl) benzaldehyde (4.46 g, 26.23 mmol) in THF (60 mL) is added MeMgBr (3M, 9.6 mL, 28.85 mmol) dropwise at -78℃. The mixture is stirred at -78℃ for 2 h. Then, the mixture is stirred at 25℃ for 16 h. After the reaction was completed, saturated NH
4Cl is added to the mixture and the mixture was extracted with EtOAc (80 mL X 2) . The organic layer was washed with brine (80 mL) , dried over anhydrous Na
2SO
4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (PE : EA = 10 : 1) to give 1- (3- (1, 1-difluoroethyl) phenyl) ethan-1-ol (4.48 g) as a yellow liquid.
1H NMR (400 MHz, CDCl
3) δ 7.53 (s, 1H) , 7.42 (dd, J = 7.9, 3.8 Hz, 3H) , 4.94 (q, J = 6.5 Hz, 1H) , 1.99 –1.88 (m, 3H) , 1.52 (d, J = 6.9 Hz, 3H) .
Step 12 1- (3- (1, 1-difluoroethyl) phenyl) ethan-1-one
1- (3- (1, 1-difluoroethyl) phenyl) ethan-1-ol (4.48 g, 24.21 mmol) was dissolved in DCM (60 mL) . Dess-Martin (15.40 g, 36.31 mmol) was added and the mixture was stirred at 25℃ for 2 h. TLC showed the oxidation was completed. The mixture was diluted with EA (420 mL) , washed with saturated Na
2S
2O
3 (10 mL) , saturated NaHCO
3 (20 mL) and brine. Then the organic layer was dried over anhydrous Na
2SO
4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (PE : EA = 10 : 1) to give 1- (3- (1, 1-difluoroethyl) phenyl) ethan-1-one (4.45 g) as a yellow liquid. MS (ES+) : 185.1 [M+1]
+.
Step 13 (R, E) -N- (1- (3- (1, 1-difluoroethyl) phenyl) ethylidene) -2-methylpropane-2-sulfinamide
1- (3- (1, 1-difluoroethyl) phenyl) ethan-1-one (2.00 g, 10.86 mmol) is dissolved in THF (30 mL) . (R) -2-methylpropane-2-sulfinamide (1.97 g, 16.29 mmol) and titanium ethoxide (7.43 g, 32.57 mmol) are added at 25℃. Then, the mixture is heated to 80℃ for 16 h. IPC by TLC. After the reaction was completed, then quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to give the title product of step 13 (3.5 g, crude) as a yellow oil, which was used for the next step directly. MS (ES+) : 288.1 [M+1]
+.
Step 14 (R) -N- ( (R) -1- (3- (1, 1-difluoroethyl) phenyl) ethyl) -2-methylpropane-2-sulfinamide
A solution of (R, E) -N- (1- (3- (1, 1-difluoroethyl) phenyl) ethylidene) -2-methylpropane-2-sulfinamide (3.50 g, 12.18 mmol) is dissolved in DCM (20 mL) and MeOH (20 mL) . Then, the mixture was added with NaBH
4 (0.55g, 14.61 mmol) at 0℃. The mixture is stirred at 25℃ for 6 h. After the reaction was completed, then quenched with H
2O (10 mL) and extracted with DCM (50 mL x 3) . The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (PE : EA = 5 : 1) to give the title product of step 14 (1.36 g ) , two step) as a yellow oil. MS (ES+) : 290.1 [M+1]
+.
1H NMR (400 MHz, CDCl
3) δ 7.48 (s, 1H) , 7.42 (m, 3H) , 4.59 (m, 1H) , 3.43 (s, 1H) , 1.93 (t, J = 18.2 Hz, 3H) , 1.53 (d, J = 6.6 Hz, 3H) , 1.24 (s, 9H) .
Step 15 (R) -1- (3- (1, 1-difluoroethyl) phenyl) ethan-1-amine
A solution of (R) -N- ( (R) -1- (3- (1, 1-difluoroethyl) phenyl) ethyl) -2-methylpropane-2-sulfinamide (1.36 g, 4.71 mmol) in HCl/dioxane (4N HCl) is stirred at 25℃ for 16 h. After the reaction was completed, the reaction was concentrated in vacuum, the precipitate filtered and washed with EA to obtain (R) -1- (3- (1, 1-difluoroethyl) phenyl) ethan-1-amine (1.23 g) as a yellow solid.
1H NMR (400 MHz, CDCl
3) δ 8.69 (s, 2H) , 7.64 (s, 1H) , 7.49 (m, 3H) , 4.42 (s, 1H) , 1.90 (t, J = 18.2 Hz, 3H) , 1.67 (s, 3H) .
Step 16 (R) -4- ( (1- (3- (1, 1-difluoroethyl) phenyl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of 4-hydroxy-N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6 -carboxamide (30.0 mg, 0.10 mmol) in DMSO (2 mL) was added (R) -1- (3- (1, 1-difluoroethyl) phenyl) ethan-1-amine (50.0 mg, 0.25 mmol) , DBU (46.1 mg, 0.3 mmol) and BOP (66.0 mg, 0.15mmol) under N
2. The mixture was stirred at room temperature for 16 h. The reaction mixture was purified by prep-HPLC, eluted with CH
3CN in H
2O (0.1%NH
4OH) from 10%to 90%to give title product of step 16 (3.11 mg) as a white solid. MS (ES+) : 469.4 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) : δ 8.36 (s, 1H) , 8.16 (m, 1H) , 7.64 (m, 1H) , 7.53 (m, 1H) , 7.42 (m, 1H) , 5.. 56 (br, m, 1H) , 3.21 (br, m, 4H) , 3.03 (s, 3H) , 2.86-2.90 (m, 3H) , 2.41 (m, 3H) , 1.71-2.01 (m, 7H) , 154-1.56 (m, 3H) .
EXAEPLE 166
(R) -4- ( (1- (1, 1-difluoro-2, 3-dihydro-1H-inden-4-yl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 4-bromo-2, 3-dihydrospiro [indene-1, 2'- [1, 3] dithiolane]
To a solution of 4-bromo-2, 3-dihydro-1H-inden-1-one (10.00 g, 47.4 mmol) and ethane-1, 2-dithiol (4.47 g, 47.4 mmol) in toluene (100 mL) was added TsOH (1.63 g, 9.48 mmol) at 25 ℃ and the resulting mixture was stirred at 25 ℃ for 16 h. 10%of NaOH (aq) (30 mL) was added. Extracted with EA (30 mL x 3) . The organic layers were combined. Washed with brine (30 mL) , dried over Na
2SO
4 and concentrated in vacuum. The residue was purified by gel chromatography (PE : EA= 100: 1 to 10: 1) to give4-bromo-2, 3-dihydrospiro [indene-1, 2'- [1, 3] dithiolane] (13.1 g) as a yellow solid.
1H NMR (400 MHz, DMSO-d
6) : δ 7.48 (m, 2H) , 7.19-7.23 (m, 1H) , 3.43-3.58 (m, 4H) , 2.89 (m, 2H) , 2.64 (m, 2H) .
Step 2 2, 4-dibromo-1, 1-difluoro-2, 3-dihydro-1H-indene
To a stirred solution of 1, 3-Dibromo-5, 5-dimethy limidazolidine-2, 4-dione (32.0 g, 112 mmol) in DCM(150 mL) was added HF-Py (70%, 32.0 mL) at -70℃. A mixture of 4-bromo-2, 3-dihydrospiro [indene-1, 2'- [1, 3] dithiolane] (8.0 g, 28.0 mmol) in DCM (50.0 mL) was dropwise added. The solution was stirred at -60℃ for 4 h and then stirred at rt for 16 h. The pH was adjusted to 9-10 with 2N NaOH and the DCM layer was washed with NaHSO
3 (50 mL) and brine (50 mL) . Dried over Na
2SO
4 and concentrated in vacuum. The residue was purified by gel chromatography (PE) to give 2, 4-dibromo-1, 1-difluoro-2, 3-dihydro-1H-indene (4.5 g) as a yellow oil.
1H NMR (400 MHz, CDCl
3) : δ 7.65 (m, 1H) , 7.55 (m, 1H) , 7.23-7.30 (m, 1H) , 4.52-4.62 (m, 1H) , 3.58-3.64 (m, 1H) , 3.20-3.26 (m, 1H) .
Step 3 4-bromo-1, 1-difluoro-1H-indene
To a solution of 2, 4-dibromo-1, 1-difluoro-2, 3-dihydro-1H-indene (6.6 g, 21.31 mmol) in DCM (50.0 mL) was added DBU (5.7 g, 31.9 mmol) at 0 ℃. The mixture was stirred at 25℃ for 16 h under N
2. DCM (100 mL) was added and washed with HCl (1N, 50.0 mL) , brine (50 mL) , dried over Na
2SO
4 and concentrated in vacuum. The residue was purified by gel chromatography (PE) to give 4-bromo-1, 1-difluoro-1H-indene (4.3 g) as a yellow oil.
1H NMR (400 MHz, CDCl
3) : δ 7.48 (m, 1H) , 7.39 (m, 1H) , 7.13 (m, 1H) , 6.88 (m, 1H) , 6.23 (m, 1H) .
Step 4 4-bromo-1, 1-difluoro-2, 3-dihydro-1H-indene
To a solution of 4-bromo-1, 1-difluoro-1H-indene (3.8 g, 16.5 mmol) and 2-nitrobenzenesulfonyl chloride (3.7 g, 16.5 mmol) in MeCN (40.0 mL) were slowly added K
3PO
4 (700 mg, 3.3 mmol) and hydrazine hydrate (1.6 g, 33.0 mmol) at 0℃. The resulting solution was stirred at 25℃ for 16 h under N
2. Water (50 mL) and EA (100 mL) were added and the mixture was extracted with EA (50mL X 3) , then EA phase was washed with brine (50 mL) , dried over Na
2SO
4 and concentrated in vacuum. The residue was purified by gel chromatography (PE) to give 4-bromo-1, 1-difluoro-2, 3-dihydro-1H-indene (3.2 g) as a yellow oil.
1H NMR (400 MHz, CDCl
3) : δ 7.60 (m, 1H) , 7.49 (m, 1H) , 7.23 (m, 1H) , 3.00-3.05 (m, 2H) , 2.56-2.66 (m, 2H) .
Step 5 1- (1, 1-difluoro-2, 3-dihydro-1H-inden-4-yl) ethan-1-one
To a stirred solution of 4-bromo-1, 1-difluoro-2, 3-dihydro-1H-indene (3.2 g, 13.8 mmol) in dioxane (35.0 mL) was added tributyl (1-ethoxyvinyl) stannane (6.0 g, 16.5 mmol) and the mixture was purged with N
2 for 15 minutes. Pd (PPh
3)
2Cl
2 (100 mg, 0.14 mmol) was added and the mixture was stirred for 16 h at 100℃ . After the reaction was completed, then quenched with HCl (1N, 50 mL) and extracted with EA (80 mL x 2) . The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated in vacuum. The residue was purified by chromatography (PE : EA = 20 : 1) to give 1- (1, 1-difluoro-2, 3-dihydro-1H-inden-4-yl) ethan-1-one (1.5g) as a yellow oil.
1H NMR (400 MHz, CDCl
3) : δ 7.99 (m, 1H) , 7.74 (m, 1H) , 7.47 (m, 1H) , 3.38-3.43 (m, 2H) , 2.54-2.66 (m, 5H) . Step 6 (R, E) -N- (1- (1, 1-difluoro-2, 3-dihydro-1H-inden-4-yl) ethylidene) -2-methylpropane-2-sulfinamide
Starting with 1- (1, 1-difluoro-2, 3-dihydro-1H-inden-4-yl) ethan-1-one, the title product was prepared by using the same method described in Step 13 of EXAMPLE 88. MS (ES+) : 300.2 [M+1]
+.
Step 7 (R) -N- ( (R) -1- (1, 1-difluoro-2, 3-dihydro-1H-inden-4-yl) ethyl) -2-methylpropane-2-sulfinamide
Starting with the product of step 6, the title product was prepared by using the same method as described in Step 14 of EXAMPLE 165. MS (ES+) : 302.0 [M+1]
+.
Step 8 (R) -1- (1, 1-difluoro-2, 3-dihydro-1H-inden-4-yl) ethan-1-amine
Starting with the product of step 7, the title product of step 8 was prepared by using the same method as described in Step 15 of EXAMPLE 165. MS (ES+) : 198.1 [M+1]
+.
Step 9 (R) -4- ( (1- (1, 1-difluoro-2, 3-dihydro-1H-inden-4-yl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the mixture of (R) -1- (1, 1-difluoro-2, 3-dihydro-1H-inden-4-yl) ethan-1-amine and 4-hydroxy-N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide , the title product was prepared by using the same method as described in Step 16 of EXAMPLE 165. MS (ES+) : 481.3 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) : δ 8.83 (s, 1H) , 8.24 (m, 1H) , 7.60 (m, 1H) , 7.35-7.38 (m, 2H) , 5.. 50 (br, 1H) , 3.47 (br, 4H) , 3.06 (m, 2H) , 3.02 (s, 3H) , 2.86-2.90 (m, 3H) , 2.54-2.68 (m, 2H) , 2.28 (s, 3H) , 1.90 (m, 4H) , 1.51-1.53 (m, 3H) .
EXAMPLE 167
(R) -4- ( (1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 2-fluoro-N-methoxy-N-methyl-3- (trifluoromethyl) benzamide
To a stirred solution of 2-fluoro-3- (trifluoromethyl) benzoic acid (10.0 g, 48.1 mmol) in DMF (100.0 mL) was added hydroxylamine hydrochloride (7.0g, 72.15 mmol) 、DIEA (18.6 g, 144.3 mmol) and HATU (36.6 g, 96.2 mmol) at rt. The mixture was stirred for 5.5 h at rt (35℃) . IPC by LCMS. After the reaction was completed, then quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, the aqueous layer was purified by chromatography silica gel column (PE : EA = 5: 1 to 3 : 1) to give 2-fluoro-N-methoxy-N-methyl-3- (trifluoromethyl) benzamide (9.3 g) as a yellow oil. MS (ES+) : 252.0 [M+1]
+.
Step 2 1- (2-fluoro-3- (trifluoromethyl) phenyl) ethan-1-one
To a stirred solution of 2-fluoro-N-methoxy-N-methyl-3- (trifluoromethyl) benzamide (9.3 g, 37.1 mmol) in THF (100.0 mL) was added MeMgBr (20mL, 60 mmol) at -78℃. The mixture was stirred for 2 h at -78℃, then heated to room temperature under N
2. IPC by LCMS. After 2 h the reaction was completed, then quenched with NH
4Cl (aq) and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, and concentrated in vacuum to give 1- (2-fluoro-3- (trifluoromethyl) phenyl) ethan-1-one (4.86 g) as an colorless oil.
1H NMR (400 MHz, CDCl
3) δ 8.07 (m, 1H) , 7.80 (m, 1H) , 7.37 (m, 1H) , 2.68 (m, 3H) .
Step 3 (R, E) -N- (1- (2-fluoro-3- (trifluoromethyl) phenyl) ethylidene) -2-methylpropane-2-sulfinamide
Starting with 1- (2-fluoro-3- (trifluoromethyl) phenyl) ethan-1-one, the title product of step 3 was prepared by using the same method described in Step 13 of EXAMPLE 165. MS (ES+) : 310.1 [M+1]
+.
Step 4 (R) -N- ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) -2-methylpropane-2-sulfinamide
Starting with the product of step 3, the title product of step 4was prepared by using the same method as described in Step 14 of EXAMPLE 165. MS (ES+) : 312.1 [M+1]
+.
Step 5 (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethan-1-aminium chloride
Starting with the product of step 4, the title product of step 5 was prepared by using the same method as described in Step 15 of EXAMPLE 165. MS (ES+) : 208.0 [M+1]
+.
Step 6 (R) -4- ( (1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the mixture of (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethan-1-aminium chloride and 4-hydroxy-N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide , the title product was prepared by using the same method as described in Step 16 of EXAMPLE 165. MS (ES+) : 491.3 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) : δ 8.40 (s, 1H) , 8.28 (m, 1H) , 7.78 (m, 1H) , 7.65 (m, 1H) , 7.38 (m, 1H) , 5.. 70 (br, 1H) , 3.47 (br, 4H) , 3.03 (s, 3H) , 2.86-2.90 (m, 3H) , 2.25 (m, 3H) , 1.90 (m, 4H) , 1.51-1.55 (m, 3H) .
EXAMPLE 168
(R) -4- ( (1- (3, 3-difluoro-2, 3-dihydrobenzofuran-7-yl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 1- (2-fluoro-3-nitrophenyl) ethan-1-one
Starting with 1-bromo-2-fluoro-3-nitrobenzene, the title product of step 1 was prepared by using the same method as described in Step 5 of EXAMPLE 166.
1H NMR (400 MHz, CDCl
3) δ 8.18 (m, 2H) , 7.40 (t, J = 8.0 Hz, 1H) , 2.72 (d, J = 5.3 Hz, 3H) .
Step 2 1- (3-amino-2-fluorophenyl) ethan-1-one
Fe powder (5.94 g, 106.05 mmol) followed by NH
4Cl (5.62 g, 106.05 mmol) in H
2O (60 mL) were added to a solution of 1- (2-fluoro-3-nitrophenyl) ethan-1-one (3.23 g, 17.67 mmol) at 55℃. The mixture was heated to reflux for 1 h. IPC by TLC (PE : EA = 5 : 1) . After completion, the mixture was filtered through celite. The aqueous layer was extracted with EA (50 mL x 3) and H
2O. The organic layer was washed with brine (50 mL) , dried over anhydrous Na
2SO
4, filtered and concentrated in vacuum to give 1- (3-amino-2-fluorophenyl) ethan-1-one (2.7 g) as a black oil. MS (ES+) : 154.1 [M+1]
+.
Step 3 1- (2-fluoro-3-iodophenyl) ethan-1-one
To a solution of CuI (13.43 g, 70.56 mmol) in CH
3CN (35 mL) was added isopentyl nitrite (8.27 g, 70.56 mmol) at 25℃. The mixture was heated to 65℃ and a solution of 1- (3-amino-2-fluorophenyl) ethan-1-one (5.40 g, 35.28 mmol) in CH
3CN (35 mL) was added dropwise at 65℃ over 1 h. The mixture was stirred at 65℃ for 16 h and then was concentrated in vacuum. The residue was purified by silica gel chromatography (PE) to give 1- (2-fluoro-3-iodophenyl) ethan-1-one (3.7g) as a white solid.
1H NMR (400 MHz, CDCl
3) δ 7.93 (t, J = 5.9 Hz, 1H) , 7.82 (t, J = 6.5 Hz, 1H) , 7.00 (t, J = 7.8 Hz, 1H) , 2.65 (d, J = 5.1 Hz, 3H) .
Step 4 ethyl 2- (3-acetyl-2-fluorophenyl) -2, 2-difluoroacetate
A solution of ethyl 2-bromo-2, 2-difluoroacetate (3.70 g, 18.27 mmol) and CuI (1.10 g, 18.27 mmol) in DMSO (7 mL) was stirred at 25℃ for 30 minutes under N
2 atmosphere. The mixture was added with a solution of 1- (2-fluoro-3-iodophenyl) ethan-1-one (1.93 g, 7.31 mmol) in DMSO (8 mL) dropwise. The mixture was stirred at 25℃ for 48 h under N
2 atmosphere. After the reaction was completed, the mixture was quenched with saturated NH
4Cl and extracted with EA (150 mL x 2) . The organic layer was washed with brine (50 mL x 2) , dried over anhydrous Na
2SO
4, filtered and concentrated in vacuum to give ethyl 2- (3-acetyl-2-fluorophenyl) -2, 2-difluoroacetate (1.9 g) as a yellow oil.
1H NMR (400 MHz, CDCl
3) δ 8.02 (d, J = 6.2 Hz, 1H) , 7.83 (d, J = 6.6 Hz, 1H) , 7.35 (d, J = 7.4 Hz, 1H) , 4.43 –4.33 (m, 2H) , 2.64 (s, 3H) , 1.34 (d, J = 7.1 Hz, 3H) .
Step 5 ethyl (R, E) -2- (3- (1- ( (tert-butylsulfinyl) imino) ethyl) -2-fluorophenyl) -2, 2-difluoroacetate
Starting with ethyl 2- (3-acetyl-2-fluorophenyl) -2, 2-difluoroacetate, the title product of step 5 was prepared by using the same method as described in Step 13 of EXAMPLE 165. MS (ES+) : 364.1 [M+1]
+.
Step 6 (R) -N- ( (R) -1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) -2-methylpropane-2-sulfinamide
A solution of ethyl (R, E) -2- (3- (1- ( (tert-butylsulfinyl) imino) ethyl) -2-fluorophenyl) -2, 2-difluoroacetate (0.93 g, 2.57 mmol) was dissolved in DCM (5 mL) and MeOH (5 mL) . Then, NaBH
4 (0.29g, 7.70 mmol) was added at 0℃. The mixture was stirred at 25℃ for 6 hours. After the reaction was completed, the mixture was quenched with saturated NH
4Cl and extracted with DCM (30 mL x 2) . The organic layer was washed with brine (50 mL) , dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel chromatography (EA) to give the title product of step 6 (0.42 g) as a white solid.
1H NMR (400 MHz, CDCl
3) δ 7.50 (dd, J = 14.3, 7.0 Hz, 1H) , 7.43 (dd, J = 13.9, 6.8 Hz, 1H) , 7.20 (q, J = 7.8 Hz, 1H) , 4.69 (dd, J
1 = 14.5, J
2 = 7.3 Hz, 1H) , 4.03 (s, 2H) , 3.61 (d, J = 7.2 Hz, 2H) , 1.94 (s, 1H) , 1.56 (m, 3H) , 1.19 (s, 9H) .
Step 7 (R) -N- ( (R) -1- (3, 3-difluoro-2, 3-dihydrobenzofuran-7-yl) ethyl) -2-methylpropane-2-sulfinamide
To a stirred solution of (R) -N- ( (R) -1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) -2-methylpropane-2-sulfinamide (0.41 g, 1.26 mmol) in THF (10 mL) were added Cs
2CO
3 (1.23 g, 3.78 mmol) and 18-crown-6 (0.17 g, 0.63 mmol) at 25℃. The resulting mixture was heated to 80℃ for 16 h. IPC by LCMS. After the reaction was completed, the mixture was extracted with EA (30 mL x 2) . The organic layer was washed with brine (30 mL) , dried over anhydrous Na
2SO
4, filtered and concentrated to give the title product (0.38 g) as a yellow oil. MS (ES+) : 304.0 [M+1]
+.
1H NMR (400 MHz, CDCl
3) δ 7.63 –7.51 (m, 1H) , 7.44 (t, J = 7.7 Hz, 1H) , 7.05 (t, J = 7.2 Hz, 1H) , 4.74 –4.59 (m, 2H) , 4.36 –4.19 (m, 1H) , 3.70 (s, 1H) , 1.53 (d, J = 6.7 Hz, 3H) , 1.22 (s, 9H) .
Step 8 (R) -1- (3, 3-difluoro-2, 3-dihydrobenzofuran-7-yl) ethan-1-aminium chloride
Starting with the product of step 4, the title product of step 8 was prepared by using the same method as described in Step 15 of EXAMPLE 165. MS (ES+) : 200.0 [M+1]
+.
Step 9 N, N, 2-trimethyl-7- (pyrrolidin-1-yl) -4- (2, 2, 2-trifluoroethoxy) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of 4-hydroxy-N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine -6-carboxamide (75 mg, 0.25 mmol) and DIEA (97 mg, 0.75 mmol) in MeCN (10 mL) was added POCl
3 at rt, The solution was stirred at 90℃ for 16 h. The mixture was concentrated in vacuum and the residue was added to 2, 2, 2-Trifluoroethanol (5 mL) , and pH = 8 was adjusted with DIPEA. The reaction was stirred at 80℃ for 2 h. The mixture was concentrated in vacuum and purified by gel chromatography silica gel column (DCM : MeOH = 20 : 1) to give the title product (20 mg) as a red oil. MS (ES+) : 384.2 [M+1]
+.
Step 10 (R) -4- ( (1- (3, 3-difluoro-2, 3-dihydrobenzofuran-7-yl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of N, N, 2-trimethyl-7- (pyrrolidin-1-yl) -4- (2, 2, 2-trifluoroethoxy) pyrido [2, 3-d] pyrimidine-6-carboxamide (20.0 mg, 0.052 mmol) and (R) -1- (3, 3-difluoro-2, 3-dihydrobenzofuran-7- yl) ethan-1-amine (51.8 mg, 0.26mmol) in DMSO (2 mL) was added DIEA (100.0 mg, 0.78 mmol) under N
2. The mixture was stirred at 120℃ for 54 h. After completed, the reaction mixture was purified by prep-HPLC, eluted with CH
3CN in H
2O (0.1%NH
4OH) from 10%to 90%, to give the title product of (9.47 mg) as a white solid. MS (ES+) : 483.2 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) : δ 8.45 (s, 1H) , 7.50-7.56 (m, 2H) , 7.10 (m, 1H) , 5.72 (br, 1H) , 4.86 (m, 1H) , 3.50 (br, 4H) , 3.03 (s, 3H) , 2.92 (m, 3H) , 2.33 (m, 3H) , 1.91 (m, 4H) , 1.53-1.55 (m, 3H) .
EXAMPLE 169
(R) -N, N, 2-trimethyl-4- ( (1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 1- (2-methyl-3- (trifluoromethyl) phenyl) ethan-1-ol
Starting with 2-methyl-3- (trifluoromethyl) benzaldehyde, the title product of step 1 was prepared by using the same method as described in Step 11 of EXAMPLE 165.
1H NMR (400 MHz, DMSO-d
6) δ 7.79 (d, J = 7.8 Hz, 1H) , 7.55 (d, J = 7.6 Hz, 1H) , 7.39 (t, J = 7.8 Hz, 1H) , 5.24 (d, J = 4.2 Hz, 1H) , 5.09 –4.99 (m, 1H) , 2.37 (s, 3H) , 1.31 (d, J = 6.4 Hz, 3H) .
Step 2 1- (2-methyl-3- (trifluoromethyl) phenyl) ethan-1-one
Starting with 1- (2-methyl-3- (trifluoromethyl) phenyl) ethan-1-ol, the title product of step 2 was prepared by using the same method as described in Step 12 of EXAMPLE 165. MS (ES+) : 203.0 [M+1]
+.
Step 3 (R, E) -2-methyl-N- (1- (2-methyl-3- (trifluoromethyl) phenyl) ethylidene) propane-2-sulfinamide
Starting with 1- (2-methyl-3- (trifluoromethyl) phenyl) ethan-1-one, the title product of step 3 was prepared by using the same method as described in Step 13 of EXAMPLE 165. MS (ES+) : 306.0 [M+1]
+.
Step 4 (R) -2-methyl-N- ( (R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) propane-2-sulfinamide
Starting with (R, E) -2-methyl-N- (1- (2-methyl-3- (trifluoromethyl) phenyl) ethylidene) propane-2-sulfinamide, the title product of step 4 was prepared by using the same method as described in Step 14 of EXAMPLE 165. MS (ES+) : 308.2 [M+1]
+.
Step 5 (R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethan-1-aminium chloride
Starting with (R) -2-methyl-N- ( (R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) propane-2-sulfinamide, the title product was prepared by using the same method as described in Step 15 of EXAMPLE 165. MS (ES+) : 204.2 [M+1]
+.
Step 6 (R) -N, N, 2-trimethyl-4- ( (1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the mixture of (R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethan-1-aminium chloride and 4-hydroxy-N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide , the title product was prepared by using the same method as described in Step 16 of EXAMPLE 165. MS (ES+) : 487.4 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) : δ 8.39 (s, 1H) , 8.28 (m, 1H) , 7.75 (m, 1H) , 7.53 (m, 1H) , 7.36 (m, 1H) , 5.. 67 (br, 1H) , 3.47 (br, 4H) , 3.03 (s, 3H) , 2.86-2.90 (m, 3H) , 2.60 (s, 3H) , 2.26 (m, 3H) , 1.90 (m, 4H) , 1.22-1.26 (m, 3H) .
EXAMPLE 170
(R) -4- ( (1- (3-cyano-2-methylphenyl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 3-acetyl-2-methylbenzonitrile
Starting with 3-bromo-2-methylbenzonitrile, the title product of step 1 was prepared by using the same method as described in Step 5 of EXAMPLE 89. MS (ES+) : 159.0 [M+1]
+.
Step 2 (R, E) -N- (1- (3-cyano-2-methylphenyl) ethylidene) -2-methylpropane-2-sulfinamide
Starting with 3-acetyl-2-methylbenzonitrile, the title product was prepared by using the same method as described in Step 13 of EXAMPLE 165. MS (ES+) : 262.1 [M+1]
+.
Step 3 (R) -N- ( (R) -1- (3-cyano-2-methylphenyl) ethyl) -2-methylpropane-2-sulfinamide
Starting with (R, E) -N- (1- (3-cyano-2-methylphenyl) ethylidene) -2-methylpropane-2-sulfinamide, the title product was prepared by using the same method as described in Step 14 of EXAMPLE 165. MS (ES+) : 264.1 [M+1]
+.
Step 4 (R) -1- (3-cyano-2-methylphenyl) ethan-1-aminium chloride
Starting with (R) -N- ( (R) -1- (3-cyano-2-methylphenyl) ethyl) -2-methylpropane-2-sulfinamide, the title product was prepared by using the same method as described in Step 15 of EXAMPLE 165. MS (ES+) : 160.1 [M+1]
+.
