WO2012177606A1 - Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as jak inhibitors - Google Patents
Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as jak inhibitors Download PDFInfo
- Publication number
- WO2012177606A1 WO2012177606A1 PCT/US2012/043099 US2012043099W WO2012177606A1 WO 2012177606 A1 WO2012177606 A1 WO 2012177606A1 US 2012043099 W US2012043099 W US 2012043099W WO 2012177606 A1 WO2012177606 A1 WO 2012177606A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- pyrazol
- pyrrolo
- cyanomethyl
- pyrimidin
- Prior art date
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- -1 Azetidinyl phenyl Chemical group 0.000 title claims abstract description 95
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical class NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 125000004076 pyridyl group Chemical group 0.000 title abstract description 4
- 229940122245 Janus kinase inhibitor Drugs 0.000 title description 26
- 239000000203 mixture Substances 0.000 claims abstract description 205
- 238000000034 method Methods 0.000 claims abstract description 78
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 39
- 230000000694 effects Effects 0.000 claims abstract description 27
- 201000011510 cancer Diseases 0.000 claims abstract description 26
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 16
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims description 287
- 125000000217 alkyl group Chemical group 0.000 claims description 166
- 150000003839 salts Chemical class 0.000 claims description 100
- 229910052739 hydrogen Inorganic materials 0.000 claims description 47
- 229910052731 fluorine Inorganic materials 0.000 claims description 42
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 40
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 36
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 33
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 24
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 22
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 21
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 21
- 125000001424 substituent group Chemical group 0.000 claims description 19
- 101000997832 Homo sapiens Tyrosine-protein kinase JAK2 Proteins 0.000 claims description 18
- 125000001153 fluoro group Chemical group F* 0.000 claims description 18
- 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 claims description 17
- 206010028537 myelofibrosis Diseases 0.000 claims description 17
- 208000014767 Myeloproliferative disease Diseases 0.000 claims description 15
- 102100033438 Tyrosine-protein kinase JAK1 Human genes 0.000 claims description 15
- 201000004681 Psoriasis Diseases 0.000 claims description 12
- 230000002401 inhibitory effect Effects 0.000 claims description 12
- 201000007224 Myeloproliferative neoplasm Diseases 0.000 claims description 11
- 208000017733 acquired polycythemia vera Diseases 0.000 claims description 11
- 208000037244 polycythemia vera Diseases 0.000 claims description 11
- 208000003476 primary myelofibrosis Diseases 0.000 claims description 11
- 208000032027 Essential Thrombocythemia Diseases 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 125000001188 haloalkyl group Chemical group 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 208000017520 skin disease Diseases 0.000 claims description 9
- 208000006386 Bone Resorption Diseases 0.000 claims description 8
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 8
- 125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 claims description 8
- 230000024279 bone resorption Effects 0.000 claims description 8
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 7
- 206010012442 Dermatitis contact Diseases 0.000 claims description 7
- 208000034578 Multiple myelomas Diseases 0.000 claims description 7
- 206010070834 Sensitisation Diseases 0.000 claims description 6