Step 5 (R) -4- ( (1- (3-cyano-2-methylphenyl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the mixture of (R) -1- (3-cyano-2-methylphenyl) ethan-1-aminium chloride and 4-hydroxy- N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide , the title product was prepared by using the same method as described in Step 16 of EXAMPLE 165. MS (ES+) : 444.4 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) : δ 8.39 (s, 1H) , 8.31 (m, 1H) , 7.75 (m, 1H) , 7.61 (m, 1H) , 7.36 (m, 1H) , 5.. 60 (br, 1H) , 3.47 (br, 4H) , 3.03 (s, 3H) , 2.86-2.90 (m, 3H) , 2.70 (s, 3H) , 2.28 (m, 3H) , 1.90 (m, 4H) , 1.22-1.26 (m, 3H) .
EXAMPLE 171
(R) -4- ( (1- (3-cyano-2-fluorophenyl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 3-acetyl-2-fluorobenzonitrile
To a stirred solution of 1- (2-fluoro-3-iodophenyl) ethan-1-one (500 mg, 1.89 mmol) in NMP (25.0 mL) was added ZnCN (666 mg, 5.67mmol) and the mixture was purged with N
2 for 15 minutes. Pd (PPh)
4 (50 mg, 0.26 mmol) was added and the mixture was stirred for 16 h at 100℃ . After the reaction was completed, then quenched with water and extracted with EA (25.0 mL x 3) . The organic layer was washed with brine (25.0 mL) , dried over anhydrous Na
2SO
4, filtered and concentrated in vacuum. The residue was purified by chromatography (EA : PE = 1 : 100 to 1: 10) to give 270 mg of product as a yellow solid. MS (ES+) : 163.1 [M+1]
+
Step 2 (R, E) -N- (1- (3-cyano-2-fluorophenyl) ethylidene) -2-methylpropane-2-sulfinamide
Starting with 3-acetyl-2-fluorobenzonitrile, the title product was prepared by using the same method as described in Step 13 of EXAMPLE 165. MS (ES+) : 266.3 [M+1]
+.
Step 3 (R) -N- ( (R) -1- (3-cyano-2-fluorophenyl) ethyl) -2-methylpropane-2-sulfinamide
Starting with (R, E) -N- (1- (3-cyano-2-fluorophenyl) ethylidene) -2-methylpropane-2-sulfinamide, the title product was prepared by using the same method as described in Step 14 of EXAMPLE 165. MS (ES+) : 268.3 [M+1]
+.
Step 4 (R) -1- (3-cyano-2-fluorophenyl) ethan-1-aminium chloride
Starting with (R) -N- ( (R) -1- (3-cyano-2-fluorophenyl) ethyl) -2-methylpropane-2-sulfinamide, the title product was prepared by using the same method as described in Step 15 of EXAMPLE 165. MS (ES+) : 164.1 [M+1]
+.
Step 5 (R) -4- ( (1- (3-cyano-2-fluorophenyl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the mixture of (R) -1- (3-cyano-2-fluorophenyl) ethan-1-aminium chloride and 4-hydroxy- N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide, the title product was prepared by using the same method as described in Step 16 of EXAMPLE 165. MS (ES+) : 448.2 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) : δ 8.39 (s, 1H) , 8.29 (m, 1H) , 7.78 (m, 2H) , 7.36 (m, 1H) , 5.. 63 (br, 1H) , 3.47 (br, 4H) , 3.03 (s, 3H) , 2.86-2.90 (m, 3H) , 2.28 (m, 3H) , 1.90 (m, 4H) , 154-1.56 (m, 3H) .
EXAMPLE 172
(R) -4- ( (1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carbonitrile
Step 1 2-amino-6-chloropyridine-3, 5-dicarbonitrile
A stirred solution of malononitrile (42.5 mL, 675.68 mmol ) , triethoxymethane (50 g, 337.84 mmol) and pyridine (27.3 mL, 337.84 mmol) was heated to reflux for 20 min. The reaction mixture was cooled down and treated with con. HCl (400 mL) . Yellow solid was precipitated out during the addition. Then the mixture was stirred at 80℃ for 1 h. The reaction mixture was cooled to rt and the precipitate was collected. The precipitate was collected and washed with H
2O, EtOH and PE. The precipitate was re-dissolved in DMF stirred at 80℃for 30 min and then H
2O was added to the mixture. The precipitate was dried in vacuum to give 2-amino-6-chloropyridine-3, 5-dicarbonitrile (29.7 g) as a yellow solid. MS (ES+) : 179.0 [M+1]
+ , 181.0 [M+1]
+.
Step 2 7-chloro-4-hydroxy-2-methylpyrido [2, 3-d] pyrimidine-6-carbonitrile
A mixture of 2-amino-6-chloropyridine-3, 5-dicarbonitrile (11 g, 61.60 mmol) and Ac
2O (130 mL) was stirred at 140℃ for 12 h. The mixture was diluted with Na
2CO
3 aq and extracted with EA (150 mL x 3) . The combined organic layer was concentrated in vacuum and the residue was purified by chromatography silica gel column (PE : EA = 6 : 1 to 4 : 1) to give 7-chloro-4-hydroxy-2-methylpyrido [2, 3-d] pyrimidine-6-carbonitrile (3.4 g, 15.38 mmol, 25.0%yield) as a yellow solid. MS (ES+) : 221.0 [M+1]
+ , 223.0 [M+1]
+.
Step 3 4-hydroxy-2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carbonitrile
To a stirred solution of 7-chloro-4-hydroxy-2-methylpyrido [2, 3-d] pyrimidine-6-carbonitrile (2.3 g, 10.45 mmol) in dioxane (25 mL) was added pyrrolidine (816 mg, 11.5 mmol) and DIEA (1.621 g, 12.55 mmol) . The mixture was stirred at room temperature for 5 h. The mixture was diluted with H
2O (50 mL) and extracted with EA (50 mL) x 3. The combined organic layer was washed with brine, dried over Na
2SO
4 and concentrated. The residue was purified by chromatography silica gel column to give 4-hydroxy-2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carbonitrile (2.2 g) as a pale yellow solid. MS (ES+) : 256.0 [M+1]
+.
Step 4 (R) -4- ( (1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carbonitrile
To a stirred solution of 4-hydroxy-2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6 -carbonitrile (500 mg, 1.96 mmol) in MeCN (15 mL) was added (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethan-1-amine (450 mg, 2.55 mmol) , DBU (900 mg, 5.88 mmol) and BOP (1.3 g, 2.4 mmol) . The mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water (50 ml) and extracted with EA (50 mL) . The combined organic layer was washed with brine (50 mL) , dried over Na
2SO
4 and concentrated in vacuum. The residue was purified by chromatography silica gel column (PE : EA = 6 : 1 to 1 : 1) to give (R) -4- ( (1- (2-fluoro- 3- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carbonitrile (650 mg) as a yellow solid. MS (ES+) : 445 [M+1]
+.
1H NMR (400 MHz, CDCl
3) : δ 8.66 (s, 1H) , 7.69 (m, 1H) , 7.50 (m, 1H) , 7.19 (m, 1H) , 5.. 79 (br, 1H) , 3.86 (br, 4H) , 2.53 (m, 3H) , 1.75 (m, 4H) , 1.61-1.65 (m, 3H) .
EXAMPLE 173
(R) -N- (1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) -2-methyl-7- (pyrrolidin-1-yl) -6- (1H-tetrazol-5-yl) pyrido [2, 3-d] pyrimidin-4-amine
A mixture of (R) -4- ( (1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carbonitrile (100 mg, 0.23 mmol) , TMSN
3 (777 mg, 6.8 mmol) and dibutylstannanone (672 mg, 2.76 mmol) in dioxane (2 ml) in a sealed tube was stirred at 100℃ for 12 h. The mixture was concentrated in vacuum and by Prep-HPLC, eluted with MeCN in H
2O (01%HCO
2H) from 20%to 95%to give the title product (14 mg) as a white solid. MS (ES+) : 488.0 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) : δ 8.37 (s, 1H) , 8.24 (m, 1H) , 7.75 (m, 1H) , 7.60 (m, 1H) , 7.32 (m, 1H) , 5.. 72 (br, 1H) , 3.16 (br, 4H) , 2.26 (m, 3H) , 1.69 (m, 4H) , 1.51-1.53 (m, 3H) .
EXAMPLE 174
(R) -4- ( (1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of (R) -4- ( (1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carbonitrile (66 mg, 0.113 mmol) in EtOH (1 ml) and H
2O (1 ml) was added KOH (416 mg, 5.65 mmol) . The mixture was stirred at 100℃ for 12 h. The pH of the mixture was adjusted to 4~5. The precipitate was collected by filtration and dried in vacuum to give the title product (20 mg) as a yellow solid. MS (ES+) : 463.0 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) : δ 8.57 (s, 1H) , 8.34 (m, 1H) , 8.01 (s, 1H) , 7.79 (m, 1H) , 7.63 (m, 2H) , 7.34 (m, 1H) , 5.. 73 (br, 1H) , 3.52 (br, 4H) , 2.26 (m, 3H) , 1.89 (m, 4H) , 1.56-1.57 (m, 3H) .
EXAMPLE 175
(R) -2-cyclopropyl-4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N-dimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 methyl 6-chloro-2- (pyrrolidin-1-yl) nicotinate
To a stirred solution of methyl 2, 6-dichloronicotinate (5 g, 24.27 mmol) in dioxane (50 mL) was added pyrrolidine (2.59 g, 36.4 mmol) and DIEA (5.1 mL, 29.12 mmol) . The mixture was stirred at room temperature for 12 h. The solvent was removed under reduced pressure. The residue was diluted with H
2O and extracted with EA. The combined organic layer was washed with brine, dried over Na
2SO
4 and concentrated in vacuum to give methyl 6-chloro-2- (pyrrolidin-1-yl) nicotinate (5.9 g) as a yellow oil. MS (ES+) : 241.0, 243.0 [M+1]
+.
Step 2 methyl 6-chloro-5-iodo-2- (pyrrolidin-1-yl) nicotinate
To a stirred solution of methyl 6-chloro-2- (pyrrolidin-1-yl) nicotinate (5.9 g, 24.6 mmol) in MeCN (60 mL) was added NIS (8.3 g, 36.9 mmol) . The mixture was stirred at room temperature for 12 h. The mixture was diluted with water and extracted with EA (50 mL X 3) . The combined organic layer was washed with 10%of Na
2S
2O
3 (aq. ) (50 mL) and brine (50 mL) , dried over Na
2SO
4 and concentrated in vacuum to give crude product which was purified by silica gel chromatography column (PE: EA=15: 1~EA) to give methyl 6-chloro-5-iodo-2- (pyrrolidin-1-yl) nicotinate (6.5 g) as a white solid. MS (ES+) : 367.0 [M+1]
+, 369.0 [M+1]
+.
Step 3 6-chloro-5-iodo-2- (pyrrolidin-1-yl) nicotinic acid
To a stirred solution of methyl 6-chloro-5-iodo-2- (pyrrolidin-1-yl) nicotinate (4.5 g, 12.3 mmol) in EtOH (25 mL) and H
2O (25 mL) was added NaOH (9.8 g, 246 mmol) . The mixture was stirred at 90℃ for 1 h. The EtOH was removed by concentration. The pH of the mixture was adjusted to 2~3 with HCl. The precipitate was collected by filtration and dried in vacuum to give 6-chloro-5-iodo-2- (pyrrolidin-1-yl) nicotinic acid (4 g, 11.4 mmol, 92.7%yield) as a yellow solid. MS (ES+) : 353.0 [M+1]
+ , 355.0 [M+3]
+
Step 4 6-chloro-5-iodo-N, N-dimethyl-2- (pyrrolidin-1-yl) nicotinamide
To a stirred solution of 6-chloro-5-iodo-2- (pyrrolidin-1-yl) nicotinic acid (4 g, 11.4 mmol) in DMF (40 mL) was added Dimethylamine hydrochloride (1.. 4 g, 17.1 mmol) , HATU (8.6 g, 22.8 mmol) and DIEA (4.4 g, 34.2 mmol) . The mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water and extracted with EA (50 mL X 3) . The combined organic layer was washed with brine (60 mL) , dried over Na
2SO
4 and concentrated in vacuum. The residue was purified by chromatography silica gel column (PE : EA = 5 : 1 to EA) to give 6-chloro-5-iodo-N, N-dimethyl-2- (pyrrolidin-1-yl) nicotinamide (4.3 g) as a pale yellow solid. MS (ES+) : 380.0 [M+1]
+ , 382.0 [M+1]
+.
Step 5 methyl 2-chloro-5- (dimethylcarbamoyl) -6- (pyrrolidin-1-yl) nicotinate
To a solution of 6-chloro-5-iodo-N, N-dimethyl-2- (pyrrolidin-1-yl) nicotinamide (4.3 g, 11.3 mmol) in MeOH (200 mL) was added Xantphos (1.9 g, 3.39 mmol) , TEA (12.6 g, 124.3 mmol) , DMF (5 mL) and Pd (OAc)
2 (760 mg, 3.39 mmol) . The mixture was degassed with CO and stirred in a high pressure reactor. The reactor was filled with CO till the pressure raised to 10MPa. The mixture was stirred at 85 ℃ for 12 h. The mixture was filtered through a pad of Celite. The filtrate was diluted with H
2O (100 mL) and extracted with DCM (200 mL X 3) . The combined organic layer was washed with brine (200 mL) , dried over Na
2SO
4 and concentrated in vacuum. The residue was purified by silica gel column (PE : EA = 6 : 1 to 1 : 1) to give methyl 2-chloro-5- (dimethylcarbamoyl) -6- (pyrrolidin-1-yl) nicotinate (2.2 g) as a brown solid. MS (ES+) : 312.0 [M+1]
+, 314.0 [M+1]
+.
Step 6 methyl 2- ( (tert-butoxycarbonyl) amino) -5- (dimethylcarbamoyl) -6- (pyrrolidin-1-yl) nicotinate
To a stirred solution of methyl 2-chloro-5- (dimethylcarbamoyl) -6- (pyrrolidin-1-yl) nicotinate (500 mg, 1.6 mmol) in dioxane (10 mL) was added tert-Butyl carbamate (940 mg, 8 mmol) , Xantphos (93mg, 0.16 mmol) , Cs
2CO
3 (1.1 g, 3.2 mmol) and Pd
2 (dba)
3 (146.4 mg, 0.16 mmol) . The mixture was degassed with N
2 and stirred at 120 ℃ for 12 h. The mixture was filtered through a pad of Celite. The filtrate was diluted with H
2O and extracted with EA. The combined organic layer was washed with brine, dried over Na
2SO
4 and concentrated in vacuum. The residue was purified by silica gel column (PE : EA = 6 : 1 to EA) to give methyl 2- ( (tert-butoxycarbonyl) amino) -5- (dimethylcarbamoyl) -6- (pyrrolidin-1-yl) nicotinate (300 mg) as a pale yellow solid. MS (ES+) : 393.0 [M+1]
+.
Step 7 2- ( (tert-butoxycarbonyl) amino) -5- (dimethylcarbamoyl) -6- (pyrrolidin-1-yl) nicotinic acid
To a stirred solution of methyl 2- ( (tert-butoxycarbonyl) amino) -5- (dimethylcarbamoyl) -6- (pyrrolidin-1-yl) nicotinate (300 mg, 0.76 mmol) in MeOH (2 mL) and H
2O (2 mL) was added KOH (144 mg, 3.8 mmol) . The mixture was stirred at 50℃ for 2 h. The pH of the mixture was adjusted to 6.0. The mixture was extracted with DCM : MeOH =10 : 1 (60 mL X 3) . The combined organic layer was washed with brine (60 mL) , dried over Na
2SO
4 and concentrated in vacuum to give 2- ( (tert-butoxycarbonyl) amino) -5- (dimethylcarbamoyl) -6- (pyrrolidin-1-yl) nicotinic acid (210 mg) as a yellow solid. MS (ES+) : 379.0 [M+1]
+.
Step 8 2-amino-5- (dimethylcarbamoyl) -6- (pyrrolidin-1-yl) nicotinic acid
2- ( (tert-butoxycarbonyl) amino) -5- (dimethylcarbamoyl) -6- (pyrrolidin-1-yl) nicotinic acid (210 mg, 0.53 mmol) in TFA (1 mL) and DCM (1 mL) was stirred at room temperature for 2 h. The mixture was concentrated in vacuum to give crude 2-amino-5- (dimethylcarbamoyl) -6- (pyrrolidin-1-yl) nicotinic acid (270 mg, crude) which was directly used in the next step. MS (ES+) : 279.0 [M+1]
+.
Step 9 2- (cyclopropanecarboxamido) -5- (dimethylcarbamoyl) -6- (pyrrolidin-1-yl) nicotinic acid
To a stirred solution of 2-amino-5- (dimethylcarbamoyl) -6- (pyrrolidin-1-yl) nicotinic acid (135 mg, 0.49 mmol) in pyridine (2 mL) was added cyclopropanecarbonyl chloride (68 mg. 0.73 mmol) . The mixture was stirred at 60 ℃ for 12 h. The solvent was removed under reduced pressure. The filtrate was diluted with H
2O (50 mL) and extracted with DCM : MeOH=10 : 1 (50 mL X 3) . The combined organic layer was dried over Na
2SO
4 and concentrated in vacuum to give 2- (cyclopropanecarboxamido) -5- (dimethylcarbamoyl) -6- (pyrrolidin-1-yl) nicotinic acid (180 mg, crude) as a yellow oil. MS (ES+) : 347.0 [M+1]
+.
Step 10 2-cyclopropyl-N, N-dimethyl-4-oxo-7- (pyrrolidin-1-yl) -3, 4-dihydropyrido [2, 3-d] pyrimidine-6-carboxamide
A mixture of 2- (cyclopropanecarboxamido) -5- (dimethylcarbamoyl) -6- (pyrrolidin-1-yl) nicotinic acid (180 mg, 0.06 mmol) in formamide (2 mL) was stirred at 180℃ for 1 h. The mixture was diluted with H
2O and extracted with EA (50 mL) and DCM (50 mL X 3) successively. The DCM phase was dried over Na
2SO
4 and concentrated in vacuum to give 2-cyclopropyl-N, N-dimethyl-4-oxo-7- (pyrrolidin-1-yl) -3, 4- dihydropyrido [2, 3-d] pyrimidine-6-carboxamide (150 mg) as a brown solid. MS (ES+) : 328 [M+1]
+.
Step 11 (R) -2-cyclopropyl-4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N-dimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the mixture of (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethan-1-aminium chloride and 2-cyclopropyl-N, N-dimethyl-4-oxo-7- (pyrrolidin-1-yl) -3, 4-dihydropyrido [2, 3-d] pyrimidine-6-carboxamide , the title product was prepared by using the same method described in Step 16 of EXAMPLE 165. MS (ES+) : 499.3 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) : δ 8.37 (s, 1H) , 8.21 (m, 1H) , 7.56 (m, 1H) , 7.48 (m, 1H) , 7.08-7.35 (m, 2H) , 5.55 (br, 1H) , 3.46 (br, 4H) , 3.03 (s, 3H) , 2.89 (m, 3H) , 2.02 (m, 1H) , 1.97 (m, 4H) , 1.51-1.53 (m, 3H) , 0.49-0.99 (m, 4H) .
EXAMPLE 176
(R) -2-cyclopropyl-4- ( (1- (1, 1-difluoro-2, 3-dihydro-1H-inden-4-yl) ethyl) amino) -N, N-dimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the mixture of (R) -1- (1, 1-difluoro-2, 3-dihydro-1H-inden-4-yl) ethan-1-amine and 2-cyclopropyl-N, N-dimethyl-4-oxo-7- (pyrrolidin-1-yl) -3, 4-dihydropyrido [2, 3-d] pyrimidine-6-carboxamide, the title product was prepared by using the same method described in Step 16 of EXAMPLE 165. MS (ES+) : 507.4 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) : δ 8.39 (s, 1H) , 8.21 (m, 1H) , 7.50 (m, 1H) , 7.34-7.40 (m, 2H) , 5.. 31 (br, 1H) , 3.47 (br, 4H) , 3.05 (br, 2H) , 3.03 (s, 3H) , 2.89 (m, 3H) , 2.60-2.67 (m, 2H) , 1.91 (m, 4H) , 1.81 (m, 1H) , 1.49-1.51 (m, 3H) , 0.39-0.99 (m, 4H) .
EXAMPLE 177
(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -6- (1- (difluoromethyl) cyclopropyl) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Step 1 methyl 2- (tributylstannyl) acrylate
To a stirred solution of tributylstannane (10 g, 34.25 mmol) , Bis (triphenylphosphine) palladium (II) chloride (840 mg, 1.20 mmol) in THF (150 mL) was dropwise added ethyl propiolate (5.73 g, 58.47 mmol) at room temperature under Ar. The mixture was stirred overnight at rt. After the reaction was completed, the mixture was concentrated. The residue was purified by silica gel column chromatography (PE) to give 11 g of the title product as yellow oil.
Step 2 (R) -ethyl 2- (2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) acrylate
The mixture of (R) -6-bromo-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine (1 g, 1.91 mmol) , ethyl 2- (tributylstannyl) acrylate (968 mg, 2.48 mmol) , CuI (363 mg, 1.91 mmol) and tetrakis (triphenylphosphine) palladium (331 mg, 0.29 mmol) in THF (20 mL) was stirred overnight at 60℃. After cooling, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (EA: PE=35%) to give 874 mg of the title product as a yellow solid. MS (ES+) : 545.0 [M+1]
+.
Step 3 (R) -ethyl 1- (2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) cyclopropanecarboxylate
To a stirred solution of trimethylsulfoxonium iodide (2.9 g, 13.4 mmol) in THF (36 mL) was added potassium tert-butoxide (1.5 g, 13.4 mmol) at 0℃ under Ar. The mixture was stirred for 1 h at 0 ℃. Then (R) -ethyl2- (2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) acrylate (729 mg, 1.34 mmol) in THF (72 mL) was added at 0 ℃. The mixture was stirred for 0.5 h at 0 ℃. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (5%MeOH: DCM) to give 151 mg of the title product as a yellow solid. MS (ES+) : 559.1 [M+1]
+.
Step 4 (R) - (1- (2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) cyclopropyl) methanol
To a stirred solution of (R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -7-hydrazinyl-N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide (70 mg, 0.12 mmol) in DCM (2.5 mL) was added 1.5 M DIBAL-H (0.5 mL, 0.75 mmol) in DCM (0.5 mL) at -70℃ under Ar. The mixture was stirred for 0.5 h at -70℃. After the reaction was completed, the reaction was quenched with potassium sodium tartrate tetrahydrate. Water and DCM were added and the mixture was stirred for 1 h at rt. The organic layer was separated, washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (5%MeOH: DCM) to give 60 mg of the title product as a yellow solid. MS (ES+) : 517.1 [M+1]
+.
Step 5 (R) -1- (2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) cyclopropanecarbaldehyde
To a stirred solution of (R) - (1- (2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) cyclopropyl) methanol (34 mg, 0.06 mmol) in DCM (1.5 mL) was added Dess-Martin (84 mg, 0.19 mmol) at 0 ℃ under Ar. The mixture was stirred for 1 h at rt. After the reaction was completed, NaHCO
3 (aq. ) was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (5%MeOH: DCM) to give 37 mg of the title product as a yellow solid. MS (ES+) : 515.1 [M+1]
+.
Step 6 (R) -6- (1- (difluoromethyl) cyclopropyl) -2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
The mixture of (R) -1- (2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) cyclopropanecarbaldehyde (37 mg, 0.07 mmol) and DAST (7 mL) in DCM (7 mL) was stirred for 16 h at 60℃ in an autoclave. After the reaction was completed, the mixture was dropped into ice-water and extracted with DCM. The organic layer was washed with NaHCO
3 (aq. ) , dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (5%MeOH: DCM) to give 41 mg of crude product as a yellow solid. MS (ES+) : 537.1 [M+1]
+.
Step 7 (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -6- (1- (difluoromethyl) cyclopropyl) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of Step 6, the title product was prepared by using the same method described in Step 2 of EXAMPLE 83. MS (ES+) : 507.1 [M+1]
+.
1H NMR (400 MHz, Chloroform-d) δ 8.63 (s, 1H) , 8.30 (bs, 1H) , 7.12 (s, 1H) , 7.05 (s, 1H) , 6.72 (s, 1H) , 5.97 (t, J = 58.0 Hz, 1H) , 5.60 (t, J = 7.2 Hz, 1H) , 3.67 (m, 4H) , 2.61 (s, 3H) , 1.73 (m, 4H) , 1.66 (d, J = 7.0 Hz, 3H) .
EXAMPLE178
7- ( ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -5-cyclopropyl-9-methyl-1, 2, 3, 3a-tetrahydropyrrolo [1”, 2”: 4', 5'] pyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-4 (5H) -one
Step 1 tert-butyl 2- (cyclopropylcarbamoyl) pyrrolidine-1-carboxylate
Starting with 1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid , the title product was prepared by using the same method as described in Step 1 of EXAMPLE 163. MS (ES+) : 199.0 [M-55]
+.
Step 2 N-cyclopropylpyrrolidine-2-carboxamide hydrochloride
Starting with the product of Step 1 , the title product was prepared by using the same method described in Step 2 of EXAMPLE 163. MS (ES+) : 155.1 [M+1]
+.
Step 3 1- (6-bromo-2-methyl-4- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidin-7-yl) -N-cyclopropylpyrrolidine-2-carboxamide
Starting with the product of Step 2 and (R) -6-bromo-7-chloro-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phen-yl) ethyl) pyrido [2, 3-d] pyrimidin-4-amine, the title product was prepared by using the same method as described in Step 3 of EXAMPLE 163. MS (ES+) : 608.0 [M+1]
+.
Step 4 5-cyclopropyl-9-methyl-7- ( ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -1, 2, 3, 3a-tetrahydropyrrolo [1”, 2”: 4', 5'] pyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-4 (5H) -one
Starting with the product of Step 3 the title product was prepared by using the same method described in Step 4 of EXAMPLE 163. MS (ES+) : 528.1 [M+1]
+.
Step 5 7- ( ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -5-cyclopropyl-9-methyl-1, 2, 3, 3a-tetrahydropyrrolo [1”, 2”: 4', 5'] pyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-4 (5H) -one
Starting with the product of Step 3, the title product was prepared by using the same method as described in Step 5 of EXAMPLE 163. MS (ES+) : 498.1 [M+1]
+.
EXAMPLE 179
N- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -9-methyl-5- (tetrahydrofuran-3-yl) -1, 2, 3, 3a, 4, 5-hexahydropyrrolo [1”, 2”: 4', 5'] pyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-7-amine
Step 1 7- ( ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -9-methyl-5- (tetrahydrofuran-3-yl) -1, 2, 3, 3a, 4, 5-hexahydropyrrolo [1”, 2”: 4', 5'] pyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-4-ol
To a stirred solution of 7- ( ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -9-methyl-5- (tetrahydrofuran-3-yl) -1, 2, 3, 3a-tetrahydropyrrolo [1”, 2”: 4', 5'] pyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-4 (5H) -one (43 mg, 0.08 mmol) in THF (2 mL) was added LiAlH
4 (107.5 mg) at 0℃ under Ar. The mixture was stirred for 0.5 h at 0℃. After the reaction was completed, the reaction was quenched with Na
2SO
4.10H
2O. Anhydrous Na
2SO
4 was added and stirred for 0.5 h, filtered and concentrated to give 34 mg of crude product as a yellow solid. MS (ES+) : 530.0 [M+1]
+.
Step 2 N- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -9-methyl-5- (tetrahydrofuran-3-yl) -1, 2, 3, 3a, 4, 5-hexahydropyrrolo [1”, 2”: 4', 5'] pyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-7-amine
The mixture of 7- ( ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -9-methyl-5- (tetrahydrofuran-3-yl) -1, 2, 3, 3a, 4, 5-hexahydropyrrolo [1”, 2”: 4', 5'] pyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-4-ol (40 mg, 0.075 mmol) in triethylsilane: TFA: DCM (1: 1: 5, 4 mL) was stirred for 2 h at rt under Ar. After the reaction was completed, the mixture was diluted with DCM, washed with NaHCO
3 (aq. ) , dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (10%MeOH: DCM) to give 9 mg of the title product as a yellow solid. MS (ES+) : 514.1 [M+1]
+.
EXAMPLE 180
N- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -9-methyl-5- (tetrahydrofuran-3-yl) -1, 2, 3, 3a, 4, 5-hexahydropyrrolo [1”, 2”: 4', 5'] pyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-7-amine
Step 1 7- ( ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -9-methyl-5- (tetrahydrofuran-3-yl) -1, 2, 3, 3a, 4, 5-hexahydropyrrolo [1”, 2”: 4', 5'] pyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-4-ol
Starting with 7- ( ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -9-methyl-5- (tetrahydrofuran-3-yl) -1, 2, 3, 3a-tetrahydropyrrolo [1”, 2”: 4', 5'] pyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-4 (5H) -one, the title product was prepared by using the same method as described in Step 5 of EXAMPLE 179. MS (ES+) : 530.0 [M+1]
+.
Step 2 N- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -9-methyl-5- (tetrahydrofuran-3-yl) -1, 2, 3, 3a, 4, 5-hexahydropyrrolo [1”, 2”: 4', 5'] pyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-7-amine
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 5 of EXAMPLE 179. MS (ES+) : 514.1 [M+1]
+.