- 208000010247 contact dermatitis Diseases 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 210000000056 organ Anatomy 0.000 claims description 6
- 230000008313 sensitization Effects 0.000 claims description 6
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 5
- 208000009525 Myocarditis Diseases 0.000 claims description 5
- 206010052779 Transplant rejections Diseases 0.000 claims description 5
- 208000019664 bone resorption disease Diseases 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- WLQRZQUNUAGWJJ-UHFFFAOYSA-N 4-[3-(cyanomethyl)-3-[4-(1h-pyrrolo[2,3-b]pyridin-4-yl)pyrazol-1-yl]azetidin-1-yl]-n-propan-2-ylbenzamide Chemical compound C1=CC(C(=O)NC(C)C)=CC=C1N1CC(CC#N)(N2N=CC(=C2)C=2C=3C=CNC=3N=CC=2)C1 WLQRZQUNUAGWJJ-UHFFFAOYSA-N 0.000 claims description 4
- QGHXERJPAFJDKB-UHFFFAOYSA-N 4-[3-(cyanomethyl)-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-1-yl]-2,5-difluoro-n-propan-2-ylbenzamide Chemical compound C1=C(F)C(C(=O)NC(C)C)=CC(F)=C1N1CC(CC#N)(N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)C1 QGHXERJPAFJDKB-UHFFFAOYSA-N 0.000 claims description 4
- MASHFINJZKINPN-MRXNPFEDSA-N 4-[3-(cyanomethyl)-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-1-yl]-n-[(1r)-1-cyclopropylethyl]-3-fluorobenzamide Chemical compound C1([C@H](NC(=O)C=2C=C(F)C(N3CC(CC#N)(C3)N3N=CC(=C3)C=3C=4C=CNC=4N=CN=3)=CC=2)C)CC1 MASHFINJZKINPN-MRXNPFEDSA-N 0.000 claims description 4
- 208000010201 Exanthema Diseases 0.000 claims description 4
- 206010048643 Hypereosinophilic syndrome Diseases 0.000 claims description 4
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- 231100000370 skin sensitisation Toxicity 0.000 claims description 4
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 3
- 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 claims description 3
- RSGDBTCJSVBZDE-UHFFFAOYSA-N 4-[3-(cyanomethyl)-3-[4-(1h-pyrrolo[2,3-b]pyridin-4-yl)pyrazol-1-yl]azetidin-1-yl]-3-fluoro-n-propan-2-ylbenzamide Chemical compound FC1=CC(C(=O)NC(C)C)=CC=C1N1CC(CC#N)(N2N=CC(=C2)C=2C=3C=CNC=3N=CC=2)C1 RSGDBTCJSVBZDE-UHFFFAOYSA-N 0.000 claims description 3
- UHEIPWYAZVECGS-CYBMUJFWSA-N 4-[3-(cyanomethyl)-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-1-yl]-2,5-difluoro-n-[(2r)-1,1,1-trifluoropropan-2-yl]benzamide Chemical compound C1=C(F)C(C(=O)N[C@H](C)C(F)(F)F)=CC(F)=C1N1CC(CC#N)(N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)C1 UHEIPWYAZVECGS-CYBMUJFWSA-N 0.000 claims description 3
- QNIHVUUXGWSWQG-UHFFFAOYSA-N 4-[3-(cyanomethyl)-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-1-yl]-2-fluoro-n-propan-2-ylbenzamide Chemical compound C1=C(F)C(C(=O)NC(C)C)=CC=C1N1CC(CC#N)(N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)C1 QNIHVUUXGWSWQG-UHFFFAOYSA-N 0.000 claims description 3
- MSRLOIHBPGCBJA-UHFFFAOYSA-N 4-[3-(cyanomethyl)-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-1-yl]-3-fluoro-n-propan-2-ylbenzamide Chemical compound FC1=CC(C(=O)NC(C)C)=CC=C1N1CC(CC#N)(N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)C1 MSRLOIHBPGCBJA-UHFFFAOYSA-N 0.000 claims description 3
- FKLLQVZKNYERJE-OAHLLOKOSA-N 4-[3-(cyanomethyl)-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-1-yl]-n-[(1r)-1-cyclopropylethyl]-2,5-difluorobenzamide Chemical compound C1([C@H](NC(=O)C=2C(=CC(=C(F)C=2)N2CC(CC#N)(C2)N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)F)C)CC1 FKLLQVZKNYERJE-OAHLLOKOSA-N 0.000 claims description 3
- NXVPNHLBWAYTTQ-UHFFFAOYSA-N 4-[3-(cyanomethyl)-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-1-yl]-n-propan-2-ylbenzamide Chemical compound C1=CC(C(=O)NC(C)C)=CC=C1N1CC(CC#N)(N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)C1 NXVPNHLBWAYTTQ-UHFFFAOYSA-N 0.000 claims description 3
- LKXFOSYTOMRBKX-KRWDZBQOSA-N 5-[3-(cyanomethyl)-3-[4-(1h-pyrrolo[2,3-b]pyridin-4-yl)pyrazol-1-yl]azetidin-1-yl]-n-[(1s)-1-cyclopropylethyl]pyridine-2-carboxamide Chemical compound C1([C@@H](NC(=O)C=2N=CC(=CC=2)N2CC(CC#N)(C2)N2N=CC(=C2)C=2C=3C=CNC=3N=CC=2)C)CC1 LKXFOSYTOMRBKX-KRWDZBQOSA-N 0.000 claims description 3