EXAMPLE 181
7- ( ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -5-isopropyl-9-methyl-1, 2, 3, 3a-tetrahydropyrrolo [1”, 2”: 4', 5'] pyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-4 (5H) -one
Step 1 tert-butyl 2- (isopropylcarbamoyl) pyrrolidine-1-carboxylate
Starting with 1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid and propan-2-amine, the title product was prepared by using the same method as described in Step 1 of EXAMPLE 163. MS (ES+) : 201.1 [M-55]
+. Step 2 N-isopropylpyrrolidine-2-carboxamide hydrochloride
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 163. MS (ES+) : 157.1 [M+1]
+.
Step 3 N-isopropyl-1- (2-methyl-4- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidin-7-yl) pyrrolidine-2-carboxamide
Starting with the product of Step 2 and (R) -6-bromo-7-chloro-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) pyrido [2, 3-d] pyrimidin-4-amine, the title product was prepared by using the same method as described in Step 3 of EXAMPLE 163. MS (ES+) : 610.0 [M+1]
+.
Step 4 5-isopropyl-9-methyl-7- ( ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -1, 2, 3, 3a-tetrahydropyrrolo [1”, 2”: 4', 5'] pyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-4 (5H) -one
Starting with the product of Step 3 , the title product was prepared by using the same method as described in Step 4 of EXAMPLE 163. MS (ES+) : 530.1 [M+1]
+.
Step 5 7- ( ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -5-isopropyl-9-methyl-1, 2, 3, 3a-tetrahydropyrrolo [1”, 2”: 4', 5'] pyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-4 (5H) -one
Starting with the product of Step 4 , the title product was prepared by using the same method as described in Step 5 of EXAMPLE 163. MS (ES+) : 500.1 [M+1]
+.
EXAMPLE 182
(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (2-methyl-2H-tetrazol-5-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Step 1 ethyl 2- (2-methyl-2H-tetrazol-5-yl) acetate
To a stirred solution of ethyl2- (2H-tetrazol-5-yl) acetate (1 g, 6.41 mmol) in DMF (20 mL) were added triethylamine (0.97 g, 9.62 mmol) and CH
3I (1.1 g, 7.69 mmol) at rt. The mixture was stirred for 3 h at rt. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (PE: EA=1: 2) to give 320 mg of the title product as yellow oil. MS (ES+) : 171.0 [M+1]
+.
Step 2 (R) -2-methyl-6- (2-methyl-2H-tetrazol-5-yl) -4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidin-7 (8H) -one
To a stirred solution of (R) -4-amino-2-methyl-6- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrimidine-5-carbaldehyde (150 mg, 0.41 mmol) in C
2H
5OH (3.0 mL) were added ethyl 2- (2-methyl-2H-tetrazol-5-yl) acetate (210 mg, 1.22 mmol) and piperidine (104 mg, 1.22 mmol) at rt. The mixture was stirred overnight at 80℃ under Ar. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (PE: EA=1: 2) to give 110 mg of the title product as a yellow solid. MS (ES+) : 476.1 [M+1]
+.
Step 3 (R) -7-chloro-2-methyl-6- (2-methyl-2H-tetrazol-5-yl) -N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of Step 2 and phenylphosphonic dichloride, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 87. MS (ES+) : 494.0 [M+1]
+.
Step 4 (R) -2-methyl-6- (2-methyl-2H-tetrazol-5-yl) -N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of Step 3 and pyrrolidine , the title product was prepared by using the same method described in EXAMPLE 51. MS (ES+) : 529.1 [M+1]
+.
Step 5 (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (2-methyl-2H-tetrazol-5-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of Step 4, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 499.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.82 (d, J = 7.8 Hz, 1H) , 8.75 (s, 1H) , 6.84 (m, 2H) , 6.71 (s, 1H) , 5.51 (m, 3H) , 4.47 (s, 3H) , 3.16 (m, 4H) , 2.41 (s, 3H) , 1.79 (m, 4H) , 1.51 (d, J = 7.0 Hz, 3H) .
EXAMPLE 183
(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (1-methyl-1H-tetrazol-5-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Step 1ethyl 2- (1-methyl-1H-tetrazol-5-yl) acetate
Starting with ethyl 2- (2H-tetrazol-5-yl) acetate and CH
3I, the title product was prepared by using the same method as described in Step 1 of EXAMPLE 182. MS (ES+) : 171.0 [M+1]
+.
Step 2 (R) -2-methyl-6- (1-methyl-1H-tetrazol-5-yl) -4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidin-7 (8H) -one
Starting with the product of step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 182. MS (ES+) : 476.1 [M+1]
+.
Step 3 (R) -7-chloro-2-methyl-6- (1-methyl-1H-tetrazol-5-yl) -N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of step 2, the title product was prepared by using the same method as described in Step 3 of EXAMPLE 182. MS (ES+) : 494.0 [M+1]
+.
Step 4 (R) -2-methyl-6- (1-methyl-1H-tetrazol-5-yl) -N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of step 3, the title product was prepared by using the same method as described in Step 4 of EXAMPLE 182. MS (ES+) : 529.1 [M+1]
+.
Step 5 (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (1-methyl-1H-tetrazol-5-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of Step 4 , the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 499.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.73 (s, 1H) , 8.65 –8.55 (m, 1H) , 6.86 (s, 1H) , 6.83 (s, 1H) , 6.70 (s, 1H) , 5.51 (m, 3H) , 4.02 (s, 3H) , 3.07 (m, 4H) , 2.41 (s, 3H) , 1.79 (m, 4H) , 1.51 (d, J = 7.1 Hz, 3H) .
EXAMPLE 184
4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- ( (R) -2-carbamoylazetidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step1 (R) -azetidine-2-carboxamide hydrochloride
The mixture of (R) -tert-butyl2-carbamoylazetidine-1-carboxylate (220 mg, 1.10 mmol) in 2NHCl/1, 4-Dioxane (11 mL) was stirred at room temperature for 1 h. After the reaction was completed, the mixture was concentrated to obtain 248 mg of the title product as a white solid. MS (ES+) : 101.1 [M+1]
+.
Step 2 7- ( (R) -2-carbamoylazetidin-1-yl) -N, N, 2-trimethyl-4- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
The mixture of (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide (176 mg, 0.37 mmol) , (R) -azetidine-2-carboxamide hydrochloride (248 mg, 1.82 mmol) and DIEA (939 mg, 7.28 mmol) in 1, 4-Dioxane (11 mL) was stirred at 60℃ overnight. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (MeOH/DCM=5%) to give 116 mg of the title product as a yellow solid. MS (ES+) : 547.1 [M+1]
+.
Step 3 4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- ( (R) -2-carbamoylazetidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 2, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 517.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.63 –8.26 (m, 2H) , 7.58 –7.44 (m, 1H) , 7.18 (s, 1H) , 6.86 (s, 1H) , 6.82 (s, 1H) , 6.71 (s, 1H) , 5.66 –5.39 (m, 3H) , 4.80 (m, 1H) , 4.11 –3.79 (m, 2H) , 3.00 (s, 3H) , 2.90 (s, 3H) , 2.55 (s, 1H) , 2.36 (s, 3H) , 2.21 (m, 1H) , 1.50 (d, J = 7.0 Hz, 3H) .
EXAMPLE 185
4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- ( (S) -2-carbamoylazetidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step1 (S) -azetidine-2-carboxamide hydrochloride
The mixture of (S) -tert-butyl 2-carbamoylazetidine-1-carboxylate (120 mg, 0.60 mmol) in 2NHCl/1, 4-Dioxane (6 mL) was stirred at room temperature for 1 h. After the reaction was completed, the mixture was concentrated to obtain 136 mg of the title product as a white solid. MS (ES+) : 101.1 [M+1]
+.
Step 2 7- ( (S) -2-carbamoylazetidin-1-yl) -N, N, 2-trimethyl-4- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1, the title product was prepared by using the same methodas described in Step 2 of EXAMPLE 184. MS (ES+) : 547.1 [M+1]
+.
Step 3 4- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- ( (S) -2-carbamoylazetidin-1-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 2, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 517.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.44 (m, 1H) , 8.18 (s, 1H) , 7.52 (m, 1H) , 7.15 (s, 1H) , 6.85 (s, 1H) , 6.81 (s, 1H) , 6.69 (s, 1H) , 5.53 (s, 2H) , 5.46 (t, J = 7.3 Hz, 1H) , 4.79 (m, 1H) , 3.86 (m, 2H) , 2.99 (s, 3H) , 2.91 (s, 3H) , 2.34 (m, 4H) , 1.49 (d, J = 7.1 Hz, 3H) .
EXAMPLE 186
(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-7- (pyrrolidin-1-yl) -6- (trifluoromethylsulfonyl) pyrido [2, 3-d] pyrimidin-4-amine
Step 1 (R) -2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -6- (trifluoromethylsulfonyl) pyrido [2, 3-d] pyrimidin-7 (8H) -one
To a stirred solution of (R) -4-amino-2-methyl-6- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrimidine-5-carbaldehyde (160 mg, 0.43 mmol) in MeOH (4 mL) were added methyl 2- (trifluoromethylsulfonyl) acetate (310 mg, 1.51 mmol) and piperidine (200 mg, 1.51 mmol) at rt. The resulting mixture was stirred at 60℃ for 16 h. After the reaction was completed, the reaction was quenched water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (PE/EA=1/1) to obtain 60 mg of pure product as a yellow solid. MS (ES+) : 526.1 [M+1]
+.
Step 2 (R) -7-chloro-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -6- (trifluoromethylsulfonyl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of Step 1, the title product was prepared by using the same method as described in Step 1 of EXAMPLE 6. MS (ES+) : 544.1 [M+1]
+.
Step 3 (R) -2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) -6- (trifluoromethylsulfonyl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of Step 2 and pyrrolidine, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 579.1 [M+1]
+.
Step 4 (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-7- (pyrrolidin-1-yl) -6- (trifluoromethylsulfonyl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of Step 3, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 549.0 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 9.30 (s, 1H) , 9.15 (d, J = 7.9 Hz, 1H) , 6.84 (s, 1H) , 6.82 (s, 1H) , 6.72 (s, 1H) , 5.54 (m, 3H) , 3.66 (m, 4H) , 2.38 (s, 3H) , 1.92 –1.83 (m, 4H) , 1.53 (d, J = 7.0 Hz, 3H) .
EXAMPLE 187
(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -6- (diethylphosphoryl) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Step 1 (R) -6- (diethylphosphoryl) -2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with diethylphosphine oxide and (R) -6-bromo-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine, the title product was prepared by using the same method as described in Step 1 of EXAMPLE 161. MS (ES+) : 551.0 [M+1]
+.
Step 2 (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -6- (diethylphosphoryl) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 521.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.69 –8.51 (m, 2H) , 6.83 (d, J = 6.9 Hz, 2H) , 6.72 (s, 1H) , 5.57 (m, 3H) , 3.72 (m, 4H) , 2.36 (s, 3H) , 2.24 –1.99 (m, 4H) , 1.87 (m, 4H) , 1.55 (d, J = 7.1 Hz, 3H) , 0.98 (m, 6H) .
EXAMPLE 188
(R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-sulfonamide
Step 1 (R) -2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-sulfonyl chloride
To a stirred solution of (R) -6- (benzylthio) -2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine (210 mg, 0.370mmol) in AcOH/H
2O (3: 1, 8.4 mL) was added NCS (148 mg, 1.11 mmol) at rt. The mixture was stirred at rt for 8 h. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with water, brine, dried over anhydrous Na
2SO
4, filtered and concentrated to obtain 442 mg of crude product as yellow oil. MS (ES+) : 544.9 [M+1]
+.
Step 2 (R) -2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-sulfonamide
The mixture of (R) -2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-sulfonyl chloride (442 mg, 0.81 mmol) in NH
3/THF (8 mL, 1 mol/L) was stirred at room temperature for 1 h. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with water, brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (MeOH/DCM=5%) to give 32 mg of the title product as a yellow solid. MS (ES+) : 526.4 [M+1]
+.
Step 3 (R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-sulfonamide
Starting with the product of step 2, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 496.0 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 9.15 (s, 1H) , 8.63 (s, 1H) , 7.47 (m, 2H) , 6.87 (s, 1H) , 6.83 (s, 1H) , 6.71 (s, 1H) , 5.52 (m, 3H) , 3.77 (m, 4H) , 2.37 (s, 3H) , 1.89 (m, 4H) , 1.53 (d, J = 7.1 Hz, 3H) .
EXAMPLE 189
(R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-sulfonamide
Step 1 (R) -6- (benzylthio) -2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
The mixture of (R) -6-bromo-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine (910 mg, 1.74 mmol) , phenylmethanethiol (1.82 g, 14.6 mmol) , DIEA (3.64 g, 28.2 mmol) , Xant-phos (910 mg, 1.57 mmol) and Pd
2 (dba)
3 (910 mg, 0.99 mmol) in 1, 4-Dioxane (182 mL) was stirred at 90℃ for 4 h. After the reaction was completed, water was added and extracted with EA. The organic layer was dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (MeOH: DCM=5%) to give 724 mg of the title product as a yellow solid. MS (ES+) : 569.0 [M+1]
+.
Step 2 (R) -N, 2-dimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-sulfonamide
To a stirred solution of (R) -6- (benzylthio) -2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine (50 mg, 0.09 mmol) in AcOH/H
2O (3: 1, 2 mL) was added NCS (35 mg, 0.26 mmol) at room temperature. The mixture was stirred at room temperature overnight. After the reaction was completed, the reaction was dropwise added to CH
3NH
2
. H
2O/THF (1: 2, 12 mL) . After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (MeOH/DCM=5%) to give 34 mg of the title product as a yellow solid. MS (ES+) : 540.0 [M+1]
+.
Step 3 (R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -N, 2-dimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-sulfonamide
Starting with the product of step 2, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 510.0 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.98 (s, 1H) , 8.66 (s, 1H) , 7.48 (d, J = 5.3 Hz, 1H) , 6.87 (s, 1H) , 6.83 (s, 1H) , 6.71 (s, 1H) , 5.64 –5.45 (m, 3H) , 3.73 (d, J = 6.3 Hz, 4H) , 2.36 (s, 3H) , 1.93 –1.83 (m, 4H) , 1.54 (d, J = 7.1 Hz, 3H) .
EXAMPLE 190
(R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (benzyl (methyl) amino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -7- (benzyl (methyl) amino) -N, N, 2-trimethyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with (R) -7-chloro-N, N, 2-trimethyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxamide and N-methyl-1-phenylmethanamine, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 568.1 [M+1]
+.
Step 2 (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (benzyl (methyl) amino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 538.2 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.49 (m, 2H) , 7.27 (m, 5H) , 6.85 (m, 2H) , 6.71 (s, 1H) , 5.51 (m, 3H) , 4.91 (m, 2H) , 2.94 (d, J = 4.3 Hz, 6H) , 2.84 (s, 3H) , 2.36 (s, 3H) , 1.51 (d, J = 7.0 Hz, 3H) .
EXAMPLE 191
(R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (cyclopentyl (methyl) amino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -7- (cyclopentyl (methyl) amino) -N, N, 2-trimethyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with (R) -7-chloro-N, N, 2-trimethyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxamide and N-methylcyclopentanamine, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 546.1 [M+1]
+.
Step 2 (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (cyclopentyl (methyl) amino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 516.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.44 (m, 2H) , 6.84 (m, 2H) , 6.70 (s, 1H) , 5.61 –5.30 (m, 3H) , 4.77 (p, J = 8.3 Hz, 1H) , 3.02 (s, 3H) , 2.84 (s, 3H) , 2.80 (s, 3H) , 2.36 (s, 3H) , 1.82 –1.46 (m, 11H) .
EXAMPLE 192
(R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (cyclopropyl (methyl) amino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -7- (cyclopropyl (methyl) amino) -N, N, 2-trimethyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with (R) -7-chloro-N, N, 2-trimethyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxamide and N-methylcyclopropanamine, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 518.1 [M+1]
+.
Step 2 (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (cyclopropyl (methyl) amino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 488.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.67 (s, 1H) , 8.56 (d, J = 3.8 Hz, 1H) , 6.93 –6.78 (m, 2H) , 6.71 (s, 1H) , 5.54 (m, 3H) , 3.15 (s, 3H) , 3.01 (s, 3H) , 2.96 (d, J = 7.7 Hz, 3H) , 2.86 –2.76 (m, 1H) , 2.39 (s, 3H) , 1.53 (d, J = 7.0 Hz, 3H) , 0.84 –0.52 (m, 4H) .
EXAMPLE 193
(R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -N, N, 2-trimethyl-7- (3- (trifluoromethyl) -5, 6-dihydro- [1, 2, 4] triazolo [4, 3-a] pyrazin-7 (8H) -yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -N, N, 2-trimethyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (3- (trifluoromethyl) -5, 6-dihydro- [1, 2, 4] triazolo [4, 3-a] pyrazin-7 (8H) -yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with (R) -7-chloro-N, N, 2-trimethyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxamide and 3- (trifluoromethyl) -5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [4, 3-a] pyrazine hydrochloride, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 639.0 [M+1]
+.
Step 2 (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -N, N, 2-trimethyl-7- (3- (trifluoromethyl) -5, 6-dihydro- [1, 2, 4] triazolo [4, 3-a] pyrazin-7 (8H) -yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 609.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.63 (s, 1H) , 8.41 (d, J = 7.9 Hz, 1H) , 6.86 (s, 1H) , 6.83 (s, 1H) , 6.70 (s, 1H) , 5.55 (s, 2H) , 5.49 (t, J = 7.3 Hz, 1H) , 4.92 (s, 2H) , 4.26 (t, J = 5.3 Hz, 2H) , 4.03 (d, J = 6.9 Hz, 2H) , 3.08 (s, 3H) , 2.92 (s, 3H) , 2.38 (s, 3H) , 1.51 (d, J = 7.0 Hz, 3H) .
EXAMPLE 194
(R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-N, N-bis (methyl-d3) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -2-methyl-N, N-bis (methyl-d3) -4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with (R) -2-methyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxylic acid and bis (methyl-d
3) amine hydrochloride , the title product was prepared by using the same method as described in Step 5 of EXAMPLE 80. MS (ES+) : 524.1 [M+1]
+.
Step 2 (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-N, N-bis (methyl-d3) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 494.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.40 (d, J = 6.4 Hz, 1H) , 8.34 (s, 1H) , 6.84 (t, J = 12.2 Hz, 2H) , 6.70 (s, 1H) , 5.55 (s, 2H) , 5.47 (q, J = 7.3 Hz, 1H) , 2.36 (d, J = 3.4 Hz, 3H) , 1.91 (m, 4H) , 1.50 (d, J = 7.1 Hz, 3H) .
EXAMPLE 195
(R) - (4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) (azetidin-1-yl) methanone
Step 1 (R) -azetidin-1-yl (2-methyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) methanone
Starting with (R) -2-methyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxylic acid and azetidine, the title product was prepared by using the same method as described in Step 5 of EXAMPLE 80. MS (ES+) : 530.1 [M+1]
+.
Step 2 (R) - (4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) (azetidin-1-yl) methanone
Starting with the product of step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 500.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.79 (d, J = 7.6 Hz, 1H) , 8.54 (s, 1H) , 6.86 (s, 1H) , 6.83 (s, 1H) , 6.72 (s, 1H) , 5.55 (m, 3H) , 4.06 (t, J = 7.8 Hz, 4H) , 2.40 (s, 3H) , 2.28 (m, 2H) , 1.93 (m, 4H) , 1.54 (d, J = 7.0 Hz, 3H) .
EXAMPLE 196
(R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -N-ethyl-N, 2-dimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -N-ethyl-N, 2-dimethyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with (R) -2-methyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxylic acid and N-methylethanamine, the title product was prepared by using the same method as described in Step 5 of EXAMPLE 80. MS (ES+) : 532.1 [M+1]
+.
Step 2 (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -N-ethyl-N, 2-dimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 502.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.41 –8.27 (m, 1H) , 8.22 (d, J = 7.6 Hz, 1H) , 6.89 –6.76 (m, 2H) , 6.69 (s, 1H) , 5.54 (s, 2H) , 5.47 (m, 1H) , 3.54 (m, 4H) , 3.04 –2.82 (m, 3H) , 2.34 (d, J = 3.8 Hz, 3H) , 1.90 (m, 4H) , 1.49 (t, J = 6.6 Hz, 3H) , 1.19 –0.96 (m, 3H) .
EXAMPLE 197
(R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -N, N-diethyl-2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -N, N-diethyl-2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with (R) -2-methyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxylic acid and diethylamine, the title product was prepared by using the same method as described in Step 5 of EXAMPLE 80. MS (ES+) : 546.1 [M+1]
+.
Step 2 (R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -N, N-diethyl-2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 516.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.84 (s, 1H) , 8.45 (d, J = 1.6 Hz, 1H) , 6.90 –6.78 (m, 2H) , 6.71 (s, 1H) , 5.74 –5.25 (m, 3H) , 3.60 (m, 4H) , 3.19 (m, 4H) , 2.41 (d, J = 3.9 Hz, 3H) , 1.97 –1.86 (m, 4H) , 1.53 (dd, J = 7.1, 2.1 Hz, 3H) , 1.19 –1.12 (m, 3H) , 1.05 (m, 3H) .
EXAMPLE 198
(R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -N-isopropyl-N, 2-dimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -N-isopropyl-N, 2-dimethyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with (R) -2-methyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxylic acid and N-methylpropan-2-amine, the title product was prepared by using the same method as described in Step 5 of EXAMPLE 80. MS (ES+) : 546.1 [M+1]
+.
Step 2 (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -N-isopropyl-N, 2-dimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 516.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.80 (m, 1H) , 8.50 –8.39 (m, 1H) , 6.92 –6.74 (m, 2H) , 6.71 (d, J = 5.1 Hz, 1H) , 5.56 –5.46 (m, 3H) , 4.82 –3.67 (m, 1H) , 3.59 –3.51 (m, 4H) , 2.92 –2.76 (m, 3H) , 2.41 (t, J = 4.4 Hz, 3H) , 1.92 (m, 4H) , 1.61 –1.47 (m, 3H) , 1.11 (m, 6H) .
EXAMPLE 199
(R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-N- (methylsulfonyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -2-methyl-N- (methylsulfonyl) -4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of (R) -2-methyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxylic acid (110 mg, 0.22 mmol) in DCM (2.0 mL) were added methanesulfonamide (210 mg, 2.20 mmol) , DMAP (134 mg, 1.10 mmol) and EDCI HCl (210 mg, 1.10 mmol) at rt. The mixture was stirred overnight at 35℃. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-HPLC (Column: Green ODS-A, 21.2*250mm, 10um; Mobile A: water with 0.05%TFA, Mobile B: CH
3CN; Gradient: 40%B over 2 min, 55%B over 15 min; Flow: 35 mL/min) to give 32 mg of the title product as a white solid. MS (ES+) : 568.0 [M+1]
+.
Step 2 (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-N- (methylsulfonyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 538.0 [M+1]
+.
1H NMR (400 MHz, Methanol-d
4) δ 8.51 (s, 1H) , 6.93 (d, J = 2.0 Hz, 2H) , 6.81 (s, 1H) , 5.66 (q, J = 7.0 Hz, 1H) , 3.70 (m, 4H) , 3.14 (s, 3H) , 2.53 (s, 3H) , 2.05 –1.88 (m, 4H) , 1.64 (d, J = 7.0 Hz, 3H) .
EXAMPLE 200
(R) -N- ( (4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3- d] pyrimidin-6-yl) sulfonyl) acetamide
Step 1 (R) -N- ( (2-methyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) sulfonyl) acetamide
To a stirred solution of (R) -N- ( (2-methyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) sulfonyl) acetamide (35 mg, 0.07 mmol) in acetic anhydride (3.5 mL) was added ZnCl
2 (4 mg, 0.03 mmol) at rt. The mixture was stirred for 2 h at 75℃ under Ar. After the reaction was completed, the mixture was concentrated to give 25 mg of crude product as yellow oil which was used in the next step without further purification. MS (ES+) : 568.0 [M+1]
+.
Step 2 (R) -N- ( (4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) sulfonyl) acetamide
Starting with the product of step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 538.0 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.90 (s, 1H) , 8.52 (d, J = 8.1 Hz, 1H) , 6.89 (s, 1H) , 6.82 (s, 1H) , 6.67 (s, 1H) , 5.58 –5.40 (m, 3H) , 3.86 (m, 4H) , 2.31 (s, 3H) , 1.83 (m, 4H) , 1.50 (d, J = 7.1 Hz, 3H) .
EXAMPLE 201
(R) - (4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) (pyrrolidin-1-yl) methanone
Step 1 (R) - (2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) (pyrrolidin-1-yl) methanone
Starting with (R) -2-methyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxylic acid and N-methylpropan-2-amine , the title product was prepared by using the same method described in Step 5 of EXAMPLE 80. MS (ES+) : 544.1 [M+1]
+.
Step 2 (R) - (4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3- d] pyrimidin-6-yl) (pyrrolidin-1-yl) methanone
Starting with the product of step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 514.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 9.12 –8.82 (m, 1H) , 8.55 (s, 1H) , 6.87 (s, 1H) , 6.83 (s, 1H) , 6.72 (s, 1H) , 5.55 (m, 3H) , 2.43 (s, 3H) , 1.90 (m, 8H) , 1.54 (d, J = 7.0 Hz, 3H) .
EXAMPLE 202
N- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -5-isopropyl-9-methyl-1, 2, 3, 3a, 4, 5-hexahydropyrrolo [1”, 2”: 4', 5'] pyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-7-amine
To a stirred solution of 7- ( ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -5-isopropyl-9-methyl-1, 2, 3, 3a-tetrahydropyrrolo [1”, 2”: 4', 5'] pyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-4 (5H) -one (30 mg, 0.06 mmol) in THF (1 mL) was added LiAlH
4 (150 mg) at 0℃. The mixture was stirred for 1.5 h at rt. After the reaction was completed, the mixture was poured into ice-water and extracted with EA. The organic layer was washed by brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (10%MeOH/EA) to give 7 mg of the pure product as a yellow solid. MS (ES+) : 486.1 [M+1]
+.
1H NMR (400 MHz, Methanol-d
4) δ 7.41 (d, J = 2.0 Hz, 1H) , 6.99 –6.90 (m, 2H) , 6.81 (d, J = 2.1 Hz, 1H) , 5.66 (m, 1H) , 4.35 –4.18 (m, 1H) , 3.85 –3.63 (m, 4H) , 2.51 (m, 4H) , 2.30 –1.84 (m, 4H) , 1.66 (m, 3H) , 1.34 (d, J = 6.5 Hz, 3H) , 1.21 (d, J = 6.4 Hz, 3H) .
EXAMPLE 203
(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Step 1 (R) -2-methyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carbonitrile
To a stirred solution of (R) -4-amino-2-methyl-6- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrimidine-5-carbaldehyde (500 mg, 1.36 mmol) in EtOH (10.0 mL) were added ethyl2-cyanoacetate (460 mg, 4.07 mmol) and piperidine (345 mg, 4.07 mmol) at rt. The mixture was stirred overnight at 80℃ under Ar. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE: EA=1: 1) to give 570 mg of crude product as a red solid which was used in the next step without further purification. MS (ES+) : 419.0 [M+1]
+.
Step 2 (R) -N-hydroxy-2-methyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboximidamide
To a stirred solution of (R) -2-methyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carbonitrile (320 mg, 0.77 mmol) in nBuOH (6.0 mL) were added NH
2OH. HCl (158 mg, 2.30 mmol) and DIEA (593 mg, 4.59 mmol) at rt. The mixture was stirred for 2 h at 100℃ under Ar. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by slurry (DCM: MeOH=9: 1) to give 40 mg of pure product as a yellow solid and 225 mg of crude product as yellow oil. MS (ES+) : 452.0 [M+1]
+.
Step 3 (R) -2-methyl-6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidin-7 (8H) -one
To a stirred solution of (R) -N-hydroxy-2-methyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carboximidamide (320 mg, 0.09 mmol) in AcOH (1.0 mL) was added acetic anhydride (0.4 mL) at rt. The mixture was stirred for 3 h at 120℃ under Ar. After the reaction was completed, water was added, adjusted pH to 8~9 by sat. NaHCO
3 (aq. ) and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-HPLC (column: Green ODS-A, 21.2 x 250mm, 10um; Mobile A: water with 0.05%TFA, Mobile B: CH
3CN; gradient: 40%B over 2 min, 55%B over 15 min; Flow: 35 mL/min) to give 60 mg of the title product as a white solid. MS (ES+) : 476.0 [M+1]
+.
Step 4 (R) -7-chloro-2-methyl-6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) pyrido [2, 3-d] pyrimidin-4-amine
The mixture of (R) -2-methyl-6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidin-7-ol (53 mg, 0.12 mmol) in phenylphosphonic dichloride (3 mL) was stirred at 120℃ for 2.5 h. After the reaction was completed, the reaction was quenched with ice-water, adjusted pH >7 with NaHCO
3 solid and extracted with EA. The residue was purified by Prep-TLC (5%MeOH/DCM) to obtain 30 mg of the title product as a yellow solid. MS (ES+) : 494.0 [M+1]
+.
Step 5 (R) -2-methyl-6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
The mixture of (R) -7-chloro-2-methyl-6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) pyrido [2, 3-d] pyrimidin-4-amine (30 mg, 0.06 mmol) , pyrrolidine (43 mg, 0.60 mmol) and DIEA (78 mg, 0.60 mmol) in 1, 4-Dioxane (2 mL) was stirred at room temperature for 1 h. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to obtain 45 mg of the title product as a yellow solid. MS (ES+) : 529.0 [M+1]
+.