- CHCJRQFURSVKCE-UHFFFAOYSA-N 5-[3-(cyanomethyl)-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-1-yl]-n-(3,3-difluorocyclobutyl)pyridine-2-carboxamide Chemical compound C1C(F)(F)CC1NC(=O)C1=CC=C(N2CC(CC#N)(C2)N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)C=N1 CHCJRQFURSVKCE-UHFFFAOYSA-N 0.000 claims description 3
- NQSJETFQTIKWPX-UHFFFAOYSA-N 5-[3-(cyanomethyl)-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-1-yl]-n-propan-2-ylpyrazine-2-carboxamide Chemical compound C1=NC(C(=O)NC(C)C)=CN=C1N1CC(CC#N)(N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)C1 NQSJETFQTIKWPX-UHFFFAOYSA-N 0.000 claims description 3
- 208000011231 Crohn disease Diseases 0.000 claims description 3
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- 108060003951 Immunoglobulin Proteins 0.000 claims description 3
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- 102000018358 immunoglobulin Human genes 0.000 claims description 3
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- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 231100000046 skin rash Toxicity 0.000 claims description 3
- 125000006582 (C5-C6) heterocycloalkyl group Chemical group 0.000 claims description 2
- QCSKBYDKODJHDX-CQSZACIVSA-N 4-[3-(cyanomethyl)-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-1-yl]-3-fluoro-n-[(2r)-1,1,1-trifluoropropan-2-yl]benzamide Chemical compound FC1=CC(C(=O)N[C@H](C)C(F)(F)F)=CC=C1N1CC(CC#N)(N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)C1 QCSKBYDKODJHDX-CQSZACIVSA-N 0.000 claims description 2
- WDEJUNVQOYTIQI-UHFFFAOYSA-N 4-[3-(cyanomethyl)-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-1-yl]-n-(2,2-difluoroethyl)-2,5-difluorobenzamide Chemical compound C1=C(F)C(C(=O)NCC(F)F)=CC(F)=C1N1CC(CC#N)(N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)C1 WDEJUNVQOYTIQI-UHFFFAOYSA-N 0.000 claims description 2
- DEKRWNRSDSDTFU-IBGZPJMESA-N 4-[3-(cyanomethyl)-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-1-yl]-n-[(1s)-1-cyclohexylethyl]-2-fluorobenzamide Chemical compound C1([C@@H](NC(=O)C=2C(=CC(=CC=2)N2CC(CC#N)(C2)N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)F)C)CCCCC1 DEKRWNRSDSDTFU-IBGZPJMESA-N 0.000 claims description 2
- MASHFINJZKINPN-INIZCTEOSA-N 4-[3-(cyanomethyl)-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-1-yl]-n-[(1s)-1-cyclopropylethyl]-3-fluorobenzamide Chemical compound C1([C@@H](NC(=O)C=2C=C(F)C(N3CC(CC#N)(C3)N3N=CC(=C3)C=3C=4C=CNC=4N=CN=3)=CC=2)C)CC1 MASHFINJZKINPN-INIZCTEOSA-N 0.000 claims description 2
- QPKKUEMOABDWJS-OAHLLOKOSA-N 4-[3-(cyanomethyl)-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-1-yl]-n-[(2r)-1,1,1-trifluoropropan-2-yl]benzamide Chemical compound C1=CC(C(=O)N[C@H](C)C(F)(F)F)=CC=C1N1CC(CC#N)(N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)C1 QPKKUEMOABDWJS-OAHLLOKOSA-N 0.000 claims description 2
- AAZMMJKJWFXIPX-UHFFFAOYSA-N 4-[3-(cyanomethyl)-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-1-yl]-n-[1-(1-methylpiperidin-4-yl)ethyl]benzamide Chemical compound C=1C=C(N2CC(CC#N)(C2)N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)C=CC=1C(=O)NC(C)C1CCN(C)CC1 AAZMMJKJWFXIPX-UHFFFAOYSA-N 0.000 claims description 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 2
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Definitions
- Y is CR 7 .
- R 1 is isopropyl, ethyl, 1 -methylpropyl, 2,2,2-trifluoro- 1-methylethyl, 1-cyclopropylethyl, 1 -cyclohexylethyl, cyclopropyl, 1- trifluoromethylcyclopropyl, 3,3-difluorocyclobutyl, or l-(l-methylpiperidin-4- yl)ethyl.
- R 1 is isopropyl
- R 1 is 1 -trifluoromethylcyclopropyl.
- R 1 is 2,2,2-trifluoroethyl.
- the compound is a compound of Formula IVa:
- the compound has Formula Ilia, wherein R 1 , R 2 , R 3 , R 5 , R 6 are defined as in embodiment (a).
- the compound has Formula IVa, wherein R 1 , R 2 , R 3 , and R 5 are defined as in embodiment (a).
- the compound has Formula Illb, wherein R 1 , R 2 , R 3 , R 5 , R 6 are defined as in embodiment (b).
- Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine).
- Suitable elution solvent composition can be determined by one skilled in the art.
- Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
- amine derivative 8 which can be converted to the corresponding aryl ester 10 by reaction with halo-substituted arylacid ester 9 in the presence of the suitable catalyst such as, but not limited to, ⁇ [2,2'-bis(diphenylphosphino)-l, l 'binaphthalene], Tol- ⁇ [2,2'-bis(di-p-tolylphosphino)-l, l 'binaphthalene], Xanthpos [4,5- bis(diphenylphosphino)-9,9-dimethylxanthene].
- the suitable catalyst such as, but not limited to, ⁇ [2,2'-bis(diphenylphosphino)-l, l 'binaphthalene], Tol- ⁇ [2,2'-bis(di-p-tolylphosphino)-l, l 'binaphthalene], Xanthpos [4,5- bis(diphenylphosphino)-9,9
- aryl amide derivatives 12 can be prepared according to the procedures outlined in Scheme 4.
- the aryl ester 16 can be hydrolyzed to the corresponding acid 19 by using an alkali such as lithium hydroxide, sodium hydroxide or potassium hydroxide.
- the acid 19 can be transfered to the arylamide 20 by reaction with an appropriate amine in the presence of a suitable coupling reagent such as, but not limited to, BOP, PyOP, HATU, HBTU, EDC, or CDI.
- Swern oxidation of 20 can produce the corresponding ketone 21 which can be converted to the ⁇ , ⁇ - unsaturated nitrile 22 by Wittig's reaction with diethyl cyanomethylphosphonate.
- Michael addition of 5 with ⁇ , ⁇ -unsaturated nitrile 21 can afford the adduct 12.
- the JAK inhibitors described herein can further be used to treat ischemia reperfusion injuries or a disease or condition related to an inflammatory ischemic event such as stroke or cardiac arrest.
- the JAK inhibitors described herein can further be used to treat endotoxin-driven disease state (e.g., complications after bypass surgery or chronic endotoxin states contributing to chronic cardiac failure).
- the JAK inhibitors described herein can further be used to treat anorexia, cachexia, or fatigue such as that resulting from or associated with cancer.
- the JAK inhibitors described herein can further be used to treat restenosis, sclerodermitis, or fibrosis.
- treating or treatment refers to one or more of (1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology); and (2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.
- treating or treatment includes preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.
- Example suitable RAF inhibitors include compounds, and their
- the selectivity can be at least about 2-fold, at least about 3-fold, at least about 5-fold, at least about 10-fold, at least about 20-fold, at least about 50-fold, or at least about 100-fold. Potency can be measured by one or more in vitro assays, such as the assays provided below in the Examples.
- the compositions of the invention contain from about 50 mg to about 500 mg of the active ingredient.
- the active ingredient contains from about 50 mg to about 500 mg of the active ingredient.
- One having ordinary skill in the art will appreciate that this embodies compounds or compositions containing about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 350 mg to about 400 mg, or about 450 mg to about 500 mg of the active ingredient.
- liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
- compositions in can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
- the insert comprises a polymer selected from polyvinylpyrrolidone (PVP), an acrylate or methacrylate polymer or copolymer (e.g., Eudragit® family of polymers from Rohm or Degussa), hydroxymethyl cellulose, polyacrylic acid, poly(amidoamine) dendrimers, poly(dimethyl siloxane), polyethylene oxide, poly(lactide-co-glycolide), poly(2-hydroxyethylmethacrylate), poly(vinyl alcohol), or poly(propylene fumarate).
- the insert comprises Gelfoam® R.
- the insert is a polyacrylic acid of 450 kDa-cysteine conjugate.