Step 6 (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of step 5, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 499.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.90 (s, 1H) , 8.77 (s, 1H) , 6.85 (s, 1H) , 6.82 (s, 1H) , 6.71 (s, 1H) , 5.66 –5.43 (m, 3H) , 2.70 (s, 3H) , 2.41 (s, 3H) , 1.90 –1.76 (m, 4H) , 1.51 (d, J = 7.1 Hz, 3H) .
EXAMPLE 204
(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -6- (benzylthio) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with (R) -6- (benzylthio) -2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 539.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.80 –8.65 (s, 1H) , 8.59 (s, 1H) , 7.26 –7.14 (m, 5H) , 6.89 (s, 1H) , 6.86 (s, 1H) , 6.73 (s, 1H) , 5.55 (m, 3H) , 4.23 –4.10 (m, 2H) , 3.64 (m, 4H) , 2.39 (s, 3H) , 1.83 (m, 4H) , 1.56 (d, J = 7.0 Hz, 3H) .
EXAMPLE 205
(R) -4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-N, N-bis (methyl-d3) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with (R) -4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2 -methyl -7 - (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxylic acid and bis (methyl-d
3) amine hydrochloride , the title product was prepared by using the same method as described in Step 5 of EXAMPLE 80. MS (ES+) : 479.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 9.17 (s, 1H) , 8.56 (d, J = 2.6 Hz, 1H) , 7.72 (t, J = 7.8 Hz, 1H) , 7.53 (t, J = 7.2 Hz, 1H) , 7.36 –7.06 (m, 2H) , 5.81 (q, J = 7.1 Hz, 1H) , 3.55 (m, 4H) , 2.39 (s, 3H) , 1.92 (m, 4H) , 1.60 (d, J = 7.0 Hz, 3H) .
EXAMPLE 206
) ethyl) amino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with (R) -7-chloro-4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide and dimethyl-D-6-amine hydrochloride , the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 453.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.59 (s, 1H) , 8.49 (s, 1H) , 7.66 (d, J = 9.8 Hz, 1H) , 7.51 (t, J = 7.2 Hz, 1H) , 7.38 –7.04 (m, 2H) , 5.76 (q, J = 7.6 Hz, 1H) , 3.03 (s, 3H) , 2.90 (d, J = 9.0 Hz, 3H) , 2.32 (s, 3H) , 1.56 (d, J = 7.0 Hz, 3H) .
EXAMPLE 207
(R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -N, N, 2-trimethyl-7- (thiazol-2-ylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of (R) -7-chloro-4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide (90 mg, 0.21 mmol) in dioxane (2 mL) were added thiazol-2-amine (130 mg, 1.30 mmol) , Cs
2CO
3 (300 mg, 0.92 mmol) , X-antphos (120 mg, 0.21 mmol) and Pd
2(dba)
3 (120 mg, 0.13 mmol) at rt. The resulting mixture was stirred at 100℃ for 2 h under Ar. After the reaction was completed, the reaction was quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-HPLC (column: Green ODS-A, 21.2 x 250mm, 10um; Mobile A: water with 0.05%TFA, Mobile B: CH
3CN; Gradient: 45%B over 2 min, 60%B over 15 min; Flow: 35 mL/min) to obtain 10.2 mg of the title product as a yellow solid. MS (ES+) : 502.0 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.69 (s, 1H) , 8.50 (d, J = 7.0 Hz, 1H) , 7.66 (d, J = 8.1 Hz, 1H) , 7.49 (m, 2H) , 7.38 –7.08 (m, 4H) , 5.77 (t, J = 7.5 Hz, 1H) , 3.02 (m, 6H) , 2.38 (s, 3H) , 1.58 (d, J = 7.0 Hz, 3H) .
EXAMPLE 208
(R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (isoindolin-2-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -7- (isoindolin-2-yl) -N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and isoindoline hydrochloride, the title product was prepared by using the same method described in Step 2 of EXAMPLE 69. MS (ES+) : 566.1 [M+1]
+.
Step 2 (R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (isoindolin-2-yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 536.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.63 –8.42 (m, 2H) , 7.48 –7.37 (m, 2H) , 7.35 –7.26 (m, 2H) , 6.86 (t, J = 12.3 Hz, 2H) , 6.71 (s, 1H) , 5.66 –5.40 (m, 3H) , 4.94 (d, J = 15.7 Hz, 2H) , 4.77 (d, J = 15.1 Hz, 2H) , 3.13 (s, 3H) , 2.98 (d, J = 5.2 Hz, 3H) , 2.41 (d, J = 4.1 Hz, 3H) , 1.53 (d, J = 7.0 Hz, 3H) .
EXAMPLE 209
(R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (3, 4-dihydroisoquinolin-2 (1H) -yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -7- (3, 4-dihydroisoquinolin-2 (1H) -yl) -N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and 1, 2, 3, 4-tetrahydroisoquinoline e , the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 580.1 [M+1]
+.
Step 2 (R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (3, 4-dihydroisoquinolin-2 (1H) -yl) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 550.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.56 (s, 1H) , 8.48 (d, J = 8.1 Hz, 1H) , 7.20 (m, 4H) , 6.85 (m, 2H) , 6.70 (s, 1H) , 5.51 (m, 3H) , 4.68 (s, 2H) , 3.71 (m, 2H) , 3.06 (s, 3H) , 2.88 (m, 5H) , 2.39 (s, 3H) , 1.51 (d, J = 7.0 Hz, 3H) .
EXAMPLE 210
(R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -7- (dicyclopropylamino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -7- (dicyclopropylamino) -N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and dicyclopropylamine hydrochloride , the title product was prepared by using the same method described in Step 2 of EXAMPLE 69. MS (ES+) : 544.1 [M+1]
+.
Step 2 (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (dicyclopropylamino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 514.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 9.07 (s, 1H) , 8.69 (d, J = 4.3 Hz, 1H) , 6.87 (m, 2H) , 6.72 (s, 1H) , 5.55 (m, 3H) , 2.98 (s, 3H) , 2.89 –2.74 (m, 5H) , 2.44 (s, 3H) , 1.54 (d, J = 7.0 Hz, 3H) , 0.90 –0.52 (m, 8H) .
EXAMPLE 211
(R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -9-cyclopropyl-2, 6-dimethyl-8, 9-dihydropyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-7 (6H) -one
Step 1 2- (cyclopropylamino) -N-methylacetamide
To a stirred solution of cyclopropanamine (932 mg, 16.35 mmol) in THF (5 mL) was added 2-bromo-N-methylacetamide (500 mg, 3.26 mmol) at rt. The mixture was stirred for 1 h at rt. After the reaction was completed, the reaction was concentrated. The residue was purified by silica gel column chromatography (7.5%MeOH/DCM) to give 343 mg of the title product as yellow oil. MS (ES+) : 129.1 [M+1]
+.
Step 2 (R) -2- ( (6-bromo-2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidin-7-yl) (cyclopropyl) amino) -N-methylacetamide
Starting with the product of step 1, the title product was prepared by using the same method as described in Step 3 of EXAMPLE 163. MS (ES+) : 581.9 [M+1]
+.
Step 3 (R) -9-cyclopropyl-2, 6-dimethyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -8, 9-dihydropyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-7 (6H) -one
Starting with the product of step 2, the title product was prepared by using the same method described in Step 4 of EXAMPLE 163. MS (ES+) : 502.1 [M+1]
+.
Step 4 (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -9-cyclopropyl-2, 6-dimethyl-8, 9-dihydropyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-7 (6H) -one
Starting with the product of step 3, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 472.1 [M+1]
+.
1H NMR (400 MHz, Methanol-d
4) δ 7.99 (s, 1H) , 6.97 (d, J = 2.3 Hz, 2H) , 6.82 (d, J = 2.0 Hz, 1H) , 5.65 (q, J = 7.1 Hz, 1H) , 4.25 (s, 2H) , 3.43 (s, 3H) , 2.84 (tt, J = 7.2, 3.9 Hz, 1H) , 2.52 (s, 3H) , 1.66 (d, J = 7.1 Hz, 3H) , 1.02 –0.94 (m, 2H) , 0.79 –0.69 (m, 2H) .
EXAMPLE 212
(R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7- ( (2-ethoxyethyl) (methyl) amino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1tert-butyl (2-ethoxyethyl) carbamate
The mixture of 2-ethoxyethan-1-amine (2 g, 22.44 mmol) , (Boc)
2O (5.39 g, 24.68 mmol) and DMAP (0.27 g, 2.20 mmol) in CH
3CN (40 mL) was stirred for 2 h at rt. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM: MeOH=9: 1) to give 3.8 g of the title product as yellow oil. MS (ES+) : 134.1 [M-56+1]
+.
Step 2 tert-butyl (2-ethoxyethyl) (methyl) carbamate
To a stirred solution of tert-butyl N- (2-ethoxyethyl) carbamate (500 mg, 2.64 mmol) and 60%NaH (158 mg, 3.96 mmol) in DMF (5mL) was added CH
3I (749 mg, 5.28 mmol) at -5~0℃. The mixture was stirred for 1h at rt under Ar. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to give 520 mg of crude product as yellow oil. MS (ES+) : 148.0 [M-56+1]
+.
Step 3 2-ethoxy-N-methylethanamine hydrochloride
The mixture of tert-butyl (2-ethoxyethyl) (methyl) carbamate (345 mg, 1.71 mmol) in 4N HCl/1, 4-Dioxane (3.0 mL) was stirred for 3 h at rt. After the reaction was completed, the mixture was concentrated to give the title product which was used to the next step directly.
Step 4 (R) -7- ( (2-ethoxyethyl) (methyl) amino) -N, N, 2-trimethyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of step 3 and (R) -7-chloro-N, N, 2-trimethyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxamid, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 550.1 [M+1]
+.
Step 5 (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7- ( (2-ethoxyethyl) (methyl) amino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of step 4, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 520.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.52 (s, 1H) , 8.47 (d, J = 5.2 Hz, 1H) , 6.85 (t, J = 12.6 Hz, 2H) , 6.71 (s, 1H) , 5.69 –5.41 (m, 3H) , 3.91 (m, 1H) , 3.64 (m, 3H) , 3.42 (m, 2H) , 3.02 (d, J = 2.7 Hz, 6H) , 2.86 (d, J = 5.0 Hz, 3H) , 2.38 (s, 3H) , 1.51 (d, J = 7.0 Hz, 3H) , 1.07 (t, J = 7.0 Hz, 3H) .
EXAMPLE 213
(R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -N, N, 2-trimethyl-7- (methyl (thiazol-2-yl) amino) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of (R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -N, N, 2-trimethyl-7- (thiazol-2-ylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide (30 mg, 0.06 mmol) in DMF (1 mL) was added NaH (3 mg, 0.12 mmol) at 0-10℃. The resulting mixture was stirred at 0-10℃ for 0.5 h under Ar. Then CH
3I (3 mg, 0.04 mmol) was added at 0-10℃. The resulting mixture was stirred at 0-10℃ for 1h. After the reaction was completed, the reaction was quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-HPLC (Column: Green ODS-A, 21.2 x 250mm, 10um; Mobile A: water with 0.05%TFA, Mobile B: CH
3CN; Gradient: 40%B over 2 min, 55%B over 15 min; Flow: 35 mL/min) to obtain 8 mg of the title product as a yellow solid. MS (ES+) : 516.0 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.59 (s, 1H) , 8.33 (d, J = 6.9 Hz, 1H) , 7.68 (d, J = 7.3 Hz, 1H) , 7.48 (m, 2H) , 7.45 (d, J = 4.8 Hz, 1H) , 7.38 –7.12 (m, 2H) , 6.88 (d, J = 4.7 Hz, 1H) , 5.77 (m, 1H) , 3.64 (s, 3H) , 3.07 (s, 3H) , 2.84 (d, J = 1.9 Hz, 3H) , 2.39 –2.33 (m, 3H) , 1.61 –1.49 (m, 3H) .
EXAMPLE 214
8- ( ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -6, 10-dimethyl-2, 3, 4, 4a-tetrahydro-1H-pyrido [1”, 2”: 4', 5'] pyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-5 (6H) -one
Step 1 tert-butyl 2- (methylcarbamoyl) piperidine-1-carboxylate
Starting with 1- (tert-butoxycarbonyl) piperidine-2-carboxylic acid and methylamine hydrochloride, the title product was prepared by using the same method as described in Step 1 of EXAMPLE 163. MS (ES+) : 143.1 [M-100+1]
+.
Step 2 N-methylpiperidine-2-carboxamide hydrochloride
The solution of tert-butyl 2- (methylcarbamoyl) piperidine-1-carboxylate (1 g, 4.1 mmol) in 4 N HCl/EA (5 mL) was stirred for 1 h at rt under Ar. After the reaction was completed, the mixture was concentrated to give 730 mg of the title product as a white solid. MS (ES+) : 143.1 [M+1]
+.
Step 3 1- (6-bromo-2-methyl-4- ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidin-7-yl) -N-methylpiperidine-2-carboxamide
Starting with (R) -6-bromo-7-chloro-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) pyrido [2, 3-d] pyrimidin-4-amine and the product of step 2, the title product was prepared by using the same method as described in Step 3 of EXAMPLE 163. MS (ES+) : 596.0 [M+1]
+.
Step 4 6, 10-dimethyl-8- ( ( (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -2, 3, 4, 4a-tetrahydro-1H-pyrido [1”, 2”: 4', 5'] pyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-5 (6H) -one
Starting with the product of step 3, the title product was prepared by using the same method as described in Step 4 of EXAMPLE 163. MS (ES+) : 516.1 [M+1]
+.
Step 5 8- ( ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -6, 10-dimethyl-2, 3, 4, 4a-tetrahydro-1H-pyrido [1”, 2”: 4', 5'] pyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-5 (6H) -one
Starting with the product of step 3, the title product was prepared by using the same method as described in Step 5 of EXAMPLE 163. MS (ES+) : 486.1 [M+1]
+.
1H NMR (400 MHz, Methanol-d
4) δ 7.96 (s, 1H) , 7.03 –6.90 (m, 2H) , 6.82 (s, 1H) , 5.68 (q, J = 6.7 Hz, 1H) , 5.05 (d, J = 13.3 Hz, 1H) , 4.30 (dd, J = 11.8, 2.8 Hz, 1H) , 3.44 (d, J = 1.4 Hz, 3H) , 2.84 (dd, J = 14.7, 11.8 Hz, 1H) , 2.55 (d, J = 1.7 Hz, 3H) , 2.26 (d, J = 4.4 Hz, 1H) , 1.97 (m, 1H) , 1.82 –1.70 (m, 2H) , 1.68 (d, J = 7.0 Hz, 3H) , 1.57 (m, 2H) .
EXAMPLE 215
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (1-methyl-1H-tetrazol-5-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Step 1 (R) -4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6- (1-methyl-1H-tetrazol-5-yl) pyrido [2, 3-d] pyrimidin-7 (8H) -one
To a stirred solution of (R) -4-amino-2-methyl-6- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrimidine-5-carbaldehyde (110 mg, 0.34 mmol) in EtOH (2.0 mL) were added ethyl2- (1-methyl-1H-tetrazol-5-yl) acetate (173 mg, 1.02 mmol) and piperidine (87 mg, 1.02 mmol) at rt. The mixture was stirred overnight at 80℃ under Ar. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (PE: EA=1: 2) to give 180 mg of crude product as a yellow solid which was used in the next step without further purification. MS (ES+) : 431.0 [M+1]
+.
Step 2 (R) -7-chloro-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (1-methyl-1H-tetrazol-5-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of step 1 and phenylphosphonic dichloride , the title product was prepared by using the same method as described in Step 2 of EXAMPLE 87. MS (ES+) : 449.0 [M+1]
+.
Step 3 (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (1-methyl-1H-tetrazol-5-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of step 2 and pyrrolidine, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 484.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.82 (m, 2H) , 7.70 (t, J = 7.4 Hz, 1H) , 7.50 (t, J = 7.1 Hz, 1H) , 7.38 –7.04 (m, 2H) , 5.79 (m, 1H) , 4.06 (s, 3H) , 3.06 (m, 4H) , 1.80 (m, 4H) , 1.56 (d, J = 7.1 Hz, 3H) .
EXAMPLE 216
(R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -N, 2-dimethyl-N- (methylsulfonyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -N, 2-dimethyl-N- (methylsulfonyl) -4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of (R) -2-methyl-N- (methylsulfonyl) -4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide (21 mg, 0.04 mmol) in DMF (1.0 mL) was added 60%NaH (20 mg) at 0~10℃ under Ar and the mixture was stirred for 10 min. Then CH
3I (2.6 mg, 0.02 mmol) was added. The mixture was stirred for 1 h at rt. Water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-HPLC (Column: Green ODS-A, 21.2 x 250mm, 10um; Mobile A: water with 0.05%TFA, Mobile B: CH
3CN; Gradient: 40%B over 2 min, 55%B over 15 min; Flow: 35 mL/min) to give 17 mg of the title product as a white solid. MS (ES+) : 582.0 [M+1]
+.
Step 2 (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -N, 2-dimethyl-N- (methylsulfonyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 552.1 [M+1]
+.
1H NMR (400 MHz, Methanol-d
4) δ 8.93 (s, 1H) , 7.39 (m, 2H) , 7.18 (s, 1H) , 5.73 (s, 1H) , 3.93 (s, 3H) , 3.65 (m, 4H) , 3.44 (s, 3H) , 2.75 (s, 3H) , 2.06 (m, 4H) , 1.71 (d, J = 6.8 Hz, 3H) .
EXAMPLE 217
(R) -4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 2-trimethylimidazo [1', 2': 1, 6] pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -7-amino-4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
The mixture of (R) -7-chloro-4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide (200 mg, 0.46 mmol) in NH
3-H
2O (3 mL) and 1.4-dioxane (3 mL) was stirred for 16 h at 80 ℃ in pressure pan. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (7.5%MeOH/EA) to give 183 mg of the title product as a yellow solid. MS (ES+) : 419.0 [M+1]
+.
Step 2 (R) -4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 2-trimethylimidazo [1', 2': 1, 6] pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of (R) -7-amino-4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide (35 mg, 0.084 mmol) and CH
3COONa (70 mg) in EtOH (2 mL) was added chloroacetaldehyde (70 mg) at rt. The mixture was stirred for 4 h at 65 ℃ under Ar. After cooling, NaHCO
3 (aq. ) was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (7.5%MeOH/EA) to give 15 mg of the title product as a yellow solid. MS (ES+) : 443.0 [M+1]
+.
1H NMR (400 MHz, Methanol-d
4) δ 8.40 (d, J = 1.5 Hz, 1H) , 8.15 (s, 1H) , 7.63 (d, J = 1.5 Hz, 1H) , 7.59 (t, J = 7.5 Hz, 1H) , 7.47 (t, J = 7.2 Hz, 1H) , 7.21 (t, J = 7.7 Hz, 1H) , 7.00 (t, J = 54.9 Hz, 1H) , 5.84 (q, J = 7.1 Hz, 1H) , 3.22 (s, 3H) , 2.97 (s, 3H) , 2.51 (s, 3H) , 1.66 (d, J = 7.2 Hz, 3H) .
EXAMPLE 218
(R) -6- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 8-trimethyl- [1, 2, 4] triazolo [1', 5': 1, 6] pyrido [2, 3-d] pyrimidine-4-carboxamide
Step 1 (R) -7-amino-4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
The solution of (R) -7-chloro-4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide (200 mg, 0.46 mmol) in NH
3-H
2O (3 mL) and 1.4-dioxane (3 mL) was stirred for 16 h at 80 ℃ in an autoclave. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with water and brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (7.5%MeOH: EA) to give 183 mg of the title product as yellow oil. MS (ES+) : 419.0 [M+1]
+.
Step 2 (R, Z) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -7- ( (hydroxyamino) methyleneamino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
The mixture of (R) -7-amino-4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide (100 mg, 0.24 mmol) and DMF-DMA (171 mg, 1.44 mmol) in isopropanol (4 mL) was stirred for 1 h at 80℃ under Ar. Then hydroxylamine hydrochloride (70 mg, 1.91 mmol) was added and the mixture was stirred for 1 h at 50 ℃ under Ar. After cooling, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (7.5%MeOH: EA) to give 72 mg of the title product as a yellow solid. MS (ES+) : 462.0 [M+1]
+.
Step 3 (R) -6- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 8-trimethyl- [1, 2, 4] triazolo [1', 5': 1, 6] pyrido [2, 3-d] pyrimidine-4-carboxamide
A mixture of (R, Z) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -7- ( (hydroxyamino) methyleneamino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide (22 mg, 0.048 mmol) in TFAA (2 mL) was stirred for 16 h at RT under Ar. After the reaction was completed, the mixture was dropped into sat. NaHCO
3 (aq. ) and extracted with EA. The organic layer was dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (5%MeOH: EA) to give 6 mg of the title product as a yellow solid. MS (ES+) : 444.1 [M+1]
+.
1H NMR (400 MHz, Methanol-d
4) δ 8.49 (d, J = 3.7 Hz, 2H) , 7.53 (t, J = 7.5 Hz, 1H) , 7.38 (t, J = 7.3 Hz, 1H) , 7.14 (t, J = 7.7 Hz, 1H) , 6.91 (t, J = 54.8 Hz, 1H) , 5.78 (q, J = 7.1 Hz, 1H) , 3.13 (s, 3H) , 2.90 (s, 3H) , 2.46 (s, 3H) , 1.60 (d, J = 7.1 Hz, 3H) .
EXAMPLE 219
(R) -4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 2-trimethyl- [1, 2, 4] triazolo [4', 3': 1, 6] pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -7-hydrazinyl-N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of (R) -7-chloro-4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino-N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide (100 mg, 0.23 mmol) in EtOH (5 mL) was added Hydrazinium hydroxide solution (143 mg, 2.86 mmol) at rt. The mixture was stirred for 3 h at rt. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to give 139 mg of crude product as a brown solid. MS (ES+) : 434.0 [M+1]
+.
Step 2 (R) -4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 2-trimethyl- [1, 2, 4] triazolo [4', 3': 1, 6] pyrido [2, 3-d] pyrimidine-6-carboxamide
The mixture of (R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -7-hydrazinyl-N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide (40 mg, 0.09 mmol) in triethyl orthoformate (3 mL) was stirred for 1 h at 120 ℃ under Ar. After cooling, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (7.5%MeOH/EA) to give 13 mg of the title product as a yellow solid. MS (ES+) : 444.0 [M+1]
+.
1H NMR (400 MHz, Methanol-d
4) δ 9.61 (s, 1H) , 8.29 (s, 1H) , 7.61 (t, J = 7.4 Hz, 1H) , 7.47 (t, J = 7.3 Hz, 1H) , 7.22 (t, J = 7.7 Hz, 1H) , 7.00 (t, J = 54.9 Hz, 1H) , 5.82 (q, J = 7.1 Hz, 1H) , 3.22 (s, 3H) , 3.02 (s, 3H) , 2.52 (s, 3H) , 1.67 (d, J = 7.1 Hz, 3H) .
EXAMPLE 220
(R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -9-cyclopropyl-2, 6-dimethyl-6, 7, 8, 9-tetrahydropyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-4-amine
Step 1 4- ( ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -9-cyclopropyl-2, 6-dimethyl-6, 7, 8, 9-tetrahydropyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-7-ol
Starting with (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -9-cyclopropyl-2, 6-dimethyl-8, 9-dihydropyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-7 (6H) -one, the title product was prepared by using the same method as described in Step 1 of EXAMPLE 179. MS (ES+) : 474.1 [M+1]
+.
Step 2 (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -9-cyclopropyl-2, 6-dimethyl-6, 7, 8, 9-tetrahydropyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-4-amine
Starting with the product of step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 179. MS (ES+) : 458.1 [M+1]
+.
1H NMR (400 MHz, Methanol-d
4) δ 7.27 (s, 1H) , 7.01 –6.89 (m, 2H) , 6.82 (d, J = 2.0 Hz, 1H) , 5.68 (q, J = 7.1 Hz, 1H) , 3.67 (t, J = 5.2 Hz, 2H) , 3.07 –2.92 (m, 4H) , 2.54 (s, 3H) , 1.67 (d, J = 7.1 Hz, 3H) , 1.01 –0.92 (m, 2H) , 0.81 –0.72 (m, 2H) .
EXAMPLE 221
N- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -6, 10-dimethyl-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrido [1”, 2”: 4', 5'] pyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-8-amine
Step 1 8- ( ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -6, 10-dimethyl-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrido [1”, 2”: 4', 5'] pyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-5-ol
Starting with 8- ( ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -6, 10-dimethyl-2, 3, 4, 4a-tetrahydro-1H-pyrido [1”, 2”: 4', 5'] pyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-5 (6H) -one, the title was prepared by using the same method as described in Step 1 of EXAMPLE 179. MS (ES+) : 488.1 [M+1]
+.
Step 2 N- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -6, 10-dimethyl-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrido [1”, 2”: 4', 5'] pyrazino [2', 3': 5, 6] pyrido [2, 3-d] pyrimidin-8-amine
Starting with the product of step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 179. MS (ES+) : 472.1 [M+1]
+.
EXAMPLE 222
(R) -1- (4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) cyclopropane-1-carboxylate
To a stirred solution of (R) -1- (2-methyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) cyclopropane-1-carboxylate (30 mg, 0.054 mmol) in EtOH/H
2O (5: 1, 1mL) were added NH
4Cl (28 mg, 0.53 mmol) and Fe (15 mg, 0.27 mmol) at rt. The mixture was stirred for 2 h at 70℃. After cooling, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA: MeOH=15: 1) to give 6.4 mg of pure product as a yellow solid. MS (ES+) : 529.1 [M+1]
+.
1H NMR (400 MHz, Chloroform-d) δ 8.31 (s, 1H) , 7.06 (s, 1H) , 6.94 (s, 1H) , 6.65 (s, 1H) , 5.50 (s, 1H) , 5.27 (m, 1H) , 5.23 (s, 1H) , 4.03 (m, 2H) , 3.72 (m, 4H) , 2.50 (s, 3H) , 2.17 –1.50 (m, 14H) .
EXAMPLE 223
(R) - (1- (4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) cyclopropyl) methanol
To a stirred solution of (R) - (1- (2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) cyclopropyl) methanol (39 mg, 0.07 mmol) in EtOH/H
2O (5: 1, 2 mL) were added NH
4Cl (78 mg, 1.46 mmol) and Fe (78 mg, 1.39 mmol) at rt. The mixture was stirred for 1.5 h at 70℃. After the reaction was completed, water was added and extracted with EA. The organic layer was dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (7.5%MeOH: DCM) to give 28.8 mg of the title product as a yellow solid. MS (ES+) : 487.1 [M+1]
+.
1H NMR (400 MHz, Methanol-d
4) δ 8.41 (s, 1H) , 7.01 –6.86 (m, 2H) , 6.82 (d, J = 2.0 Hz, 1H) , 5.67 (q, J = 7.0 Hz, 1H) , 3.93 –3.82 (m, 4H) , 3.31 –3.30 (m, 2H) , 2.53 (s, 3H) , 2.00 (m, 4H) , 1.66 (d, J = 7.1 Hz, 3H) , 1.14 (m, 4H) .
EXAMPLE 224
(R) -1- (4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) -N, N-dimethylcyclopropanecarboxamide
Step 1 (R) -1- (2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) cyclopropanecarboxylic acid
The mixture of (R) -ethyl1- (2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) cyclopropanecarboxylate (73 mg, 0.17 mmol) in MeOH (20 mL) and 2N NaOH (20 mL) was stirred for 16 h at 60℃ under Ar. After cooling, the mixture was adjusted pH<7 by 1N HCl and then extracted with EA. The organic layer was dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (7.5%MeOH/DCM) to give 38 mg of the title product as a yellow solid. MS (ES+) : 531.0 [M+1]
+.
Step 2 (R) -N, N-dimethyl-1- (2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) cyclopropanecarboxamide
Starting with (R) -1- (2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) cyclopropanecarboxylic acid and dimethylamine, the title product was prepared by using the same method described in Step 5 of EXAMPLE 80. MS (ES+) : 558.1 [M+1]
+.
Step 3 (R) -1- (4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) -N, N-dimethylcyclopropanecarboxamide
Starting with the product of step 2, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 528.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 9.40 (s, 1H) , 8.56 (s, 1H) , 6.85 (d, J = 4.5 Hz, 2H) , 6.74 (s, 1H) , 5.60 (m, 3H) , 3.75 (m, 4H) , 2.65 (s, 6H) , 2.47 (s, 3H) , 1.86 (m, 4H) , 1.66 –1.50 (m, 7H) .
EXAMPLE 225
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- ( (1-methyl-1H-pyrazol-4-yl) ethynyl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
The mixture of (R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine (60 mg, 0.13 mmol) , 4-ethynyl-1-methyl-1H-pyrazole (100 mg, 0.94 mmol) , CuI (32.4 mg, 0.17 mmol) and (PPh
3)
2PdCl
2 (56.4 mg, 0.08 mmol) in Et
3N (6 mL) was stirred at 95 ℃ overnight. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA: PE=9: 1) to give 10.2 mg of the title product as a yellow solid. MS (ES+) : 506.1 [M+1]
+.
1H NMR (400 MHz, Chloroform-d) δ 8.46 (s, 1H) , 7.68 –7.54 (m, 3H) , 7.46 (t, J = 7.1 Hz, 1H) , 7.17 (t, J = 7.7 Hz, 1H) , 6.90 (t, J = 55.0 Hz, 1H) , 5.81 –5.69 (m, 1H) , 3.92 (m, 7H) , 2.54 (s, 3H) , 1.93 (m, 4H) , 1.77 (d, J = 7.0 Hz, 3H) .
EXAMPLE 226
(R) -4- (4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) -2-methylbut-3-yn-2-ol
Starting with (R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine and 2-methylbut-3-yn-2-ol , the title product was prepared by using the same method as described in EXAMPLE 225. MS (ES+) : 484.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.76 (s, 1H) , 8.61 (s, 1H) , 7.67 (t, J = 7.4 Hz, 1H) , 7.51 (t, J = 7.2 Hz, 1H) , 7.37 –7.04 (m, 2H) , 5.76 (m, 1H) , 5.51 (s, 1H) , 3.81 (m, 4H) , 2.31 (s, 3H) , 1.99 –1.84 (m, 4H) , 1.57 (d, J = 7.0 Hz, 3H) , 1.48 (s, 6H) .
EXAMPLE 227
(R) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) -4- ( (1- (3- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide (65 mg, 0.13 mmol) in DMF (2.3 mL) and THF (5 mL) was added tert-butyl nitrite (0.5 mL) at rt. The mixture was stirred for 2 h at 60℃ under Ar. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by prep-HPLC (Column: Green ODS-A, 21.2 x 250mm, 10um; Mobile A: water with 0.05%TFA, Mobile B: CH
3CN; Gradient: 45%B over 2 min, 60%B over 15 min; Flow: 35 mL/min) to give 12.6 mg of the title product as a yellow solid. MS (ES+) : 473.1 [M+1]
+.
1H NMR (400 MHz, Chloroform-d) δ 8.11 (d, J = 20.4 Hz, 1H) , 7.75 –7.39 (m, 4H) , 6.81 (s, 1H) , 5.64 (d, J = 7.9 Hz, 1H) , 3.60 (m, 2H) , 3.37 (m, 2H) , 3.09 (d, J = 8.7 Hz, 3H) , 2.89 (d, J = 10.5 Hz, 3H) , 2.55 (s, 3H) , 1.66 (dd, J = 21.0, 7.0 Hz, 3H) .
EXAMPLE 228
(R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -N, N, 2-trimethyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of (R) -7-chloro-N, N, 2-trimethyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxamide (100 mg, 0.21 mmol) in THF (10 mL) were added Pd (dppf) Cl
2 (100 mg, 0.14 mmol) , NaBH
4 (50 mg, 1.35 mmol) and N, N, N, N-tetramethylethylenediamine (120 mg, 1.03 mmol) at rt. The mixture was stirred for 2 h at rt under Ar. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to give 290 mg of crude product which was used in the next step without further purification. MS (ES+) : 449.0 [M+1]
+.
Step 2 (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 419.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 9.02 (d, J = 2.3 Hz, 1H) , 8.98 (d, J = 2.1 Hz, 1H) , 6.90 (s, 1H) , 6.85 (s, 1H) , 6.71 (s, 1H) , 5.69 –5.47 (m, 3H) , 3.05 (s, 3H) , 3.02 (s, 3H) , 2.48 (s, 3H) , 1.56 (d, J = 7.0 Hz, 3H) .
EXAMPLE 229
(R) -4- ( (1- (3-bromo-5- (trifluoromethyl) phenyl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide (85 mg, 0.17 mmol) in ACN (17 mL) were added tert-butyl nitrite (170 mg, 1.65 mmol) and CuBr (170 mg, 1.19 mmol) at 0℃. The mixture was stirred overnight at RT under Ar. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-HPLC (Column: Green ODS-A, 21.2 x 250mm, 10um; Mobile A: water with 0.05%TFA, Mobile B: CH
3CN; Gradient: 45%B over 2 min, 60%B over 15 min; Flow: 35 mL/min) to give 21.2 mg of the title product as a white solid. MS (ES+) : 551.0 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.49 (s, 1H) , 8.37 (s, 1H) , 7.95 (s, 1H) , 7.82 (d, J = 8.1 Hz, 2H) , 5.63 –5.47 (m, 1H) , 3.51 (m, 2H) , 3.03 (s, 3H) , 2.90 (d, J = 5.8 Hz, 3H) , 2.35 (s, 3H) , 1.97 –1.87 (m, 4H) , 1.56 (d, J = 7.0 Hz, 3H) .
EXAMPLE 230
(R) -4- ( (1- (3-chloro-5- (trifluoromethyl) phenyl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin- 1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide and CuCl, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 229. MS (ES+) : 507.0 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.80 (s, 1H) , 8.44 (s, 1H) , 7.84 (s, 1H) , 7.80 (d, J = 8.6 Hz, 1H) , 7.73 (s, 1H) , 5.60 (m, 1H) , 3.53 (m, 2H) , 3.04 (s, 3H) , 2.92 (d, J = 6.4 Hz, 3H) , 2.38 (s, 3H) , 1.99 –1.86 (m, 4H) , 1.59 (d, J = 7.0 Hz, 3H) .
EXAMPLE 231
(R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (bis (2-methoxyethyl) amino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -7- (bis (2-methoxyethyl) amino) -N, N, 2-trimethyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with (R) -7-chloro-N, N, 2-trimethyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) pyrido [2, 3-d] pyrimidine-6-carboxamide and bis (2-methoxyethyl) amine, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 69. MS (ES+) : 580.0 [M+1]
+.
Step 2 (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (bis (2-methoxyethyl) amino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of step 1, the title product was prepared by using the same method as described in Step 2 of EXAMPLE 83. MS (ES+) : 550.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.74 (s, 1H) , 8.50 (d, J = 5.2 Hz, 1H) , 6.85 (m, 2H) , 6.71 (s, 1H) , 5.53 (m, 3H) , 3.76 (m, 2H) , 3.62 (m, 2H) , 3.50 (m, 4H) , 3.22 (s, 6H) , 3.02 (s, 3H) , 2.86 (d, J = 4.4 Hz, 3H) , 2.40 (s, 3H) , 1.52 (d, J = 7.0 Hz, 3H) .
EXAMPLE 232
(R) -4- (1- (3-acetamido-5- (trifluoromethyl) phenyl) ethylamino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
The mixture of (R) -4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide (45 mg, 0.09 mmol) and acetic anhydride (11.25 mg, 0.11 mmol) in AcOH (4.5 mL) was stirred at 110℃ for 1 h. After the reaction was completed, the mixture was poured into ice-water, adjusted pH=8 with NaHCO
3 (aq. ) and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (MeOH: DCM=10%) to give 20.6 mg of the title product as a yellow solid. MS (ES+) : 530.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 10.36 (d, J = 12.7 Hz, 1H) , 8.94 (s, 1H) , 8.49 (d, J = 6.6 Hz, 1H) , 7.95 (d, J = 9.4 Hz, 1H) , 7.83 (m, 1H) , 7.47 (d, J = 9.3 Hz, 1H) , 5.57 (d, J = 10.3 Hz, 1H) , 3.03 (s, 3H) , 2.92 (d, J = 8.4 Hz, 3H) , 2.40 (d, J = 5.3 Hz, 3H) , 2.05 (s, 3H) , 1.92 (m, 4H) , 1.58 (d, J = 7.0 Hz, 3H) .
EXAMPLE 233
(R) -N, N, 2-trimethyl-4- ( (1- (3- (methylamino) -5- (trifluoromethyl) phenyl) ethyl) amino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -N, N, 2-trimethyl-4- ( (1- (3- (N-methylacetamido) -5- (trifluoromethyl) phenyl) ethyl) amino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of (R) -4- ( (1- (3-acetamido-5- (trifluoromethyl) phenyl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide (100 mg, 0.19 mmol) in DMF (20.0 mL) were added Cs
2CO
3 (123 mg, 0.38 mmol) and CH
3I (134 mg, 0.95 mmol) at rt. The mixture was stirred for 2 h at rt. After the reaction was completed, water was added and extracted with DCM: MeOH=9: 1. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (DCM: MeOH=9: 1) to give 102 mg of crude product as a yellow solid. MS (ES+) : 544.1 [M+1]
+. Step 2 (R) -N, N, 2-trimethyl-4- ( (1- (3- (methylamino) -5- (trifluoromethyl) phenyl) ethyl) amino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of (R) -N, N, 2-trimethyl-4- ( (1- (3- (N-methylacetamido) -5- (trifluoromethyl) phenyl) ethyl) amino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide (100 mg, 0.18 mmol) in EtOH (20.0 mL) was added con. HCl (5.0 mL) at rt. The mixture was stirred overnight at rt under pressure tin. After the reaction was completed, water was added, adjusted pH to 7~8 by sat. NaHCO
3 (aq. ) and extracted with DCM: MeOH=9: 1 three times. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-HPLC (Column: Green ODS-A, 21.2 x 250mm, 10um; Mobile A: water with 0.05%HCOOH, Mobile B: CH
3CN; Gradient: 40%B over 2 min, 55%B over 15 min; Flow: 35 mL/min) to give 5.6 mg of the title product as a yellow solid. MS (ES+) : 502.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.56 (s, 1H) , 8.46 (s, 1H) , 6.93 –6.78 (m, 2H) , 6.73 (s, 1H) , 5.58 (m, 2H) , 3.82 (s, 3H) , 3.58 (m, 4H) , 3.05 (s, 3H) , 2.93 (d, J = 9.1 Hz, 3H) , 2.68 (s, 3H) , 1.98 (m, 4H) , 1.55 (d, J = 7.0 Hz, 3H) .
EXAMPLE 234
(R) -N, N, 2-trimethyl-4- (1- (3- (methylsulfonamido) -5- (trifluoromethyl) phenyl) ethylamino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -N, N, 2-trimethyl-4- ( (1- (3- (N- (methylsulfonyl) methylsulfonamido) -5- (trifluoromethyl) phenyl) ethyl) amino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide (50 mg, 0.10 mmol) in DCM (5.0 mL) were added TEA (52 mg, 0.51 mmol) and methanesulfonyl chloride (39 mg, 0.34 mmol) at rt. The mixture was stirred for 1 h at 35 ℃ under Ar. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to give 78 mg of crude product as a yellow solid. MS (ES+) : 644.0 [M+1]
+.
Step 2 (R) -N, N, 2-trimethyl-4- ( (1- (3- (methylsulfonamido) -5- (trifluoromethyl) phenyl) ethyl) amino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of (R) -N, N, 2-trimethyl-4- ( (1- (3- (N- (methylsulfonyl) methylsulfonamido) -5- (trifluoromethyl) phenyl) ethyl) amino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide (70 mg, 0.11 mmol) in THF/H
2O (4: 1, 3 mL) was added LiOH
. H
2O (12 mg, 0.27 mmol) at rt. The mixture was stirred for 3 h at rt. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by prep-HPLC (Column: Green ODS-A, 21.2 x 250mm, 10um; Mobile A: water with 0.05%TFA, Mobile B: CH
3CN; Gradient: 40%B over 2 min, 55%B over 15 min; Flow: 35 mL/min) to give 15.5 mg of the title product as a yellow solid. MS (ES+) : 566.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ10.16 (s, 1H) , 8.42 (s, 1H) , 8.37 (s, 1H) , 7.61 –7.46 (m, 2H) , 7.35 (d, J = 7.3 Hz, 1H) , 5.54 (m, 1H) , 3.51 (m, 4H) , 3.03 (s, 6H) , 2.89 (d, J = 10.0 Hz, 3H) , 2.35 (d, J = 3.3 Hz, 3H) , 1.97 –1.85 (m, 4H) , 1.56 (d, J = 7.0 Hz, 3H) .
EXAMPLE 235
(R) -6- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 2, 8-tetramethyl- [1, 2, 4] triazolo [1', 5': 1, 6] pyrido [2, 3-d] pyrimidine-4-carboxamide
Step 1 (R, E) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -7- (N'-hydroxyacetimidamido) -N, N, 2- trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of (R) -7-amino-4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide (70 mg, 0.17 mmol) in IPA (14 mL) was added 1, 1-dimethoxy-N, N-dimethylethanamine (280 mg, 2.1 mmol ) at room temperature under Ar. The mixture was stirred at 80℃ for 1 h and subsequently cooled to 0℃. NH
2OH
. HCl (433 mg, 10.83 mmol) was added and the mixture was stirred at 0℃ for 1 h. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to obtain 75 mg of crude product as a yellow solid which was used in the next step without further purification. MS (ES+) : 476.1 [M+1]
+.
Step 2 (R) -6- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 2, 8-tetramethyl- [1, 2, 4] triazolo [1', 5': 1, 6] pyrido [2, 3-d] pyrimidine-4-carboxamide
To a stirred solution of (R, E) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -7- (N'-hydroxyacetimidamido) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide (25 mg, 0.053 mmol) in CHCl
3 (5 mL) was slowly added POCl
3 (60 mg, 0.39 mmol) . The mixture was stirred at 60℃ for 30 min. After the reaction was completed, the mixture was poured into ice-water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-HPLC (Column: Green ODS-A, 21.2 x 250mm, 10um; Mobile A: water with 0.05%TFA, Mobile B: CH
3CN; Gradient: 50%B over 2 min, 70%B over 15 min; Flow: 35 mL/min) to give 5.1 mg of the title product as a white solid. MS (ES+) : 458.0 [M+1]
+.
1H NMR (400 MHz, Methanol-d
4) δ 8.51 (s, 1H) , 7.60 (t, J = 7.4 Hz, 1H) , 7.47 (t, J = 7.1 Hz, 1H) , 7.22 (t, J = 7.7 Hz, 1H) , 7.00 (t, J = 54.9 Hz, 1H) , 5.85 (m, 1H) , 3.21 (s, 3H) , 2.99 (s, 3H) , 2.62 (s, 3H) , 2.54 (s, 3H) , 1.68 (d, J = 7.2 Hz, 3H) .
EXAMPLE 236
(R) -7- (bis (2-methoxyethyl) amino) -4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of (R) -7-chloro-4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide (60 mg, 0.13 mmol) in 1.4-dioxane (2 mL) were added 2-methoxy-N- (methoxymethyl) ethan-1-amine (182 mg, 1.37 mmol) and DIEA (177 mg, 1.16 mmol) at rt. The mixture was stirred for 2 h at 100℃ under Ar. After cooling, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA: MeOH=10: 1) to give 30.1 mg of pure product as a yellow solid. MS (ES+) : 535.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.81 (s, 1H) , 8.54 (s, 1H) , 7.76 –7.63 (m, 1H) , 7.51 (t, J = 7.2 Hz, 1H) , 7.38 –7.05 (m, 2H) , 5.89 –5.67 (m, 1H) , 3.75 (m, 2H) , 3.68 –3.57 (m, 2H) , 3.49 (m, 4H) , 3.24 (d, J = 3.8 Hz, 6H) , 3.02 (s, 3H) , 2.87 (d, J = 7.3 Hz, 3H) , 2.35 (s, 3H) , 1.57 (d, J = 7.1 Hz, 3H) .
EXAMPLE 237
(R) -1- (4- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) cyclopropanecarboxylic acid
A mixture of (R) -ethyl1- (2-methyl-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethylamino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) cyclopropanecarboxylate (18 mg, 0.034 mmol) in MeOH (1.4 mL) and NaOH (2N, 1.4 mL) was stirred for 6 h at 60℃ under Ar. After the reaction was completed, the mixture was adjusted pH=6 by 1N HCl and extracted with 10%MeOH/DCM. The organic layer was dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (10%MeOH: DCM+4%AcOH) to give 3.8 mg of the title product as a yellow solid. MS (ES+) : 501.1 [M+1]
+.
1H NMR (400 MHz, Methanol-d
4) δ 8.34 (s, 1H) , 6.95 (m, 2H) , 6.80 (s, 1H) , 5.63 (m, 1H) , 3.93 (m, 4H) , 2.49 (d, J = 8.7 Hz, 3H) , 2.04-2.00 (m, 4H) , 1.63 (m, 7H) .
EXAMPLE 238
(R) -6- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 8-trimethyltetrazolo [1', 5': 1, 6] pyrido [2, 3-d] pyrimidine-4-carboxamide
To a stirred solution of (R) -7-chloro-4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -N, N, 2-trimethylpyrido [2, 3-d] pyrimidine-6-carboxamide (150 mg, 0.34 mmol) in DMSO (15 mL) was added NaN
3 (37.5 mg, 0.58 mmol) at rt. The mixture was stirred at 90℃ for 5 h. After the reaction was completed, water was added and the mixture was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-HPLC (Column: Green ODS-A, 21.2 x 250mm, 10um; Mobile A: water with 0.05%TFA, Mobile B: CH
3CN; Gradient: 50%B over 2 min, 70%B over 15 min; Flow: 35 mL/min) to give 25.6 mg of the title product as a white solid. MS (ES+) : 445.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 9.11 (d, J = 6.9 Hz, 1H) , 8.81 (s, 1H) , 7.72 (t, J = 7.6 Hz, 1H) , 7.53 (t, J = 7.1 Hz, 1H) , 7.42 –7.01 (m, 2H) , 5.81 (m, 1H) , 3.12 (s, 3H) , 2.91 (s, 3H) , 2.54 (s, 3H) , 1.63 (d, J = 7.0 Hz, 3H) .
EXAMPLE 239
(R) - (1- (4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) cyclopropyl) methanol
Step 1 (R) -ethyl 2- (4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) acrylate
To a stirred solution of (R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine (200 mg, 0.42 mmol) in THF (20 mL) were added ethyl2- (tributylstannyl) acrylate (423 mg, 1.09 mmol) , CuI (158.6 mg, 0.83 mmol) and Pd (PPh
3)
4 (145 mg, 0.13 mmol) at rt. The mixture was evacuated by Ar three times and stirred for 4 h at 60℃. After the reaction was completed, water was added and extracted with EA. The organic layer was dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (10%MeOH/DCM) and Prep-HPLC (Column: Green ODS-A, 21.2 x 250mm, 10um; Mobile A: water with 0.05%HCOOH, Mobile B: CH
3CN; Gradient: 40%B over 2 min, 55%B over 15 min; Flow: 35 mL/min) to give 149 mg of the title product as a yellow solid. MS (ES+) : 500.1 [M+1]
+.
Step 2 (R) -ethyl 1- (4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) cyclopropanecarboxylate
To a stirred solution of trimethylsulfoxonium iodide (612.8 mg, 2.78 mmol) in THF (10 mL) was added t-BuOK (312 mg, 2.78 mmol) at 0℃. The mixture was stirred for 1 h at 0℃ under Ar. Then (R) -ethyl2- (4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) acrylate (139 mg, 0.278 mmol) in THF (24.7 mL) was added into the mixture at 0℃. The mixture was stirred for 0.5 h at 0℃ under Ar. After the reaction was completed, water was added and the mixture was extracted with EA. The organic layer was dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA) to give 75.6 mg of the title product as a yellow solid. MS (ES+) : 514.1 [M+1]
+. Step 3 (R) - (1- (4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) cyclopropyl) methanol
To a stirred solution of (R) -ethyl 1- (4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) cyclopropanecarboxylate (65.6 mg, 0.13 mmol) in DCM (8.8 mL) was added DIBAL-H (1.5N, 0.25 mL, 0.39 mmol) at -70℃. The mixture was stirred for 0.5 h at -70℃ under Ar. After the reaction was completed, the reaction was quenched by 340 mg of potassium sodium tartrate tetrahydrate. Water was added and he mixture was extracted with DCM. The organic layer was dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (5%MeOH: DCM) to give 18 mg of the title product as a white solid. MS (ES+) : 472.1 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 9.77 (s, 1H) , 8.61 (s, 1H) , 7.79 (t, J = 7.5 Hz, 1H) , 7.55 (t, J = 7.1 Hz, 1H) , 7.40 –7.02 (m, 2H) , 5.88 (m, 1H) , 4.83 (s, 1H) , 3.80 (m, 4H) , 2.44 (s, 3H) , 1.92 (m, 4H) , 1.65 (d, J = 7.1 Hz, 3H) , 1.08 (m, 4H) .
EXAMPLE 240
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (5-methyl-4H-1, 2, 4-triazol-3-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Step 1 (R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of (R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxylic acid (200 mg, 0.45 mmol) and NH
4Cl (238 mg, 4.50 mmol) in DMF (10 mL) were added DIEA (580 mg, 4.50 mmol) and HATU (188 mg, 0.48 mmol) at rt. The mixture was stirred at rt for 2 h. After the reaction was completed, water was added and the mixture was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (MeOH/DCM=10%) to give 73 mg of the title product as a yellow solid. MS (ES+) : 445.1 [M+1]
+.
Step 2 (R, E) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -N- (1- (dimethylamino) ethylidene) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
The mixture of (R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide (73 mg, 0.16 mmol) and 1, 1-dimethoxy-N, N-dimethylethanamine (580 mg, 4.35 mmol) in 1, 4-dioxane (14.5 mL) was stirred at 100℃ for 1 h. After the reaction was completed, the mixture was concentrated to obtain the title product as a yellow solid. MS (ES+) : 514.1 [M+1]
+.
Step 3 (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (5-methyl-4H-1, 2, 4-triazol-3-yl) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
To a stirred solution of (R, E) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -N- (1- (dimethylamino) ethylidene) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide (crude from above step) in AcOH (13.6 mL) was added 98%Hydrazinium hydroxide solution in AcOH (0.7 ml) at rt. The mixture was stirred for 0.5 h at 90℃ under Ar. After the reaction was completed, the solution was directly purified by Prep-HPLC (Column: Green ODS-A, 21.2 x 250mm, 10um; Mobile A: water with 0.05%HCOOH, Mobile B: CH
3CN; Gradient: 40%B over 2 min, 55%B over 15 min; Flow: 35 mL/min) to give 3.7 mg of the title product as a yellow solid. MS (ES+) : 483.1 [M+1]
+.
1H NMR (400 MHz, Methanol-d
4) δ 8.51 (d, J = 5.8 Hz, 1H) , 7.58 (t, J = 7.5 Hz, 1H) , 7.49 (t, J = 7.1 Hz, 1H) , 7.24 (t, J = 7.8 Hz, 1H) , 6.99 (t, J = 54.8 Hz, 1H) , 5.86 (m, 1H) , 3.34 (m, 4H) , 2.52 (s, 3H) , 2.46 (s, 3H) , 1.88 (m, 4H) , 1.64 (d, J = 7.1 Hz, 3H) .
EXAMPLE 241
(R) -4- ( (1- (3- (dimethylamino) -5- (trifluoromethyl) phenyl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide (80 mg, 0.16 mmol) in DCM (8 mL) were added 35%Formaldehyde (80 mg, 2.67 mmol) , STAB (112 mg, 0.53 mmol) and AcOH (32 mg, 0.53 mmol) at rt. The mixture was stirred for 1 h at rt under Ar. After the reaction was completed, the reaction was quenched with water and the mixture was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-TLC (EA+1d TEA) and Prep-HPLC (Column: Green ODS-A, 21.2 x 250mm, 10um; Mobile A: water with 0.05%HCOOH, Mobile B: CH
3CN; Gradient: 40%B over 2 min, 55%B over 15 min; Flow: 35 mL/min) to give 9.8 mg of pure product as a white solid. MS (ES+) : 516.1 [M+1]
+.
1H NMR (400 MHz, Methanol-d
4) δ 8.32 (d, J = 7.4 Hz, 1H) , 7.11 –6.92 (m, 2H) , 6.80 (s, 1H) , 5.73 –5.58 (m, 1H) , 3.64 (m, 2H) , 3.49 (m, 2H) , 3.12 (d, J = 3.6 Hz, 3H) , 2.98 (m, 9H) , 2.47 (d, J = 3.7 Hz, 3H) , 2.10 –1.90 (m, 4H) , 1.63 (d, J = 7.1 Hz, 3H) .
EXAMPLE 242
(R) -4- ( (1- (3-fluorobenzofuran-7-yl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 1- (2-fluoro-3-nitrophenyl) ethan-1-one
1-bromo-2-fluoro-3-nitrobenzene (5.00 g, 22.73 mmol) was dissolved in dioxane (50 mL) . Tributyl (1-ethoxy vinyl) stannane (9.84 g, 27.24 mmol) was added and the mixture was purged with N
2 for 15 minutes. Pd (PPh
3)
2Cl
2 (0.16 g, 0.28 mmol) was added and the mixture was heated to 95 ℃ for 16 h under N
2 atmosphere. After completion, the mixture was treated with HCl (1N, 30 mL) and stirred for 1 hour. The aqueous layer was extracted with DCM (50 m x 3) and H
2O. The organic layer was washed with brine (50 mL) , dried over anhydrous Na
2SO
4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (PE : EA = 5 : 1) to give 1- (2-fluoro-3-nitrophenyl) ethan-1-one (3.23 g) as a yellow liquid.
1H NMR (400 MHz, CDCl
3) δ 8.18 (dt, J = 15.9, 8.3 Hz, 2H) , 7.40 (t, J = 8.0 Hz, 1H) , 2.72 (d, J = 5.3 Hz, 3H) .
Step 2 1- (3-amino-2-fluorophenyl) ethan-1-one
Fe powder (5.94 g, 106.05 mmol) followed by NH
4Cl (5.62 g, 106.05 mmol) in H
2O (60 mL) were added to a solution of 1- (2-fluoro-3-nitrophenyl) ethan-1-one (3.23 g, 17.67 mmol) at 55 ℃. The mixture was heated to reflux for 1 h. IPC by TLC (PE : EA = 5 : 1) . After completion, the mixture was filtered through celite. The aqueous layer was extracted with EA (50 mL x 3) and H
2O. The organic layer was washed with brine (50 mL) , dried over anhydrous Na
2SO
4, filtered and concentrated in vacuum to give 1- (3-amino-2-fluorophenyl) ethan-1-one (2.7 g) as a black oil. MS (ES+) : 154.1 [M+1]
+.
Step 3 1- (2-fluoro-3-iodophenyl) ethan-1-one
To a solution of CuI (13.43 g, 70.56 mmol) in CH
3CN (35 mL) was added isopentyl nitrite (8.27 g, 70.56 mmol) at 25℃. The mixture was heated to 65℃ and a solution of 1- (3-amino-2-fluorophenyl) ethan-1-one (5.40 g, 35.28 mmol) in CH
3CN (35 mL) was added dropwise at 65℃ over 1 h. The mixture was stirred at 65℃ for 16 h and then was concentrated in vacuum. The residue was purified by silica gel chromatography (PE) to give 1- (2-fluoro-3-iodophenyl) ethan-1-one (3.7g) as a white solid.
1H NMR (400 MHz, CDCl
3) δ 7.93 (t, J = 5.9 Hz, 1H) , 7.82 (t, J = 6.5 Hz, 1H) , 7.00 (t, J = 7.8 Hz, 1H) , 2.65 (d, J = 5.1 Hz, 3H) .
Step 4 ethyl 2- (3-acetyl-2-fluorophenyl) -2, 2-difluoroacetate
A solution of ethyl 2-bromo-2, 2-difluoroacetate (3.70 g, 18.27 mmol) and CuI (1.10 g, 18.27 mmol) in DMSO (7 mL) was stirred at 25℃ for 30 minutes under N
2 atmosphere. The mixture was added with a solution of 1- (2-fluoro-3-iodophenyl) ethan-1-one (1.93 g, 7.31 mmol) in DMSO (8 mL) dropwise. The mixture was stirred at 25℃ for 48 h under N
2 atmosphere. IPC by TLC (PE: EA = 10 : 1) . After the reaction was completed, the mixture was quenched with saturated NH
4Cl and extracted with EA (150 mL x 2) . The organic layer was washed with brine (50 mL x 2) , dried over anhydrous Na
2SO
4, filtered and concentrated in vacuum to give ethyl 2- (3-acetyl-2-fluorophenyl) -2, 2-difluoroacetate (1.9 g, 7.31 mmol, 40%yield) as a yellow oil.
1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 6.2 Hz, 1H) , 7.83 (d, J = 6.6 Hz, 1H) , 7.35 (d, J = 7.4 Hz, 1H) , 4.43 –4.33 (m, 2H) , 2.64 (s, 3H) , 1.34 (d, J = 7.1 Hz, 3H) .
Step 5 ethyl (R, E) -2- (3- (1- ( (tert-butylsulfinyl) imino) ethyl) -2-fluorophenyl) -2, 2-difluoroacetate
Ethyl 2- (3-acetyl-2-fluorophenyl) -2, 2-difluoroacetate (1.90 g, 7.31 mmol) in THF (20 mL) . (R) -2-methylpropane-2-sulfinamide (1.33 g, 10.96 mmol) and titanium ethoxide (5.00 g, 21.93 mmol) were added at 25℃. Then, the mixture was heated to 80℃ for 16 h. After the reaction was completed, the mixture was extracted with EA (50 mL x 2) . The organic layer was washed with brine (50 mL) , dried over anhydrous Na
2SO
4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (PE: EA=5: 1) to give the title compound (1.56 g) as a yellow solid. MS (ES+) : 364.1 [M+1]
+.
1H NMR (400 MHz, CDCl
3) δ 7.80 (d, J = 6.9 Hz, 1H) , 7.75 (dd, J = 14.2, 7.2 Hz, 1H) , 7.32 (dd, J = 17.2, 8.4 Hz, 1H) , 2.75 (s, 2H) , 1.33 (s, 3H) , 1.31 (s, 9H) , 1.23 (s, 3H) .
Step 6 (R) -N- ( (R) -1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) -2-methylpropane-2-sulfinamide
A solution of the product of Step 5 (0.93 g, 2.57 mmol) was dissolved in DCM (5 mL) and MeOH (5 mL) . Then, NaBH
4 (0.29g, 7.70 mmol) was added at 0℃. The mixture was stirred at 25℃ for 6 hours. After the reaction was completed, the mixture was quenched with saturated NH
4Cl and extracted with DCM (30 mL x 2) . The organic layer was washed with brine (50 mL) , dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel chromatography (EA) to give the title compound (0.42 g) as a white solid.
1H NMR (400 MHz, CDCl
3) δ 7.50 (dd, J = 14.3, 7.0 Hz, 1H) , 7.43 (dd, J = 13.9, 6.8 Hz, 1H) , 7.20 (q, J = 7.8 Hz, 1H) , 4.69 (dd, J = 14.5, 7.3 Hz, 1H) , 4.03 (s, 2H) , 3.61 (d, J = 7.2 Hz, 2H) , 1.94 (s, 1H) , 1.56 (t, J = 7.5 Hz, 3H) , 1.19 (d, J = 8.5 Hz, 9H) .
Step 7 (R) -N- ( (R) -1- (3-fluorobenzofuran-7-yl) ethyl) -2-methylpropane-2-sulfinamide
To a stirred solution of the product of Step 6 (0.30 g, 0.93 mmol) in THF (10 mL) were added t-BuOK (0.31 g, 2.79 mmol) and 18-crown-6 (0.12 g, 0.46 mmol) at 25℃. The resulting mixture was heated to 80℃for 16 hours. IPC by LCMS. After the reaction was completed, the mixture was extracted with EA (30 mL x 2) . The organic layer was washed with brine (30 mL) , dried over anhydrous Na
2SO
4, filtered and concentrated to give 0.26 g crude as a yellow oil. MS (ES+) : 284.0 [M+1]
+.
1H NMR (400 MHz, CDCl
3) δ 7.64 –7.59 (m, 1H) , 7.53 (d, J = 7.7 Hz, 1H) , 7.33 (t, J = 5.6 Hz, 1H) , 5.00 (td, J = 13.3, 6.7 Hz, 1H) , 3.70 (s, 1H) , 1.64 (d, J = 6.7 Hz, 3H) , 1.23 (s, 9H) .
Step 8 (R) -1- (3-fluorobenzofuran-7-yl) ethan-1-amine
To a stirred solution of the product of Step 7 (0.26 g, 0.92 mmol) in dioxane (5 mL) was added HCl/dioxane (4N, 15 mL) . The resulting mixture was stirred at 25℃ for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, the precipitate filtered and washed with EA (5 mL) to give 0.16 g crude product as a yellow solid. MS (ES+) : 180.1 [M+1]
+.
1H NMR (400 MHz, CDCl
3) δ 8.77 (s, 2H) , 7.69 –7.49 (m, 3H) , 4.96 (s, 1H) , 3.71 (d, J = 6.9 Hz, 1H) , 2.33 (s, 3H) .
Step 9 (R) -4- ( (1- (3-fluorobenzofuran-7-yl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of N, N, 2-trimethyl-7- (pyrrolidin-1-yl) -4- (2, 2, 2-trifluoroethoxy) pyrido [2, 3-d] pyrimidine-6-carboxamide (30.0 mg, 0.078 mmol) and (R) -1- (3-fluorobenzofuran-7-yl) ethan-1-amine hydrochloride (80.0 mg, 0.37mmol) in DMSO (2 mL) was added DIEA (100.0 mg, 0.78 mmol) under N
2. The mixture was stirred at 120 ℃ for 54 h. After completed, the reaction mixture was purified by prep-HPLC, eluted with CH
3CN in H
2O (0.1%NH
4OH) from 10%to 90%, to give the title product (5.66 mg) as a white solid. MS (ES+) : 463.4 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) : δ 8.43 (s, 1H) , 8.30 (m, 1H) , 8.24 (m, 1H) , 7.54 (m, 1H) , 7.43 (m, 1H) , 7.27- 7.31 (m, 1H) , 6.00 (br, 1H) , 3.50 (br, 4H) , 3.03 (s, 3H) , 2.91 (m, 3H) , 2.33 (m, 3H) , 1.91 (m, 4H) , 1.61-1.63 (m, 3H) .
EXAMPLE 243
(R) -4- ( (1- (3-cyano-2-fluorophenyl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 3-acetyl-2-fluorobenzonitrile
To a stirred solution of 1- (2-fluoro-3-iodophenyl) ethan-1-one (3 g, 11.37 mmol) in toluene (50.0 mL) was added Bis (2-methoxyethyl) amino sulfur trifluoride (7.53 g, 34.08 mmol) at 0℃. The mixture was stirred for 16 h at 65℃. After the reaction was completed, Potassium Carbonate was added and then quenched with water and extracted with EA (60.0 mL x 3) . The organic layer was washed with brine (50.0 mL) , dried over anhydrous Na
2SO
4, filtered and concentrated in vacuum. The residue was purified by silica gel column chromatography to give 536 mg of the title product as a yellow oil. MS (ES+) : 286.1 [M+1]
+.
1H NMR (400 MHz, CDCl3) δ 7.82 (t, J = 6.8 Hz, 1H) , 7.52 (t, J = 7.6 Hz, 1H) , 6.96 (t, J = 7.6 Hz, 1H) , 1.99 (t, J = 18.8 Hz, 3H) .
Step 2 1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethan-1-one
To a stirred solution of 3-acetyl-2-fluorobenzonitrile (536 mg, 0.83 mmol) in dioxane (5.0 mL) was added tributyl (1-ethoxyvinyl) stannae (358 mg, 0.99 mmol) and the mixture was purged with N
2 for 15 minutes. Pd (PPh
3)
2 Cl
2 (6 mg, 0.0083 mmol) was added and the mixture was stirred for 16 h at 100℃ . After the reaction was completed, the mixture was treated with HCl (1N, 30 mL) and stirred for 1 hour. then quenched with water and extracted with EA (25.0 mL x 3) . The organic layer was washed with brine (25.0 mL) , dried over anhydrous Na
2SO
4, filtered and concentrated in vacuum. The residue was purified by silica gel colum chromatography to give 255 mg of the title product as a yellow oil. MS (ES+) : 202.2 [M+1]
+.
1H NMR (400 MHz, CDCl
3) δ 7.94 (t, J = 7.6 Hz, 1H) , 7.73 (t, J = 6.8 Hz, 1H) , 7.31 –7.24 (m, 1H) , 2.67 (d, J = 5.2 Hz, 3H) , 2.03 (t, J = 18.8 Hz, 3H) .
Step 3 (R, E) -N- (1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethylidene) -2-methylpropane-2-sulfinamide
To a stirred solution of 1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethan-1-one (255 mg, 0.98mmol) in THF (5.0 mL) was added (R) -2-methylpropane-2-sulfinamide (180 mg, 1.49 mmol) and titanium ethoxide (677 mg, 2.96 mmol) at room temperature. The mixture was stirred at 80 ℃ for 16 h. After the reaction was completed, then quenched with water (10.0 mL) and extracted with EA (25.0 mL x 3) . The organic layer was washed with brine (25.0 mL) , dried over anhydrous Na
2SO
4, filtered and concentrated in vacuum. The residue was purified by silica gel column chromatography to give 252 mg of the title product as a yellow liquid. MS (ES+) : 306.1 [M+1]
+.
Step 4 (R) -N- ( (R) -1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) -2-methylpropane-2-sulfinamide
A mixture of (R, E) -N- (1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethylidene) -2-methylpropane-2-sulfinamide (252 mg, 0.83 mmol) in THF (5 mL) and cooled to 0℃. Sodium borohydride (32 mg, 0.83 mmol) was added and the resulting mixture and the mixture was stirred at room temperature for 6 h. After the reaction was completed, then quenched with water and the mixture was extracted with EA. The organic layer was washed with brine (25.0 mL) , dried over anhydrous Na
2SO
4, filtered and concentrated in vacuum. The residue was purified by silica gel column chromatography to give 178 mg of product as a yellow oil. MS (ES+) : 308.1 [M+1]
+.
Step 5 (R) -1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethan-1-amine
To a stirred solution of (R) -N- ( (R) -1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) -2-methylpropane-2-sulfinamide (178 mg, 0.58 mmol) in 1, 4-dioxane (5.0 mL) was cooled to 0℃ and treated with 4 N HCl in 1, 4-dioxane (5 mL) . The mixture was stirred for 6 h at rt. After the reaction was completed, the reaction mixture was concentrated in vacuum, and the precipitate filtered and washed with diethyl ether to obtain the title compound (100 mg) as a white solid. MS (ES+) : 203.2 [M+1]
+.
Step 5 (R) -4- ( (1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of 4-hydroxy-N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide (50.0 mg, 0.17 mmol) in DMSO (2 mL) was added (R) -1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethan-1-amine (50.6 mg, 0.25 mmol) , DBU (76.1 mg, 0.5 mmol) and BOP (110.5 mg, 0.25mmol) under N
2. The mixture was stirred at room temperature for 16 h. The reaction mixture was purified by prep-HPLC, eluted with CH3CN in H
2O (0.1%NH
4OH) from 10%to 90%to the title product (4.6 mg) as a white solid. MS (ES+) : 473.2 [M+1]
+.
1H NMR (400 MHz, CD3OD-d4) : δ 8.31 (s, 1H) , 7.52 (m, 1H) , 7.41 (m, 1H) , 7.16 (m, 1H) , 5.. 78 (m, 1H) , 4.58 (br, 1H) , 3.31-3.65 (m, 4H) , 3.13 (s, 3H) , 3.02 (m, 3H) , 2.36 (s, 3H) , 1.94-2.03 (m, 7H) , 1.62 (m, 3H) .
EXAMPLE 244
(R) -5- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 7-trimethyl-2- (pyrrolidin-1-yl) -1, 8-naphthyridine-3-carboxamide
Step 1 methyl 6- ( (tert-butoxycarbonyl) amino) -2- (pyrrolidin-1-yl) nicotinate
To a stirred solution of methyl 6-chloro-2- (pyrrolidin-1-yl) nicotinate (2.5 g, 10.4 mmol) in dioxane (60.0 mL) was added tert-Butyl carbamate (6.08 g, 52.0 mmol) , Xantphos (120 mg, 0.208 mmol) , Cs
2CO
3 (13.56 g, 41.6 mmol) and Pd
2 (dba)
3 (190 mg, 0.208 mmol) . The mixture was degassed with N
2 and stirred at 120 ℃ for 12 h. The mixture was filtered through a pad of Celite. The filtrate was diluted with H
2O and extracted with EA. The combined organic layer was washed with brine, dried over Na
2SO
4 and concentrated in vacuum. The residue was purified by silica gel column chromatography (PE : EA = 6 : 1 to EA) to give the title product (2.3 g) as a pale yellow solid. MS (ES+) : 322.4 [M+1]
+.
Step 2 methyl 6-amino-2- (pyrrolidin-1-yl) nicotinate
A solution of the product of Step 1 (2.3 g, 7.2 mmol) in TFA (5 mL) and DCM (10 mL) was stirred at room temperature for 3 h. The mixture was concentrated in vacuum to give the title product (2.0 g, crude) which was directly used in the next step. MS (ES+) : 222.0 [M+1]
+.
Step 3 5-hydroxy-N, N, 7-trimethyl-2- (pyrrolidin-1-yl) -1, 8-naphthyridine-3-carboxami de
A solution of methyl 6-amino-2- (pyrrolidin-1-yl) nicotinate (2.0 g, 8.5 mmol) and PPA (10.0 g, 85 mmol) in ethyl 3-oxobutanoate (5 ml) was stirred at 135 ℃ for 16 h. The mixture solution was added to ice water (100 ml) , adjust PH>7 by Na
2CO
3, extracted with EA (50 ml x 3) . The organic layer was washed with brine (50 ml) , dried over Na
2SO
4, Flited and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH= 100: 1 to 20: 1) to give the title product (2.5 g) as a yellow solid. MS (ES+) : 301.2 [M+1]
+.
Step 4 5-chloro-N, N, 7-trimethyl-2- (pyrrolidin-1-yl) -1, 8-naphthyridine-3-carboxamide
To a solution of the product of Step3 (2.5 g, 8.3 mmol) in CH
3CN (30mL) was added POCl
3 (4.0 g, 24.9 mmol) and DIEA (3.2 g, 24.9 mmol) . The mixture was heated to 90℃ for 16 h under N
2 atmosphere. The mixture was diluted with H
2O (50 mL) and extracted with EA (30 mL x 3) . The combined organic layer was washed with brine (30 mL) , dried over Na
2SO
4 and concentrated in vacuum. The residue was purified by prep-TLC (DCM/MeOH = 10 : 1) to give the title product (1.7 g) as a yellow solid. MS (ES+) : 319.2 [M+1]
+ , 321.2 [M+3]
+.
Step 5 (R) -5- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 7-trimethyl-2- (pyrrolidin-1-yl) -1, 8-naphthyridine-3-carboxamide
To a stirred solution of 55-chloro-N, N, 7-trimethyl-2- (pyrrolidin-1-yl) -1, 8-naphthyridine-3-carboxamide (200 mg, 0.67 mmol) in dioxane (20 mL) was added (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethan-1-amine hydrochloride (300 mg, 1.33 mmol) , BINAP (19 mg, 0.03 mmol) , Cs
2CO
3 (546 mg, 1.68 mmol) and Pd (OAc)
2 (6.8 mg, 0.03 mmol) . The mixture was degassed with N
2 and stirred at 110 ℃ for 16 h under N
2 atmosphere. The mixture was filtered through a pad of Celite. The filtrate was diluted with H
2O (20 mL) and extracted with EA (20 mL X 3) . The combined organic layer was washed with brine, dried over Na
2SO
4 and concentrated in vacuum. The residue was purified by prep-HPLC eluted with MeCN in H
2O (0.1%HCOOH) from 20%to 95%to the title product (41 mg) as a yellow solid. MS (ES+) : 472.2 [M+1]
+.
1H NMR (400 MHz, MeOH-d
4) : δ 8.53 (s, 1H) , 7.61-7.56 (m, 2H) , 7.32-7.30 (m, 1H) , 7.16-6.80 (m, 1H) , 6.28 (s, 1H) , 5.32 (m, 1H) , 3.67 -3.50 (m, 4H) , 3.16 (s, 3H) , 3.06 (m, 3H) , 2.46 (s, 3H) , 2.00 (s, 4H) , 1.73-1.70 (m, 3H) .
EXAMPLE 245
(R) -5- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 7-trimethyl-2- (pyrrolidin-1-yl) -1, 6-naphthyridine-3-carboxamide
Step 1 Methyl 6-chloro-2- (pyrrolidin-1-yl) nicotinate
To a stirred solution of methyl 2, 6-dichloronicotinate (5 g, 24.27 mmol) in dioxane (50 mL) was added pyrrolidine (2.59 g, 36.4 mmol) and DIEA (5.1 mL, 29.12 mmol) . The mixture was stirred at room temperature for 12 h. The solvent was removed under reduced pressure. The residue was diluted with H
2O and extracted with EA. The combined organic layer was washed with brine, dried over Na
2SO
4 and concentrated in vacuum to give the title product (5.9 g) as a yellow oil. MS (ES+) : 241.0, 243.0 [M+1]
+.
Step 2 Methyl 6-chloro-5-iodo-2- (pyrrolidin-1-yl) nicotinate
To a stirred solution of the product od Step 1 (5.9 g, 24.6 mmol) in MeCN (60 mL) was added NIS (8.3 g, 36.9 mmol) . The mixture was stirred at room temperature for 12 h. The mixture was diluted with water and extracted with EA (50 mL X 3) . The combined organic layer was washed with 10%of Na
2S
2O
3 aq. (50 mL) and brine (50 mL) , dried over Na
2SO
4 and concentrated in vacuum to give crude product which was purified by silica gel column chromatography (PE: EA=15: 1~EA) to give the title product (6.5 g) as a white solid. MS (ES+) : 367.0 [M+1]
+.
Step 3 6-chloro-5-iodo-2- (pyrrolidin-1-yl) nicotinic acid
To a stirred solution of the product of Step 2 (4.5 g, 12.3 mmol) in EtOH (25 mL) and H
2O (25 mL) was added NaOH (9.8 g, 246 mmol) . The mixture was stirred at 90 ℃ for 1 h. EtOH was removed by concentration. The mixture was adjusted to pH 2~3 with HCl (1N) . The precipitate was collected by filtration and dried in vacuum to give the title product (4 g) as a yellow solid. MS (ES+) : 353.0 [M+1]
+.
Step 4 6-chloro-5-iodo-N, N-dimethyl-2- (pyrrolidin-1-yl) nicotinamide
To a stirred solution of the product od Step 3 (4 g, 11.4 mmol) in DMF (40 mL) was added dimethylamine hydrochloride (1.4 g, 17.1 mmol) , HATU (8.6 g, 22.8 mmol) and DIEA (4.4 g, 34.2 mmol) . The mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water and extracted with EA (50 mL X 3) . The combined organic layer was washed with brine (60 mL) , dried over Na
2SO
4 and concentrated in vacuum. The residue was purified by silica gel column chromatography (PE : EA = 5 : 1 to EA) to the title product (4.3 g) as a pale yellow solid. MS (ES+) : 380.0 [M+1]
+.
Step 5 Methyl 2-chloro-5- (dimethylcarbamoyl) -6- (pyrrolidin-1-yl) nicotinate
To a solution of the product of Step 4 (4.3 g, 11.3 mmol) in MeOH (200 mL) was added Xantphos (1.9 g, 3.39 mmol) , TEA (12.6 g, 124.3 mmol) , DMF (5 mL) and Pd (OAc)
2 (760 mg, 3.39 mmol) . The mixture was degassed with CO and stirred in a high-pressure reactor. The reactor was filled with CO till the pressure raised to 10MPa. The mixture was stirred at 85 ℃ for 12 h. The mixture was filtered through a pad of Celite. The filtrate was diluted with H
2O (100 mL) and extracted with DCM (200 mL X 3) . The combined organic layer was washed with brine (200 mL) , dried over Na
2SO
4 and concentrated in vacuum. The residue was purified by silica gel column (PE : EA = 6 : 1 to 1 : 1) to give the title product (2.2 g) as a brown solid. MS (ES+) : 312.0 [M+1]
+.
Step 6 Methyl 2- (1- (tert-butoxy) -1, 3-dioxobutan-2-yl) -5- (dimethylcarbamoyl) -6- (pyrrolidin-1-yl) nicotinate
A mixture of the product of Step 5 (500 mg, 1.60 mmol) , tert-butyl 3-oxobutanoate (1010 mg, 6.41 mmol) , Pd (OAc)
2 (36 mg, 0.16 mmol) , 2-di-t-butylphosphino-2'-methylbiphenyl (50 mg, 0.16 mmol) and K
3PO
4 (1021 mg, 4.81 mmol) in toluene (20 mL) was degassed and purged with N
2 3 times. Then, the mixture was stirred at 110℃ for 16 h under N
2 atmosphere. The mixture was filtered through a pad of Celite. The filtrate was diluted with H
2O (50 mL) and extracted with EA (30 mL x 3) . The combined organic layer was washed with brine (30 mL) , dried over Na
2SO
4 and concentrated in vacuum. The residue was purified by silica gel column chromatography (PE : EA = 10 : 1) to give the title product (350 mg) as a brown solid. MS (ES+) : 434.1 [M+1]
+.
Step 7 Methyl 5- (dimethylcarbamoyl) -2- (2-oxopropyl) -6- (pyrrolidin-1-yl) nicotinate
A solution od the product of Step 6 (350 mg, 0.81 mmol) in TFA (5 mL) was heated to 45℃ for 2 h under N
2 atmosphere. TFA was removed by reduced pressure. The crude title product (260 mg, 0.78 mmol) was obtained as a yellow oil. MS (ES+) : 334.1 [M+1]
+.
Step 8 5-hydroxy-N, N, 7-trimethyl-2- (pyrrolidin-1-yl) -1, 6-naphthyridine-3-carboxamide
A solution of the product of Step 7 (210 mg, 0.63 mmol) in NH
3
. MeOH (15mL) was heated to 80℃ in a stuffy tank for 2 h. The solvent was removed by reduced pressure. The crude title product (200 mg) was obtained as a yellow oil. MS (ES+) : 301.1 [M+1]
+.
Step 9 5-chloro-N, N, 7-trimethyl-2- (pyrrolidin-1-yl) -1, 6-naphthyridine-3-carboxamide
A solution of the product of Step 8 (200 mg, 0.67 mmol) in CH
3CN (10mL) was treated with POCl
3 (613 mg, 4.00 mmol) and DIEA (432 mg, 3.35 mmol) . The mixture was heated to 90℃ for 16 h under N
2 atmosphere. The mixture was diluted with H
2O (50 mL) and extracted with EA (30 mL X 3) . The combined organic layer was washed with brine (30 mL) , dried over Na
2SO
4 and concentrated in vacuum. The residue was purified by prep-TLC (DCM/MeOH = 10 : 1) to the title product (73 mg) as a yellow solid. MS (ES+) : 319.1 [M+1]
+.
Step 10 (R) -5- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 7-trimethyl-2- (pyrrolidin-1-yl) -1, 6-naphthyridine-3-carboxamide
To a stirred solution of 5the product of Step 9 (73 mg, 0.23 mmol) in dioxane (10 mL) was added (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethan-1-amine hydrochloride (103 mg, 0.46 mmol) , BINAP (14 mg, 0.023 mmol) , Cs
2CO
3 (225 mg, 0.69 mmol) and Pd (OAc)
2 (5 mg, 0.023 mmol) . The mixture was degassed with N
2 and stirred at 110 ℃ for 16 h under N
2 atmosphere. The mixture was filtered through a pad of Celite. The filtrate was diluted with H
2O (20 mL) and extracted with EA (20 mL x 3) . The combined organic layer was washed with brine, dried over Na
2SO
4 and concentrated in vacuum. The residue was purified by prep-HPLC, eluted with a gradient of MeCN in H
2O (0.1%HCOOH) from 20%to 95%to give the title product (6.06 mg) as a yellow solid. MS (ES+) : 472.1 [M+1]
+.
1H NMR (400 MHz, MeOD-d
4) : δ 8.32 (s, 1H) , 7.61 –7.51 (m, 1H) , 7.43 (s, 1H) , 7.18 (dd, J = 14.0, 6.7 Hz, 1H) , 6.99 (t, J = 54.8 Hz, 1H) , 6.59 (s, 1H) , 5.70 (q, J = 6.92 Hz, 1H) , 3.61 (s, 2H) , 3.45 (s, 2H) , 3.14 (s, 3H) , 3.01 (d, J = 7.48 Hz, 3H) , 2.26 (s, 3H) , 1.98 (s, 4H) , 1.62 (d, J = 6.92 Hz, 3H) .
EXAMPLE 246
3- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 1-trimethyl-6- (pyrrolidin1-yl) -1H-pyrazolo [3, 4-b] pyridine-5-carboxamide
Step 1 3-amino-N, N, 1-trimethyl-6- (pyrrolidin-1-yl) -1H-pyrazolo [3, 4-b] pyridine-5-carboxamide
To a solution of 6-chloro-5-cyano-N, N-dimethyl-2- (pyrrolidin -1-yl) pyridine-3-carboxamide (900 mg, 3.23 mmol) in EtOH (20 mL) , was added methylhydrazine; sulfuric acid (2.3 g, 16.14 mmol) , TEA (2.7 mL, 19.37 mmol) , and the reaction was stirred at 100 ℃ for 16 h. The reaction mixture was poured into water (100 mL) , and extracted with EA (3 × 50 mL) . The organic layer was washed with saturated NaCl (3 × 50 mL) . The EA layer was dried by Na
2SO
4, filtered and concentrated in vacuum to afford the title product (1 g, 3.47 mmol, crude) as a yellow solid. The crude product was used for the next step directly. MS (ES+) : 289.2 [M+1]
+.
Step 2 3- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N, 1-trimethyl-6- (pyrrolidin-1-yl) -1H-pyrazolo [3, 4-b] pyridine-5-carboxamide
To a solution of the product of Step 1 (80 mg, 0.28 mmol) in AcOH (2 mL) was added 1- [3- (difluoromethyl) -2-fluorophenyl] ethan-1-one (209 mg, 1.11 mmol) . The reaction was stirred at 50 ℃ for 1h under N
2 and then treated with sodium cyanoboranuide (52 mg, 0.83 mmol) . The reaction mixture was stirred at 50 ℃ for16 h under N
2. The reaction mixture was poured into NaHCO
3 (50 mL) and extracted with DCM (3 x 25 mL) . The organic layer was washed with saturated NaCl (3 X 10 mL) . The DCM layer was dried by Na
2SO
4, filtered and concentrated in vacuum to afford a crude product which was purified by prep-HPLC to afford the title product (13 mg) as a white solid. MS (ES+) : 461.2 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 7.85 (s, 1H) , 7.63 (s, 1H) , 7.46 (s, 1H) , 7.38 –7.05 (m, 2H) , 6.64 (d, J = 8.0 Hz, 1H) , 5.18 –5.04 (m, 1H) , 3.51 (s, 3H) , 3.43 (s, 2H) , 3.28 (s, 2H) , 2.99 (s, 3H) , 2.88 (s, 3H) , 1.86 (t, J = 6.4 Hz, 4H) , 1.46 (d, J = 6.8 Hz, 3H) .
EXAMPLE 247A&247B
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6- (1-isopropyl-1H-tetrazol-5-yl) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6- (2-isopropyl-2H-tetrazol-5-yl) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
Step 1 (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-7- (pyrrolidin-1-yl) -6- (1H-tetrazol-5-yl) -N- ( (2- (trimethylsilyl) ethoxy) methyl) pyrido [2, 3-d] pyrimidin-4-amine
To a solution of the product of Step 2 of Example 254 (300 mg, 0.54 mmol) in 1, 4-dioxane (5 mL) , was added azidotrimethylsilane (1.9 g, 16.19 mmol) , dibutyldichlorostannane (1.6 g, 6.47 mmol) . The reaction mixture was stirred at 100 ℃ for 12 h under N
2. The reaction mixture was poured into water (100 mL) , and extracted with EA (3 x 50 mL) . The organic layer was washed with NaCl (3 x 25 mL) . The EA layer was dried over Na
2SO
4, filtered and concentrated in vacuum to afford a crude product. The crude product was purified by silica gel column chromatography eluted with a gradient of 0 to 50%EA in PE to give the title compound (100 mg) as a yellow solid. MS (ES+) : 600.2 [M+1]
+.
Step 2 (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6- (1-isopropyl-1H-tetrazol-5-yl) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6- (2-isopropyl-2H-tetrazol-5-yl) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-4-amine
To a solution of (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-7- (pyrrolidin-1-yl) -6- (1H-tetrazol-5-yl) -N- ( (2- (trimethylsilyl) ethoxy) methyl) pyrido [2, 3-d] pyrimidin-4-amine (60 mg, 0.1 mmol) in DMF (1 mL) , was added N”-tert-butyl-N, N, N', N'-tetramethyl guanidine (34 mg, 0.2 mmol) , 2-iodopropane (290 mg, 1.7 mmol) . The reaction was stirred at rt for 2 h under N
2. The reaction mixture was filtered and purified by prep-HPLC, eluted with a gradient of CH
3CN in H
2O (0.1%NH
4OH) from 10%to 90%to give title product of EXAMPLE 247A (0.95 mg) EXAMPLE 247B (1.5 mg) as white solid.
EXAMPLE 247A MS (ES+) : 512.2 [M+1]
+.
1H NMR (400 MHz, MeOD) δ 8.47 (s, 1H) , 7.55 (t, J = 7.4 Hz, 1H) , 7.46 (t, J = 7.0 Hz, 1H) , 7.22 (t, J = 7.7 Hz, 1H) , 6.99 (t, J = 54.9 Hz, 1H) , 5.79 (d, J = 7.1 Hz, 1H) , 5.33 (d, J = 4.7 Hz, 1H) , 3.19 (s, 2H) , 3.00 (s, 2H) , 2.40 (s, 3H) , 1.86 (s, 4H) , 1.61 (d, J = 7.0 Hz, 6H) , 1.55 (s, 3H) .
EXAMPLE 247B MS (ES+) : 512.2 [M+1]
+.
1H NMR (400 MHz, MeOD) δ 8.56 (s, 1H) , 7.55 (t, J = 7.4 Hz, 1H) , 7.45 (t, J = 7.2 Hz, 1H) , 7.21 (t, J = 7.6 Hz, 1H) , 7.00 (t, J = 54.9 Hz, 1H) , 5.82 –5.76 (m, 1H) , 5.26 –5.21 (m, 1H) , 3.23 (s, 2H) , 3.00 (t, J = 6.5 Hz, 2H) , 2.38 (s, 3H) , 1.86 (t, J = 6.4 Hz, 4H) , 1.71 (d, J = 6.7 Hz, 6H) , 1.61 (d, J = 7.1 Hz, 3H) .
EXAMPLE 248
(R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-cyclopropyl-N, N-dimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -2-cyclopropyl-N, N-dimethyl-4- ( (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of 2-cyclopropyl-4-hydroxy-N, N-dimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide (130.0 mg, 0.4 mmol) in DMSO (3 mL) was added (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethan-1-amine (270.0 mg, 1 mmol) , DBU (180.0 mg, 1.2 mmol) and BOP (270.0 mg, 0.6mmol) under N
2. The mixture was stirred at room temperature for 16 h. The reaction mixture was purified by prep-TLC (EA) , to give title product (200 mg) as a white solid. MS (ES+) : 544.4 [M+1]
+.
Step 2 (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-cyclopropyl-N, N-dimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of the product od Step 1 (200 mg, 0.37 mmol) in HOAc (2 mL) was added Zn (750 mg, 11.1 mmol) . The mixture was stirred at 60 ℃ for 1.5 h. The solvent was removed and the mixture was diluted with DCM : MeOH =20 : 1. The mixture was filtered and the filtrate was concentrated and purified by prep-HPLC eluted with CH
3CN in H
2O (0.1%NH
4OH) from 10%to 90%to give the title product (50 mg) as a white solid. MS (ES+) : 514.2 [M+1]
+.
1H NMR (400 MHz, DMSO) δ 8.35 (s, 1H) , 8.11 (s, 1H) , 6.78 (dd, J = 18.1, 8.0 Hz, 2H) , 6.68 (s, 1H) , 5.51 (s, 2H) , 5.23 (s, 1H) , 3.48 (s, 2H) , 3.30 (s, 2H) , 3.02 (s, 3H) , 2.88 (d, J = 10.7 Hz, 3H) , 1.90 (t, J = 6.2 Hz, 5H) , 1.47 (d, J = 7.0 Hz, 3H) , 1.00 (s, 1H) , 0.83 (s, 1H) , 0.74 (m, 2H) .
EXAMPLE 249
(R) -4- ( (1- (3-bromo-5- (1, 1-difluoroethyl) phenyl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 1, 3-dibromo-5- (1, 1-difluoroethyl) benzene
To a stirred solution of 1- (3, 5-dibromophenyl) ethan-1-one (5.0 g, 18.0 mmol) in Bis (2- methoxyethyl) aminosulfur trifluoride (15 mL) was added 1 drop ethanol . The mixture was stirred at 40 ℃ for 16 h. After the reaction was completed, the mixture was quenched with ice water (50 mL) and extracted with EA (30.0 mL x 3) . The organic layer was washed with brine (25.0 mL) , dried over anhydrous Na
2SO
4, filtered and concentrated in vacuum. The residue was purified by chromatography (PE : EA = 20 : 1) to give the title product (4.0 g) of as a colorless oil .
1H NMR (400 MHz, CDCl
3) δ 7.73 (s, 1H) , 7.58 (s, 2H) , 1.89 (t, J = 18.2 Hz, 3H) .
Step 2 1- (3-bromo-5- (1, 1-difluoroethyl) phenyl) ethan-1-one
To a stirred solution of the product of step 1 (4.0 g, 13.3 mmol) in dioxane (70 mL) was added tributyl (1-ethoxyvinyl) stannane (5.5 g, 13.3 mmol) and the mixture was purged with N
2 for 15 minutes. Pd (PPh
3)
2Cl
2 (105 mg, 0.13 mmol) was added and the mixture was stirred for 16 h at 100℃ . After the reaction was completed, the mixture was treated with HCl (1N, 50 mL) and stirred for 1 h. Water was added and the mixture was extracted with EA (50.0 mL X 3) . The organic layer was washed with brine (50 mL) , dried over anhydrous Na
2SO
4, filtered and concentrated in vacuum. The residue was purified by silica gel column chromatography to give 3.0 g of the title product as a colorless oil.
1H NMR (400 MHz, CDCl
3) δ 8.13 (s, 1H) , 8.00 (s, 1H) , 7.85 (s, 1H) , 2.62 (s, 3H) , 1.89-1.99 (m, 3H) .
Step 3 (R, E) -N- (1- (3-bromo-5- (1, 1-difluoroethyl) phenyl) ethylidene) -2-methylpropa ne-2-sulfinamide
To a stirred solution of the product od Step 2 (2.1 g, 8.0 mmol) in THF (40 mL) was added (R) -2-methylpropane-2-sulfinamide (1.45 g, 12.0 mmol) and titanium ethoxide (5.5 g, 24.0 mmol) . The mixture was stirred at 80 ℃ for 16 h. The reaction mixture was diluted with water and extracted with EA (30 mL X 3) . The combined organic layer was washed with brine (30 mL) , dried over Na
2SO
4 and concentrated in vacuum. The residue was purified by silica gel column chromatography (PE : EA = 5 : 1 to EA) to give the title product (2.5 g) as a yellow solid. MS (ES+) : 366.0 [M+1]
+, 368.0 [M+1]
+.
Step 4 (R) -N- ( (R) -1- (3-bromo-5- (1, 1-difluoroethyl) phenyl) ethyl) -2-methylpropane-2-sulfinamide
To a solution of the product of Step 3 (2.5 g, 6.8 mmol) in THF (30 mL) was added NaBH
4 (517 mg, 13.6 mmol) . The mixture was stirred at rt for 16 h. The reaction mixture was diluted with water and extracted with EA (40 mL x 3) . The combined organic layer was washed with brine (50 mL) , dried over Na
2SO
4 and concentrated in vacuum. The residue was purified by silica gel column chromatography (PE : EA = 20 : 1 to PE : EA =1: 1) to give the title product (1.9 g) as a yellow oil. MS (ES+) : 3 68.0 [M+1]
+, 370.0 [M+1]
+.
Step 5 (R) -1- (3-bromo-5- (1, 1-difluoroethyl) phenyl) ethan-1-amine
To a stirred solution of the product of Step 4 (1.9 g, 5.2 mmol) in 1, 4-dioxane (5.0 mL) cooled to 0 ℃was treated with 4 N HCl in 1, 4-dioxane (20 mL) . The mixture was stirred for 6 h at rt. After the reaction was completed, the reaction mixture was concentrated in vacuum, the precipitate was filtered and washed with diethyl ether to obtain the title product. MS (ES+) : 264.1 [M+1]
+, 266.1 [M+1]
+.
Step 6 (R) -4- ( (1- (3-bromo-5- (1, 1-difluoroethyl) phenyl) ethyl) amino) -N, N, 2-trimethyl -7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of the product of Step 5 (75 mg, 0.25 mmol) in DMSO (2 mL) was added 4-hydroxy-N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide (50.0 mg, 0.17mmol) , DBU (76 mg , 0.5 mmol) and BOP (111 mg, 0.25 mmol) under N
2. The mixture was stirred at room temperature for 16 h. The reaction mixture was purified by prep-HPLC eluted with CH
3CN in H
2O (0.1%NH
4OH) from 10%to 90%) to get the title product (9.7 mg) as a yellow solid. MS (ES+) : 547.1 [M+1]
+, 549.1 [M+1]
+.
1H NMR (400 MHz, MeOH-d
4) δ 8.26 (m, 1H) , 7.68 (m, 1H) , 7.53-7.58 (m, 2H) , 5.56 (m, 1H) , 3.64 (s, 2H) , 3.48 (s, 2H) , 3.13 (s, 3H) , 3.00 (m, 3H) , 2.40 (s, 3H) , 2.00 (s, 4H) , 1.84 (t, J = 18.2 Hz, 3H) , 1.56 (d, J = 7.1 Hz, 3H) .
EXAMPLE 250
(R) -4- ( (1- (3-amino-5- (1, 1-difluoroethyl) phenyl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 1- (3-bromo-5-nitrophenyl) ethan-1-one
To a stirred solution of 1, 3-dibromo-5-nitrobenzene (5 g, 17.8 mmol) in dioxane (50 mL) was added tributyl (1-ethoxyvinyl) stannane (6.4 g, 17.8 mmol) and the mixture was purged with N
2 for 15 minutes. Pd (PPh
3)
2Cl
2 (126 mg, 0.18 mmol) was added and the mixture was stirred for 16 h at 100 ℃. After the reaction was completed, the mixture was treated with HCl (1N, 50 mL) and stirred for 1 h. Then quenched with water and extracted with EA (50.0 mL X 3) . The organic layer was washed with brine (50.0 mL) , dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel column chromatography to give the title product (2.2 g) as a yellow solid. MS (ES+) : 245.0 [M+1]
+.
Step 2 1-bromo-3- (1, 1-difluoroethyl) -5-nitrobenzene
To a stirred solution of the product of Step 1 (2.2 g, 9.0 mmol) in bis (2-methoxyethyl) aminosulfur trifluoride (6 mL) was added 1 drop ethanol . The mixture was stirred at 40℃ for 16 h. After the reaction was completed, the mixture was treated with K
2CO
3 and stirred for 1 hour. then quenched with water and extracted with EA (25.0 mL x 3) . The organic layer was washed with brine (25.0 mL) , dried over anhydrous Na
2SO
4, filtered and concentrated in vacuum. The residue was purified by silica gel column chromatography to give 1.86 g of the title product as a yellow solid. MS (ES+) : 267.1 [M+1]
+.
1H NMR (400 MHz, CDCl
3) δ 8.44 (s, 1H) , 8.32 (s, 1H) , 7.98 (s, 1H) , 1.96 (t, J = 18.2 Hz, 3H) .
Step 3 1- (3- (1, 1-difluoroethyl) -5-nitrophenyl) ethan-1-one
To a stirred solution of 1-bromo-3- (1, 1-difluoroethyl) -5-nitrobenzene (1.8 g, 6.77 mmol) in dioxane (20 mL) was added tributyl (1-ethoxyvinyl) stannane (2.93 g, 8.12 mmol) and the mixture was purged with N
2 for 15 minutes. Pd (PPh
3)
2 Cl
2 (470 mg, 0.67 mmol) was added and the mixture was stirred for 16 h at 100 ℃ . After the reaction was completed, the mixture was treated with HCl (1N, 25 mL) and stirred for 1 hour. then quenched with water and extracted with EA (25.0 mL x 3) . The organic layer was washed with brine (25.0 mL) , dried over anhydrous Na
2SO
4, filtered and concentrated in vacuum. The residue was purified by silica gel column chromatography to give 484 mg of the title product as a yellow solid. MS (ES+) : 229.4 [M+1]
+. 1H NMR (400 MHz, CDCl
3) δ 8.84 (s, 1H) , 8.56 (s, 1H) , 8.40 (s, 1H) , 2.72 (s, 3H) , 2.01 (t, J = 18.2 Hz, 3H) .
Step 4 (R, E) -N- (1- (3- (1, 1-difluoroethyl) -5-nitrophenyl) ethylidene) -2-methylpropane-2-sulfinamide
To a stirred solution of 1- (3- (1, 1-difluoroethyl) -5-nitrophenyl) ethan-1-one (484 m g, 2.11 mmol) in THF (5 mL) were added (R) -2-methylpropane-2-sulfinamide (382 m g, 3.16 mmol) and titanium ethoxide (1.44 g, 6.34 mmol) . The mixture was stirred at 80 ℃ for 16 h. The reaction mixture was diluted with water and extracted with EA (25 mL x 3) . The combined organic layer was washed with brine (25 mL) , dried over Na
2SO
4 and concentrated in vacuum. The residue was purified by silica gel column chromatography (PE : EA = 5 : 1 to EA) to give the title product (440 mg) as a yellow oil. MS (ES+) : 333.4 [M+1]
+.
Step 5 (R) -N- ( (R) -1- (3- (1, 1-difluoroethyl) -5-nitrophenyl) ethyl) -2-methylpropane-2-sulfinamide
To a solution of the product of Step 4 (440 mg, 1.32 mmol) in THF (10 mL) was added NaBH
4 (55 mg, 1.46 mmol) . The mixture was stirred at rt for 16 h. The reaction mixture was diluted with water and extracted with EA (25 mL x 3) . The combined organic layer was washed with brine (25 mL) , dried over Na
2SO
4 and concentrated in vacuum. The residue was purified by silica gel column chromatography (PE : EA = 20 : 1 to PE : EA =1: 1) to give the title product (289 mg) as a yellow oil. MS (ES+) : 334.5 [M+1]
+.
Step 6 (R) -1- (3- (1, 1-difluoroethyl) -5-nitrophenyl) ethan-1-amine
To a stirred solution of the product of Step 5 (289 mg, 0.86 mmol) in 1, 4-Dioxane (5.0 mL) cooled to 0 ℃ was added a solution of 4 N HCl in 1, 4-dioxane (5 mL) . The mixture was stirred for 6 h at rt. After the reaction was completed, the reaction mixture was concentrated in vacuum. The precipitate was filtered and washed with diethyl ether to obtain the title product (130 mg) as a yellow solid. MS (ES+) : 266.1 [M+1]
+.
Step 7 (R) -4- ( (1- (3- (1, 1-difluoroethyl) -5-nitrophenyl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of the product of Step 6 (130 mg, 0.488 mmol) in DMSO (3 mL) was added 4-hydroxy-N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide (100 mg, 0.407mmol) , DBU (186 mg, 1.22mmol) and BOP (270 mg, 0.611 mmol) under N
2. The mixture was stirred at room temperature for 16 h. The reaction mixture was purified by prep-PLC, to get 165 mg of the title product as a yellow solid. MS (ES+) : 514.6 [M+1]
+.
Step 8 (R) -4- ( (1- (3-amino-5- (1, 1-difluoroethyl) phenyl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a solution of the product of Step 7 (165 mg, 0.321 mmol) in AcOH (2mL) was added Zn at rt. The mixture was heated to 60 ℃ for 2 h. The reaction mixture was diluted with water and extracted with EA (25 mL X 3) . The combined organic layer was washed with brine (25 mL) , dried over Na
2SO
4 and concentrated in vacuum. The residue was purified by prep-HPLC to give the title product (19.52 mg) as a white solid. MS (ES+) : 484.2 [M+1]
+.
1H NMR (400 MHz, MeOH-d
4) δ 8.28 (d, J = 6.5 Hz, 1H) , 6.88 (d, J = 7.1 Hz, 1H) , 6.84 (d, J = 9.7 Hz, 1H) , 6.72 (s, 1H) , 5.56 (s, 1H) , 4.56 (s, 1H) , 3.64 (s, 2H) , 3.48 (s, 2H) , 3.12 (s, 3H) , 3.00 (d, J = 10.4 Hz, 3H) , 2.42 (s, 3H) , 2.00 (s, 4H) , 1.84 (t, J = 18.2 Hz, 3H) , 1.56 (d, J = 7.1 Hz, 3H) .
EXAMPLE 251
(R) -4- ( (1- (4-amino-6- (trifluoromethyl) pyridin-2-yl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 2-chloro-N- (4-methoxybenzyl) -6- (trifluoromethyl) pyridin-4-amine
To a stirred solution of 2-chloro-4-iodo-6- (trifluoromethyl) pyridine (5 g, 16.26 mmol) and PMBNH
2 in toluene (30 mL) was added Cs
2CO
3 and Pd (dppf) Cl
2. The mixture was stirred for 6 h at 100℃. The reaction mixture was diluted with water and extracted with EA (50 mL X 3) . The combined organic layer was washed with brine (50 mL) , dried over Na
2SO
4 and concentrated in vacuum. The residue was purified by silica gel column chromatography (PE : EA = 20 : 1 to PE: EA=5: 1) to give the title product (1.3 ) as a yellow oil. MS (ES+) : 317.2 [M+1]
+.
Step 2 (R) -N- ( (R) -1- (4- ( (4-methoxybenzyl) amino) -6- (trifluoromethyl) pyridin-2-yl) ethyl) -2-methylpropane-2-sulfinamide
Starting with the product of Step1, the title product was prepared by using the same methods as described in Step 3, Step 4 and Step 5 of Example 250. MS (ES+) : 430.2 [M+1]
+.
Step 3 (R) -N- ( (R) -1- (4-amino-6- (trifluoromethyl) pyridin-2-yl) ethyl) -2-methylpropane-2-sulfinamide
To a solution of Step 2 (470 mg, 1.09 mmol) in DCM (10 mL) and H
2O (10 mL) at 0 ℃ was added DDQ (371 mg, 1.64 mmol) . The mixture was stirred at rt for 16 h. The reaction mixture was diluted with water and extracted with EA (25 mL x 3) . The combined organic layer was washed with brine (25 mL) , dried over Na
2SO
4 and concentrated in vacuum. The residue was purified by silica gel column chromatography (PE : EA = 20 : 1 to EA ) to give the title product (268 mg) as a brown oil. MS (ES+) : 310.2 [M+1]
+.
Step 4 (R) -2- (1-aminoethyl) -6- (trifluoromethyl) pyridin-4-amine
Starting with the product of Step3, the title product was prepared by using the same method as described in Step 6 of Example 250. MS (ES+) : 206.0 [M+1]
+.
Step 5 (R) -4- ( (1- (4-amino-6- (trifluoromethyl) pyridin-2-yl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step4, the title product was prepared as a white solid by using the same methods as described in Step 7 of Example 250. MS (ES+) : 489.3 [M+1]
+.
1H NMR (400 MHz, MeOD) δ 8.28 (d, J = 2.8 Hz, 1H) , 6.80 (s, 1H) , 6.72 (d, J = 14.0 Hz, 1H) , 5.48 (d, J = 7.3 Hz, 1H) , 3.64 (s, 2H) , 3.48 (s, 2H) , 3.16 (s, 3H) , 3.04 (d, J = 7.1 Hz, 3H) , 2.40 (d, J = 6.1 Hz, 3H) , 2.00 (s, 4H) , 1.56 (d, J = 7.1 Hz, 3H) .
EXAMPLE 252
(R) -4- ( (1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 1- (2-fluoro-3-nitrophenyl) ethan-1-one
To a solution of 1-bromo-2-fluoro-3-nitrobenzene (5.00 g, 22.73 mmol) in dioxane (50 mL) was added tributyl (1-ethoxy vinyl) stannane (9.84 g, 27.24 mmol) and the mixture was purged with N
2 for 15 minutes. Pd (PPh
3)
2Cl
2 (0.16 g, 0.28 mmol) was added and the mixture was heated to 95 ℃ for 16 h under N
2 atmosphere. The mixture was then treated with HCl (1N, 30 mL) and stirred for 1 h. The aqueous layer was extracted with DCM (50 m x 3) and H
2O. The organic layer was washed with brine (50 mL) , dried over anhydrous Na
2SO
4, filtered and concentrated in vacuum. The residue was purified by silica gel column chromatography (PE : EA = 5 : 1) to give the title product (3.23 g) as a yellow liquid.
1H NMR (400 MHz, CDCl
3) δ 8.18 (dt, J = 15.9, 8.3 Hz, 2H) , 7.40 (t, J = 8.0 Hz, 1H) , 2.72 (d, J = 5.3 Hz, 3H) .
Step 2 1- (3-amino-2-fluorophenyl) ethan-1-one
Fe powder (5.94 g, 106.05 mmol) and NH
4Cl (5.62 g, 106.05 mmol) were added to a solution of the product of Step 1 (3.23 g, 17.67 mmol) in H
2O (60 mL) at 55 ℃. The mixture was heated to reflux for 1 h. The mixture was then filtered through celite. The aqueous layer was extracted with EA (50 mL x 3) . The organic layer was washed with brine (50 mL) , dried over anhydrous Na
2SO
4, filtered and concentrated in vacuum to give the title product (2.7 g) as a black oil. MS (ES+) : 154.1 [M+1]
+.
Step 3 1- (2-fluoro-3-iodophenyl) ethan-1-one
To a solution of CuI (13.43 g, 70.56 mmol) in CH
3CN (35 mL) was added isopentyl nitrite (8.27 g, 70.56 mmol) at 25℃. The mixture was heated to 65℃ and a solution of 1- (3-amino-2-fluorophenyl) ethan-1-one (5.40 g, 35.28 mmol) in CH
3CN (35 mL) was added dropwise at 65℃ over 1 h. The mixture was stirred at 65℃ for 16 h and then was concentrated in vacuum. The residue was purified by silica gel chromatography (eluted with PE) to give the title product (3.7g) as a white solid.
1H NMR (400 MHz, CDCl
3) δ 7.93 (t, J = 5.9 Hz, 1H) , 7.82 (t, J = 6.5 Hz, 1H) , 7.00 (t, J = 7.8 Hz, 1H) , 2.65 (d, J = 5.1 Hz, 3H) .
Step 4 ethyl 2- (3-acetyl-2-fluorophenyl) -2, 2-difluoroacetate
A solution of ethyl 2-bromo-2, 2-difluoroacetate (3.70 g, 18.27 mmol) and CuI (1.10 g, 18.27 mmol) in DMSO (7 mL) was stirred at 25℃ for 30 minutes under N
2 atmosphere. The mixture was treated with a solution of 1- (2-fluoro-3-iodophenyl) ethan-1-one (1.93 g, 7.31 mmol) in DMSO (8 mL) dropwise. The mixture was stirred at 25℃ for 48 h under N
2 atmosphere. The mixture was then quenched with saturated NH
4Cl and extracted with EA (150 mL x 2) . The organic layer was washed with brine (50 mL X 2) , dried over anhydrous Na
2SO
4, filtered and concentrated in vacuum to give the title product (1.9 g) as a yellow oil.
1H NMR (400 MHz, CDCl
3) δ 8.02 (d, J = 6.2 Hz, 1H) , 7.83 (d, J = 6.6 Hz, 1H) , 7.35 (d, J = 7.4 Hz, 1H) , 4.43 –4.33 (m, 2H) , 2.64 (s, 3H) , 1.34 (d, J = 7.1 Hz, 3H) .
Step 5 ethyl (R, E) -2- (3- (1- ( (tert-butylsulfinyl) imino) ethyl) -2-fluorophenyl) -2, 2-difluoroacetate
Starting with the product of Step 4, the title product was prepared as a white solid by using the same methods as described in Step 4 of Example 250. MS (ES+) : 364.1 [M+1]
+.
1H NMR (400 MHz, CDCl
3) δ 7.80 (d, J = 6.9 Hz, 1H) , 7.75 (dd, J = 14.2, 7.2 Hz, 1H) , 7.32 (dd, J = 17.2, 8.4 Hz, 1H) , 2.75 (s, 2H) , 1.33 (s, 3H) , 1.31 (s, 9H) , 1.23 (s, 3H) .
Step 6 (R) -N- ( (R) -1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) -2-methylpropane-2-sulfinamide
To a solution of the product of Step 5 (0.93 g, 2.57 mmol) in DCM (5 mL) and MeOH (5 mL) wad added NaBH
4 (0.29g, 7.70 mmol) at 0℃. The mixture was stirred at 25℃ for 6 h. The mixture was then quenched with saturated NH
4Cl and extracted with DCM (30 mL X 2) . The organic layer was washed with brine (50 mL) , dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by silica gel column chromatography (eluted with EA) to give the title product (0.42 g) as a white solid.
1H NMR (400 MHz, CDCl
3) δ 7.50 (dd, J = 14.3, 7.0 Hz, 1H) , 7.43 (dd, J = 13.9, 6.8 Hz, 1H) , 7.20 (q, J = 7.8 Hz, 1H) , 4.69 (dd, J = 14.5, 7.3 Hz, 1H) , 4.03 (s, 2H) , 3.61 (d, J = 7.2 Hz, 2H) , 1.94 (s, 1H) , 1.56 (t, J = 7.5 Hz, 3H) , 1.19 (d, J = 8.5 Hz, 9H) .
Step 7 (R) -2- (3- (1-aminoethyl) -2-fluorophenyl) -2, 2-difluoroethan-1-ol hydrochloride
A solution of the product of Step 6 (200 mg, 0.62 mmol) in 1, 4-dioxane (5.0 mL) was stirred at 17℃ for 16 h. The reaction mixture was then concentrated in vacuum and the precipitate filtered and washed with EA to obtain the title product (130 mg) as a yellow solid. MS (ES+) : 220.1 [M+1]
+.
Step 8 (R) -4- ( (1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of the product of Step7 (55 mg, 0.25 mmol) in DMSO (1 mL) was added 4-hydroxy-N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide (50 mg, 0.17 mmol) , DBU (76 mg, 0.50 mmol) and BOP (110 mg, 0.25 mmol) under N
2. After the mixture was stirred at room temperature for 16 h, the reaction mixture was purified by prep-HPLC to get 13.46 mg of the title product as a white solid. MS (ES+) : 503.1 [M+1]
+.
1H NMR (400 MHz, MeOH-d
4) δ 8.31 (s, 1H) , 7.55 (q, J = 8.1 Hz, 1H) , 7.44 (t, J = 7.0 Hz, 1H) , 7.19 (t, J = 7.5 Hz, 1H) , 5.84 –5.75 (m, 1H) , 4.01 (t, J = 13.7 Hz, 2H) , 3.63 (s, 2H) , 3.48 (s, 2H) , 3.14 (s, 3H) , 3.01 (d, J = 8.3 Hz, 3H) , 2.37 (s, 3H) , 1.99 (s, 4H) , 1.62 (d, J = 7.1 Hz, 3H) .
EXAMPLE 253
(R) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) -4- ( (1- (6- (trifluoromethyl) -1H-indol-4-yl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 1- (6- (trifluoromethyl) -1H-indol-4-yl) ethan-1-one
To a solution of 4-bromo-6- (trifluoromethyl) -1H-indole (0.82 g, 3.11 mmol) in dioxane (10 mL) were added tributyl (1-ethoxy vinyl) stannane (1.35 g, 3.72 mmol) and Pd (PPh
3)
2Cl
2 (22 mg, 0.031 mmol) was added under N
2. After the mixture was heated to 100 ℃ for 16 h under N
2 atmosphere, the mixture was treated with HCl (1N, 5 mL) and stirred for 1 h. The aqueous layer was extracted with DCM (20 mL x 3) . The organic layer was washed with brine (20 mL) , dried over anhydrous Na
2SO
4, filtered and concentrated in vacuum. The residue was purified by silica gel column chromatography (PE : EA = 5 : 1) to give the title product (0.68 g) as a yellow solid.
1H NMR (400 MHz, CDCl
3) δ 8.64 (s, 1H) , 7.96 (s, 1H) , 7.89 (s, 1H) , 7.54 (s, 1H) , 7.43 (s, 1H) , 2.76 (s, 3H) . Step 2 (R, E) -2-methyl-N- (1- (6- (trifluoromethyl) -1H-indol-4-yl) ethylidene) propane-2-sulfinamide
Starting with the product of Step 1, the title product was prepared as a white solid by using the same methods as described in Step 4 of Example 250. MS (ES+) : 331.1 [M+1]
+.
Step 3 (R) -1- (6- (trifluoromethyl) -1H-indol-4-yl) ethan-1-amine hydrochloride
Starting with the product of Step 2, the title product was prepared as a white solid by using the same methods as described in Step 5 and 6 of Example 250. MS (ES+) : 229.1 [M+1]
+.
Step 4 (R) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) -4- ( (1- (6- (trifluoromethyl) -1H-indol-4-yl) ethyl) amino) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 3, the title product was prepared as a white solid by using the same methods as described in Step 7 of Example 252. MS (ES+) : 512.2 [M+1]
+.
1H NMR (400 MHz, MeOH-d
4) δ 8.26 (s, 1H) , 7.60 (s, 1H) , 7.38 (d, J = 24.0 Hz, 2H) , 6.72 (d, J = 15.6 Hz, 1H) , 6.16 –6.05 (m, 1H) , 3.62 (s, 2H) , 3.46 (s, 2H) , 3.10 (s, 3H) , 2.97 (d, J = 20.8 Hz, 3H) , 2.41 (s, 3H) , 1.98 (t, J = 6.6 Hz, 4H) , 1.73 (d, J = 7.0 Hz, 3H) .
EXAMPLE 254A&254B
3- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -
N,
N, 1-trimethyl-6- (pyrrolidin1-yl) -1H-pyrazolo [3, 4-b] pyridine-5-carboxamide
Step 1 (R) -4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carbonitrile
To a solution of 4-hydroxy-2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carbonitrile (800 mg, 3.13 mmol) in MeCN (10 mL) were added (1R) -1- [3- (difluoromethyl) -2-fluorophenyl] ethan-1-amine (890 mg, 4.70 mmol) , (1H-1, 2, 3-benzotriazol-1-yloxy) tris (dimethylamino) phosphanium; hexafluoro-λ^5-phosphanuide (2.1g, 4.70 mmol) , DBU (0.70 mL, 4.70 mmol) . After stirring at rt for 12 h under N
2, the reaction mixture was poured into water (100 mL) , and extracted with EA (3 X 50 mL) . The organic layer was washed with NaCl (3 x 25 mL) . The EA layer was dried over Na
2SO
4, filtered and concentrated to afford a crude product. The crude product was purified by silica gel column chromatography eluted with a gradient of 0 to 5%MeOH in DCM to afford the title product (800 mg) as a yellow solid. MS (ES+) : 427.2 [M+1]
+.
Step 2 (R) -4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) ( (2- (trimethylsilyl) ethoxy) methyl) amino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carbonitrile
To a solution of the product of Step 1 (600 mg, 1.41 mmol) in DMF (10 mL) was added NaH (60 %) (68 mg, 2.81 mmol) . After the resulting mixture was stirred at rt for 0.5 h, SEM-Cl (0.4mL, 2.11 mmol) was added at 0 ℃ , and the resulting mixture was stirred at rt for 4 h. The reaction mixture was poured into saturated NH
4Cl (100 mL) , and extracted with EA (3 X 50 mL) . The organic layer was washed with NaCl (3 x 50 mL) . The EA layer was dried by Na
2SO
4, filtered and concentrated in vacuum to afford a crude product. The crude product was purified by flash silica chromatography eluted with a gradient of 0 to 30%EA in PE to afford the title product (300 mg) as a yellow solid. MS (ES+) : 557.6 [M+1]
+.
Step 3 (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-7- (pyrrolidin-1-yl) -6- (1H-tetrazol-5-yl) pyrido [2, 3-d] pyrimidin-4-amine
To a solution of the product of Step 2 (300 mg, 0.54 mmol) in 1, 4-dioxane (5 mL) , were added azidotrimethylsilane (2.2 mL, 16.19 mmol) , dibutyldichlorostannane (1.4 mL, 6.47 mmol) . The reaction mixture was stirred at 100 ℃ for 12 h under N
2, and then was poured into water (100 mL) , and extracted with EA (3 x 50 mL) . The organic layer was washed with NaCl (3 X 25 mL) . The EA layer was dried over Na
2SO
4, filtered and concentrated in vacuum to afford a crude product. The crude product was purified by silica gel column chromatography eluted with a gradient of 0 to 5%MeOH in DCM to afford the title product (100 mg) as a yellow solid. MS (ES+) : 470.2 [M+1]
+.
Step 4 ethyl (R) -2- (5- (4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) -1H-tetrazol-1-yl) acetate or ethyl (R) -2- (5- (4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidin-6-yl) -2H-tetrazol-2-yl) acetate
To a solution of the product of Step 3 (80 mg, 0.17 mmol) in DMF (1 mL) , were added N”-tert-butyl-N, N, N', N'-tetramethylguanidine (30 mg, 0.17 mmol) and ethyl 2-bromoacetate (0.08 mL, 0.68 mmol) . The reaction was stirred at rt for 4 h under N
2, and then was poured into water (50mL) , and extracted with EA (3 x 50 mL) . The organic layer was washed with NaCl (3 x 25 mL) . The EA layer was dried over Na
2SO
4, filtered and concentrated to afford a crude product. The crude product was purified by silica gel column chromatography eluted with a gradient of 0 to 5%MeOH in DCM to afford the title products as a white solid. MS (ES+) : 556.4 [M+1]
+.
1H NMR (400 MHz, MeOH-d
4) δ 8.50 (s, 1H) , 7.57 (t, J = 8.0 Hz, 1H) , 7.47 (t, J = 8.0 Hz, 1H) , 7.22 (t, J = 8.0 Hz, 1H) , 6.99 (t, J = 56.0 Hz, 1H) , 5.80 (q, J = 6.8 Hz, 1H) , 5.34 (s, 1H) , 4.94 (s, 2H) , 4.11 (q, J = 8.0 Hz, 2H) , 3.22-3.26 (m, 4H) , 2.40 (s, 3H) , 1.87 (s, 4H) , 1.62 (d, J = 7.2 Hz, 3H) , 1.12 (t, J = 7.2 Hz, 3H) .
EXAMPLE 255
4- ( (1- (2-amino-6- (trifluoromethyl) pyrimidin-4-yl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 (R) -4- (1-aminoethyl) -6- (trifluoromethyl) pyrimidin-2-amine hydrochloride
Starting with 4-chloro-6- (trifluoromethyl) pyrimidin-2-amine, the title product was prepared by using the same methods as described in Step 1 of Example 253, Step 4, 5 and 6 of Example 250. MS (ES+) : 207.1 [M+1]
+
Step 2 4- ( (1- (2-amino-6- (trifluoromethyl) pyrimidin-4-yl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1, the title product was prepared as a white solid by using the same methods as described in Step 7 of Example 252. MS (ES+) : 490.0 [M+1]
+.
1H NMR (400 MHz, MeOD-d6) δ 8.28 (s, 1H) , 6.93 (d, J = 12.8 Hz, 1H) , 5.43 –5.33 (m, 1H) , 3.66 (s, 2H) , 3.48 (s, 2H) , 3.14 (s, 3H) , 3.01 (s, 3H) , 2.37 (s, 3H) , 1.99 (s, 4H) , 1.60 (d, J = 7.2Hz, 3H) .
EXAMPLE 256
(R) -4- ( (1- (3-amino-5- (difluoromethyl) phenyl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Step 1 1-bromo-3- (difluoromethyl) -5-nitrobenzene
To a stirred solution of 3-bromo-5-nitrobenzaldehyde (4 g, 17.4 mmol) in DCM (40 mL) was added DAST (14 g, 87 mmol) dropwise. The mixture was stirred at rt for 12 h, and the poured into ice water slowly. The pH of the mixture was adjust to 8 with Na
2CO
3 (aq. ) The mixture was then extracted with DCM. The organic layer was combined, washed with brine, dried over Na
2SO
4 and concentrated to give the title product (3.9 g) as a yellow solid.
1H NMR (400 MHz, DMSO) δ 8.56 (s, 1H) , 8.40 (s, 1H) , 8.28 (s, 1H) , 7.19 (t, J = 55.0 Hz, 1H) .
Step 2 (R) -4- ( (1- (3-amino-5- (difluoromethyl) phenyl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
Starting with the product of Step 1, the title product was prepared as a white solid by using the same methods as described in Example 250. MS (ES+) : 470.4 [M+1]
+.
1H NMR (400 MHz, DMSO) δ 8.39 (d, J = 9.2 Hz, 1H) , 8.14 (s, 1H) , 6.79 (dd, J = 77.5, 35.0 Hz, 3H) , 6.57 (s, 1H) , 5.47 (s, 1H) , 5.35 (s, 2H) , 3.48 (s, 4H) , 3.02 (s, 3H) , 2.89 (d, J = 8.0 Hz, 3H) , 2.33 (s, 3H) , 1.90 (s, 4H) , 1.48 (d, J = 6.8 Hz, 3H) .
EXAMPLE257A&257B
(R) -4- ( (1- (3-amino-2-fluoro-5- (trifluoromethyl) phenyl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
(R) -4- ( (1- (3-amino-4-fluoro-5- (trifluoromethyl) phenyl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide
To a stirred solution of (R) -4- ( (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -N, N, 2-trimethyl-7- (pyrrolidin-1-yl) pyrido [2, 3-d] pyrimidine-6-carboxamide (50 mg, 0.1 mmol) in MeCN (2 mL) was added Selectfluor (38 mg, 0.1 mmol) . The mixture was stirred at rt for 12 h and then filtered. The filtrate was concentrated and the residue was purified by prep-HPLC eluted with a gradient of CH
3CN in H
2O (0.1%NH
4OH) from 10%to 90%to give title product of 257B (6.5 mg) 257A (3.9 mg) as white solid.
257A MS (ES+) : 506.3 [M+1]
+.
1H NMR (400 MHz, DMSO) δ 8.39 (s, 1H) , 8.14 (s, 1H) , 6.93 (d, J = 7.5 Hz, 2H) , 5.76 (ddd, J = 15.5, 8.2, 3.2 Hz, 1H) , 5.62 (s, 2H) , 3.56 –3.40 (m, 4H) , 3.03 (s, 3H) , 2.89 (s, 3H) , 2.30 (s, 3H) , 1.90 (t, J = 6.2 Hz, 4H) , 1.50 (d, J = 7.0 Hz, 3H) .
257B MS (ES+) : 506.3 [M+1]
+.
1H NMR (400 MHz, DMSO) δ 8.35 (s, 1H) , 8.11 (d, J = 7.6 Hz, 1H) , 7.05 (d, J = 7.5 Hz, 1H) , 6.87 (d, J = 8.5 Hz, 1H) , 5.59 (s, 2H) , 5.43 (s, 1H) , 3.48 (s, 4H) , 3.02 (s, 3H) , 2.88 (d, J = 9.6 Hz, 3H) , 2.32 (s, 3H) , 1.90 (s, 4H) , 1.48 (d, J = 6.9 Hz, 3H) .
EXAMPLE 258
(R) 5- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N-dimethyl-2- (pyrrolidin-1-yl) -7, 8-dihydro-6H-cyclopenta [b] [1, 8] naphthyridine-3-carboxamide
Step 1 5-chloro-N, N-dimethyl-2- (pyrrolidin-1-yl) -7, 8-dihydro-6H-cyclopenta [b] [1, 8] naphthyridine-3-carboxamide
To a solution of 2-amino-5- (dimethylcarbamoyl) -6- (pyrrolidin-1-yl) nicotinic acid (557 mg, 2.0 mmol) in toluene (10 mL) were added cyclopentanone (168 mg, 2.0 mmol) and POCl
3 (2 mL) . The solution was stirred at 90 ℃ for 4 h. The solution was concentrated and poured into ice-water (5 mL) . The solution was diluted with saturated NaHCO3 (aq) until it is basic. The mixture was extracted with DCM (50 mL x 3) , nd the combined organic layer was washed with brine, dried over Na2SO4, concentrated and purified by silica gel column chromatography (DCM/MeOH = 95: 5) to afford the title product (350 mg) as brown solid. MS (ES+) : 345.2 and 347.2 [M+1]
+.
Step 2 (R) 5- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -N, N-dimethyl-2- (pyrrolidin-1-yl) -7, 8-dihydro-6H-cyclopenta [b] [1, 8] naphthyridine-3-carboxamide
Amixture of the product of step 1 (68.9 mg, 0.20 mmol) , 1- (3- (difluoromethyl) -2-fluorophenyl) ethan-1-amine hydrochloride (54.1 mg, 0.24 mmol) , Pd
2 (dba)
3 (9.2 mg, 0.01 mmol) , BINAP (12.5 mg, 0.02 mmol) and Cs
2CO
3 (130.4 mg, 0.40 mmol) in dioxane (2 mL) was stirred at 100 ℃ for 10 h under N
2 atmosphere. The mixture was concentrated and purified by silica gel column chromatography (DCM/MeOH = 10: 1) to afford product (12 mg) as yellow solid. MS (ES+) : 498.4 [M+1]
+.
Claims (20)
- A compound of Formula I or a pharmaceutically acceptable salt thereof,whereinQ 1is CR 3a or N;Q 2 and Q 3 are independently CR 3 or N, provided that one of Q 2 or Q 3 is N;Q 4 is N or CR 6;Q 5 is O, N or NR 1;Y 1 is O, S, NR c or a bond;Y and Q 5 may be connected with two atoms, independently selected from O, N, S or C, to form a five-membered heterocycle or five-membered heteroaryl;R 1 is independently selected from the group consisting of hydrogen, -C 1-10alkyl, -C 0-6alkylene-C 6-10aryl, C 0- 6alkylene-5-10-membered heteroaryl, -C 0-6alkylene-C 3-6cycloalkyl, C 0-6alkylene-3-6 membered heterocyclyl;R 1 is optionally substituted with one or two R 2a;R c are independently hydrogen, -C 1-6alkyl, -C 1-6haloalkyl, -C 2-6alkenyl, -C 2-6alkynyl, -C 3-10cycloalkyl, -C 4- 10cycloalkenyl, -3-10-membered heterocyclyl, -C 6-10aryl, -5-10-membered heteroaryl;R 1 and R c may be taken together with the atom (s) to which they are attached to form an optionally substituted 5-10 membered carbocyclyl, or heterocyclyl which contains 1-3 heteroatoms and is optionally substitute with 0-5 occurrences of R 10; R 1 and R c are independently substituted with 0-5 occurrences of R 10;L 1 and L 3 are independently -C 0-10alkylene, -C 3-10cycloalkylene -C 2-10alkenylene, -C 2-10alkynylene, -C 0- 6alkylene-C 6-10aryl, -C 0-6alkylene-heteroaryl, -C 0-10alkylene-3-6 membered heterocyclyl or L 1 and L 3 are absent and L 2 is directly connected with R 2 and the carbon atom of the ring with chemical bonds;L 2 is O, S, S (O) , S (O) 2, C (O) NR 1aS (O) 2, S (O) (NH) , S (O) (NCN) , C (O) , C (O) -C (O) , C (O) O, NR 1a, NR 1aC (O) , NR 1aC (O) -C (O) NR 1a, NR 1aS (O) 2, NR 1aS (O) 2NR 1a or L 2 is absent and L 1 and L 3 are connected with a chemical bond;R 1a is independently selected from the group consisting of hydrogen, -C 1-4alkyl, -C 0-10alkylene-C 6-10aryl, -C 0- 10alkylene-5-10-membered heteroaryl, -C 0-10alkylene-C 3-6cycloalkyl, -C 0-10alkylene-3-6-membered heterocyclyl;R 2 is selected from the group consisting of -C 1-6alkyl, -C 1-6haloalkyl, -C 2-6alkenyl, -C 2-6alkynyl, -C 0-10alkylene-C 3-10cycloalkyl, -C 4-10cycloalkenyl, -C 0-10alkylene-3-10-membered heterocyclyl, -C 0-10alkylene-C 6-10aryl, -C 0- 10alkylene-5-10-membered heteroaryl, -C 0-10alkyleneNR aR b, -C 0-10alkylene-P (O) R aR b, -C 0-10alkylene-P (O) (OR a) (OR b) , -C 0-10alkylene-NR cC (O) NR aR b, -C 0-10alkylene-NR cC (O) R 1a, wherein the -C 1-6alkyl, -C 1- 6haloalkyl, -C 2-6alkenyl, -C 2-6alkynyl, -C 3-10cycloalkyl, -C 4-10cycloalkenyl, -3-10-membered heterocyclyl, -C 6- 10aryl, -5-10-membered heteroaryl are all optionally substituted by one or more R 2a; R 2 and R 1a together with N atom to which they are attached, can form a 5-6 membered heterocyclyl which may contain an additional heteroatom such as O, NR 1a or S;R a may be connected with Y through a bond to form an additional 5 to 7 membered ring;-NR cC (CO) -of R 2 may be directly connected to Y through a bond when R 1a is absent;R 2a is independently selected from the group consisting of halo, OH, cyano, C 1-6 alkyl, C 3-6cycloalkyl, C 1-6 alkoxy, -SC 1-6alkyl, -C 3-6cycloalkyloxy, hydroxy, amino, -C (O) NR aR b, S (O) 2R a, -S (O) (NCN) R a, -P (O) R aR b, -P (O) (OR a) (OR b) , -NR cC (O) NR a 2, -NR cS (O) 2NR a 2, -NR cS (O) 2R a, -NR aR b, -NR aC (O) OR a, -S (O) 2NR aR b, - NR cS (O) 2NR aR b, -C (O) R a, -C 1-6heteroalkyl, 5-10-membered heteroaryl, 3-10-membered heterocyclyl, or heterocyclylalkyl;R a, R b and R c are independently hydrogen, -C 1-6alkyl, -C 1-6haloalkyl, -C 2-6alkenyl, -C 2-6alkynyl, -C 3- 10cycloalkyl, -C 4-10cycloalkenyl, -3-10-membered heterocyclyl, -C 6-10aryl, -5-10-membered heteroaryl; R a and R b, R b and R c may be taken together with the atom (s) to which they are attached to form an optionally substituted 5-10 membered carbocyclyl, or heterocyclyl which contains 0-3 heteroatoms and is optionally substitute with 0-5 occurrences of R 10; R a, R b and R c are independently substituted with 0-5 occurrences of R 10; R 10 is independently selected from C 1-6 alkyl, C 1-6alkoxy, halo, hydroxy, oxo, amino, C 0-6alkylene-C (OH) R aR b, C 0-6alkylene-NR bR c , C 0-6alkylene-NR bR c, C 0-6alkylene-C (O) NR aR b, C 0-6alkylene-NR cC (O) R b, C 0-6alkylene-S (O) 2R b, C 0-6alkylene-S (O) 2NR aR b, C 0-6alkylene-NR cS (O) 2R b, C 0-6alkylene-NR cS (O) 2NR aR b, C 0-6alkylene-P (O) R aR b, C 0-6alkylene-P (O) (OR a) (OR b) , C 0-6alkylene-cyano, C 0-6alkylene-C 3-8 cycloalkyl, C 0-6alkylene-5-10 membered heterocyclyl, C 0-6alkylene-C 6-10 aryl, C 0-6alkylene-5-10 membered heteroaryl; two adjacent R 10 are taken together with the atom (s) to which they are attached to form an optionally substituted 5-10 membered carbocyclyl or 5-10 membered heterocyclyl;R 3 and R 3a are selected from hydrogen, CN, -C 1-6alkyl, -C 1-6haloalkyl, -C 2-6alkenyl, -C 2-6alkynyl, -C 3- 6cycloalkyl, -NR aR b, -OR 3a, -SR 3a; where R 3a is H, C 1-6alkyl, C 1-6hahoalkyl, -C 3-6cycloalkyl, 5-6 membered heterocyclyle;R 4 and R 4a are selected from H, -C 1-6alkyl, -C 1-6haloalkyl; R 4 and R 4a together with the atom to which they are attached to form a 2-6membered cycloalkyl; or R 4 can be connected with an atom of ring A to form a 5-10 membered carbocyclyle or 5-10 membered heterocyclyle;is selected from the group consisting of C 6-10aryl, 5-10-membered heteroaryl and 8-10-membered bicyclic heterocycle;R 5 is independently selected from -C 1-6alkyl, -C 1-6haloalkyl, -OC 1-6alk, -OC 1-6haloalkyl, halo, hydroxy, oxo, -C 0-6alkylene-NR aR b, -C 0-6alkylene-C (O) NR aR b, -C 0-6alkylene-NR cC (O) R b, -C 0-6alkylene-S (O) 2R b, -C 0- 6alkylene-S (O) 2NR aR b, -C 0-6alkylene-NR cS (O) 2R b, -C 0-6alkylene-NR cS (O) 2NR aR b, -C 0-6alkylene-P (O) R aR b, -C 0-6alkylene-P (O) (OR a) (OR b) , -C 0-6alkylene-P (O) R a) R b, -C 0-6alkylene-cyano, -C 0-6alkylene-C 3-8cycloalkyl, -C 0-6alkylene-3-10 membered heterocyclyl, -C 0-6alkylene-C 6-10aryl, -C 0-6alkylene-5-10 membered heteroaryl; -C 2-6alkenyl, -C 2-6alkynyl, -C 0-6alkylene-C 3-10cycloalkyl, -C 4-10cycloalkenyl, -C 0-6alkylene-5-10-membered heteroaryl; two adjacent R 5 are taken together with the atom (s) to which they are attached to form an optionally substituted 5-10 membered carbocyclyl or 5-10 membered heterocyclyl; R 5 is optionally substituted with one or more R 10;R 6 is selected from hydrogen, -C 1-6 alkyl, -OC 1-6alkyl, -C 1-6haloalkyl, halo, hydroxy, -C 0-6alkylene-NR aR b , -C 0-6alkylene-C (O) NR aR b, -C 0-6alkylene-NR cC (O) R b, -C 0-6alkylene-S (O) 2R b, -C 0-6alkylene-S (O) 2NR aR b, -C 0- 6alkylene-NR cS (O) 2R b, -C 0-6alkylene-NR cS (O) 2NR aR b, -C 0-6alkylene-P (O) R aR b, -C 0-6alkylene-P (O) (OR a) (OR b) , -C 0-6alkylene-cyano, -C 0-6alkylene-C 3-8 cycloalkyl, -C 0-6alkylene-3-10 membered heterocyclyl, C 0-6alkylene-C 6-10 aryl, -C 0-6alkylene-5-10 membered heteroaryl, -C 2-6alkenyl, -OC 2-6alkenyl, -C 2-6alkynyl, -OC 0-6alkyleneC 3-10cycloalkyl, -C 4-10cycloalkenyl, -OC 0-6alkylene-C 6-10aryl, -O-C 0-6alkylene-5-10-membered heteroaryl;n is 1, 2 or 3.
- A compound of Formula XI or a pharmaceutically acceptable salt thereof,R 1, R 2, R 3, R 4, R 4a, R 5, L 1, L 2, L 3, ring A and n are as defined in Formula I; Y 1 is O, S, NR c or absent; R c and R 1 may be taken together with the atom (s) to which they are attached to form an optionally substituted 5-10 membered carbocyclyl, or heterocyclyl which contains 0-3 heteroatoms and is optionally substitute with 0-5 occurrences of R 10; R 10 is defined as for Formula I in Claim 1.
- A compound of Formula XII or a pharmaceutically acceptable salt thereof,R 1, R 2, R 3, R 4, R 4a, R 5, L 1, L 2, L 3, Q 1, Q 3 and n are as defined in Formula I; Q 6 and Q 7 are each independently O, S, N, NR c or CR 6; Y 1 is O, S, NR c or absent; R c and R 1 may be taken together with the atom (s) to which they are attached to form an optionally substituted 5-10 membered carbocyclyl, or heterocyclyl which contains 0-3 heteroatoms and is optionally substitute with 0-5 occurrences of R 10; R 10 is defined as for Formula I in Claim 1.
- A compound of Formula XIII or a pharmaceutically acceptable salt thereof,R 1, R 2, R 3, R 4, R 4a, R 5, L 1, L 2, L 3, Q 1, Q 3, Q 6, Q 7 and n are as defined in Formula I; Q 6 and Q 7 are each independently O, S, N, NR c or CR 6; Y 1 is O, S, NR c or absent; R c and R 1 may be taken together with the atom (s) to which they are attached to form an optionally substituted 5-10 membered carbocyclyl, or heterocyclyl which contains 0-3 heteroatoms and is optionally substitute with 0-5 occurrences of R 10; R 10 is defined as for Formula I in Claim 1.
- A compound of Formula XIV or a pharmaceutically acceptable salt thereof,R 3, R 4, R 4a, R 5 and n are as defined in Formula I; L 2 is O, -C (O) , NR c or absent; R 2 is -C 0-10alkylene-C 3- 10cycloalkyl, -C 0-10alkylene-3-10-membered heterocyclyl, -C 0-10alkylene-5-10-membered heteroaryl, -C 0- 10alkylene-NR aR b; R 2 is optionally substituted by one or more R 2a; Ring B is selected from -C 0-10alkylene-C 3- 10cycloalkyl, -C 0-10alkylene-3-10-membered heterocyclyl, -C 0-10alkylene-5-10-membered heteroaryl; Ring B is optionally substituted by one or more R 2a; R a, R b, R c and R 2a are defined as in Formula I.
- A compound of Formula XV or a pharmaceutically acceptable salt thereof,R 3, R 4, R 4a, R 5 and n are as defined in Formula I; L 2 is O, -C (O) , NR c or absent; R 2 is -C 0-10alkylene-C 3- 10cycloalkyl, -C 0-10alkylene-3-10-membered heterocyclyl, -C 0-10alkylene-5-10-membered heteroaryl, -C 0- 10alkylene-NR aR b; R 2 is optionally substituted by one or more R 2a; Ring B is selected from -C 0-10alkylene-C 3- 10cycloalkyl, -C 0-10alkylene-3-10-membered heterocyclyl, -C 0-10alkylene-5-10-membered heteroaryl; Ring B is optionally substituted by one or more R 2a; R a, R b, R c and R 2a are defined as in Formula I.
- A compound of Formula XVI or a pharmaceutically acceptable salt thereof,R 3, R 4, R 4a, R 5, Q 1, Q 3 and n are as defined in Formula I; Q 6 and Q 7 are each independently CH, N, NR c, O or S, provided at least one of Q 6 and Q 7 is N, NR c, O or S; L 2 is O, -C (O) , NR c or absent; R 2 is -C 0-10alkylene-C 3- 10cycloalkyl, -C 0-10alkylene-3-10-membered heterocyclyl, -C 0-10alkylene-5-10-membered heteroaryl, -C 0- 10alkylene-NR aR b; R 2 is optionally substituted by one or more R 2a; Ring B is selected from -C 0-10alkylene-C 3- 10cycloalkyl, -C 0-10alkylene-3-10-membered heterocyclyl, -C 0-10alkylene-5-10-membered heteroaryl; Ring B is optionally substituted by one or more R 2a; R a, R b, R c and R 2a are defined as in Formula I.
- A compound of Formula XVII or a pharmaceutically acceptable salt thereof,R 3, R 4, R 4a, R 5, Q 1, Q 3 and n are as defined in Formula I; Q 6 and Q 7 are each independently CH, N, NR c, O or S, provided at least one of Q 6 and Q 7 is N, NR c, O or S; L 2 is O, -C (O) , NR c or absent; R 2 is -C 0-10alkylene-C 3- 10cycloalkyl, -C 0-10alkylene-3-10-membered heterocyclyl, -C 0-10alkylene-5-10-membered heteroaryl, -C 0- 10alkylene-NR aR b; R 2 is optionally substituted by one or more R 2a; Ring B is selected from -C 0-10alkylene-C 3- 10cycloalkyl, -C 0-10alkylene-3-10-membered heterocyclyl, -C 0-10alkylene-5-10-membered heteroaryl; Ring B is optionally substituted by one or more R 2a; R a, R b, R c and R 2a are defined as in Formula I.
- A compound of Formula XVIII or a pharmaceutically acceptable salt thereof,R 3, R 4, R 4a, R 5, Q 1, Q 3 and n are as defined in Formula I; Q 6 and Q 7 are each independently CH, N, NR c, O or S, provided at least one of Q 6 and Q 7 is N, NR c, O or S; L 2 is O, -C (O) , NR c or absent; R 2 is -C 0-10alkylene-C 3- 10cycloalkyl, -C 0-10alkylene-3-10-membered heterocyclyl, -C 0-10alkylene-5-10-membered heteroaryl, -C 0- 10alkylene-NR aR b; R 2 is optionally substituted by one or more R 2a; Ring B is selected from -C 0-10alkylene-C 3- 10cycloalkyl, -C 0-10alkylene-3-10-membered heterocyclyl, -C 0-10alkylene-5-10-membered heteroaryl; Ring B is optionally substituted by one or more R 2a; R a, R b, R c and R 2a are defined as in Formula I.
- A compound of Formula XIX or a pharmaceutically acceptable salt thereof,R 3, R 4, R 4a, R 5, Q 1, Q 3 and n are as defined in Formula I; Q 6 and Q 7 are each independently CH, N, NR c, O or S, provided at least one of Q 6 and Q 7 is N, NR c, O or S; L 2 is O, -C (O) , NR c or absent; R 2 is -C 0-10alkylene-C 3- 10cycloalkyl, -C 0-10alkylene-3-10-membered heterocyclyl, -C 0-10alkylene-5-10-membered heteroaryl, -C 0- 10alkylene-NR aR b; R 2 is optionally substituted by one or more R 2a; Ring B is selected from -C 0-10alkylene-C 3- 10cycloalkyl, -C 0-10alkylene-3-10-membered heterocyclyl, -C 0-10alkylene-5-10-membered heteroaryl; Ring B is optionally substituted by one or more R 2a; R a, R b, R c and R 2a are defined as in Formula I.
- A compound of Formula XXI or a pharmaceutically acceptable salt thereof,Q 1, Q 2, Q 3, R 1, R 4, R 4a, R 5, ring A and n are defined as in Formula I; X is C (O) , C (R 7) 2; R 7 is independently selected from hydrogen, -C 1-6 alkyl, -C 1-6haloalkyl, -C 0-6alkylene-NR aR b , -C 0-6alkylene-C (O) NR aR b, -C 0- 6alkylene-NR cC (O) R b, -C 0-6alkylene-S (O) 2R b, -C 0-6alkylene-S (O) 2NR aR b, -C 0-6alkylene-NR cS (O) 2R b, -C 0- 6alkylene-NR cS (O) 2NR aR b, -C 0-6alkylene-P (O) R aR b, -C 0-6alkylene-P (O) (OR a) (OR b) , -C 0-6alkylene-cyano, -C 0- 6alkylene-C 3-8 cycloalkyl, -C 0-6alkylene-3-10 membered heterocyclyl, C 0-6alkylene-C 6-10 aryl, -C 0-6alkylene-5-10 membered heteroaryl, -C 2-6alkenyl, -C 2-6alkynyl; R f is selected from R b, -C (O) R b and -S (O) 2R b; Rb is defined as in Formula I.
- A compound of Formula XXII or a pharmaceutically acceptable salt thereof,R 4, R 4a, R 5, Q 1, Q 2, Q 3, ring A and n are as defined in Formula I; X is C (O) , C (R 7) 2; R 7 is independently selected from hydrogen, -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6haloalkyl, -C 0-6alkylene-NR aR b , -C 0-6alkylene-C (O) NR aR b, -C 0-6alkylene-NR cC (O) R b, -C 0-6alkylene-S (O) 2R b, -C 0-6alkylene-S (O) 2NR aR b, -C 0-6alkylene-NR cS (O) 2R b, -C 0-6alkylene-NR cS (O) 2NR aR b, -C 0-6alkylene-P (O) R aR b, -C 0-6alkylene-P (O) (OR a) (OR b) , -C 0- 6alkylene-cyano, -C 0-6alkylene-C 3-8 cycloalkyl, -C 0-6alkylene-3-10 membered heterocyclyl, C 0-6alkylene-C 6-10 aryl, -C 0-6alkylene-5-10 membered heteroaryl, -C 2-6alkenyl, -C 2-6alkynyl; Ring B is selected -C 3-10cycloalkyl, -3-10-membered heterocyclyl, -5-10-membered heteroaryl; Ring B is optionally substituted by one or more R 2a; R f is selected from R b, -C (O) R b and -S (O) 2R b; R b and R 2a are defined as in Formula I.
- A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound or pharmaceutically acceptable salt thereof according to any of Claims 1-16.
- A method of a compound according to any of Claims 1-16 or a pharmaceutically acceptable sale thereof for treating a disease or condition mediated by the interaction of SOS1 and a RAS protein and /or RAC1.
- A method of treating cancer, wherein the method comprising administering to a subject a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof according to any of Claims 1-16 or the pharmaceutical composition of Claim 17, wherein the cancer is selected from, but not limited to, lung cancer, breast cancer, ovarian cancer, prostate cancer, liver cancer, gastric cancer, esophageal cancer, pancreatic cancer, colon cancer, kidney cancer, head and neck cancer, bladder cancer, or a sarcoma.
- A pharmaceutical composition comprising the compound of Claims 1-16 or a pharmaceutically acceptable salt, stereoisomer or tautomer, or prodrug thereof and a pharmaceutically acceptable carrier and/or an antineoplastic agent, such as RAS inhibitors, SOS2 inhibitors, kinase inhibitors (such as a MEK inhibitor or an EGFR inhibitor) , angiogenesis inhibitors, cell proliferation and survival signal inhibitors, apoptosis inducers and agents, chemotherapies, RNAi therapies, IDO inhibitors, TDO inhibitors, IDO/TDO dual inhibitors, EP4 antagonists, EP2/EP4 dual antagonists, immunotherapies such as CTLA4 antibody, PD-1 antibody, PD-L1 antibody, LAG-3 antibody, TIM-3, and the like, for the treatment of cancer.
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