- Step 2 tert-butyl 3-(cyanomethylene)azetidine-l-carboxylate
- Step 3 tert-butyl 3-(cyanomethyl)-3- [4-(l - ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ - 1H- pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl]azetidine-l-carboxylate
- Step 5 5- ⁇ 3-(cyanomethyl)-3-[4-(l- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -lH- pyrrolo[2, 3-b]pyridin-4-yl)-lH-pyrazol-l-yl]azetidin-l-yl ⁇ -N-[ ( 1S)-1- cyclopropyle
- Step 1 methyl 5- ⁇ 3-(cyanomethyl)-3-f4-(7- ⁇ f2-(trimethylsilyl)ethoxyJmethyl ⁇ -7H- pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]azetidin-l-yl ⁇ pyrazine-2-carboxylate
- Example 26 4- ⁇ 3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-l-yl]azetidin-l-yl ⁇ -N-(2,2,2-trifluoro-l-methylethyl)benzamide
- Step 3 4- ⁇ 3-(cyanomethyl)-3-[ 4-(7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-lH-pyrazol-l- yl]azetidin-l-yl ⁇ -2,5-difluoro-N-[(lS)-2,2,2-trifluoro-l-methylethyl]benzamide
- N,N-Diisopropylethylamine (0.11 mL, 0.62 mmol) was added to a mixture of ⁇ 3-[4-(7- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-l-yl]azetidin-3-yl ⁇ acetonitrile dihydrochloride (110 mg, 0.22 mmol) and 5- chloro-N-[(lS)-2,2,2-trifluoro-l-methylethyl]pyrazine-2-carboxamide (52 mg, 0.21 mmol) in NMP (3.0 mL).
- Step 3 5- ⁇ 3-(cyanomethyl)-3-[ 4-(7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-lH-pyrazol-l- yl]azetidin-l-yl ⁇ -N-[(lS)-2,2,2-trifluoro-l-methylethyl]pyrazine-2-carboxamide
- Step 1 5-chloro-N-[(lS)-l-cyclopropyl-2,2,2-trifluoroethyl]pyrazine-2-carboxamide N,N-Diisopropylethylamine (1.3 mL, 7.5 mmol) was added to a mixture of 5- chloropyrazine-2-carboxylic acid (0.40 g, 2.5 mmol), N,N,N',N'-tetramethyl-0-(7- azabenzotriazol-l-yl)uronium hexafluorophosphate (1.0 g, 2.8 mmol) and (lS)-l- cyclopropyl-2,2,2-trifluoroethanamine hydrochloride (0.44 g, 2.5 mmol) (ASIBA Pharmatech, Cat.#: 70092-HCl) in methylene chloride (10 mL).
- N,N-Diisopropylethylamine (0.71 mL, 4.1 mmol) was added to a mixture of ⁇ 3-[4-(7- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-l-yl]azetidin-3-yl ⁇ acetonitrile dihydrochloride (0.70 g, 1.4 mmol) and 5- chloro-N-[l-(trifluoromethyl)cyclopropyl]pyrazine-2-carboxamide (0.36 g, 1.4 mmol) in NMP (5.0 mL).
- the above cell lines can also be used to examine the effects of compounds on phosphorylation of JAK kinases or potential downstream substrates such as STAT proteins, Akt, Shp2, or Erk. These experiments can be performed following an overnight cytokine starvation, followed by a brief preincubation with compound (2 hours or less) and cytokine stimulation of approximately 1 hour or less. Proteins are then extracted from cells and analyzed by techniques familiar to those schooled in the art including Western blotting or ELISAs using antibodies that can differentiate between phosphorylated and total protein. These experiments can utilize normal or cancer cells to investigate the activity of compounds on tumor cell survival biology or on mediators of inflammatory disease.
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Abstract
Description
Claims
Priority Applications (14)
Application Number | Priority Date | Filing Date | Title |
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EA201490042A EA201490042A1 (en) | 2011-06-20 | 2012-06-19 | AZETIDINYL-PHENYL-, PYRIDYL- OR PYRAZYNYLKARBOXAMID DERIVATIVES AS INHIBITORS |
BR112013032720A BR112013032720A2 (en) | 2011-06-20 | 2012-06-19 | "azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as jak inhibitors, composition and use of said derivatives" |
CN201280037078.XA CN103797010B (en) | 2011-06-20 | 2012-06-19 | As the azetidinyl phenyl of JAK inhibitor, pyridyl or pyrazinyl carboxamides derivatives |
MX2013015087A MX344479B (en) | 2011-06-20 | 2012-06-19 | Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as jak inhibitors. |
NZ618982A NZ618982B2 (en) | 2011-06-20 | 2012-06-19 | Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as jak inhibitors |
AU2012273164A AU2012273164B2 (en) | 2011-06-20 | 2012-06-19 | Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as JAK inhibitors |
JP2014517080A JP5876146B2 (en) | 2011-06-20 | 2012-06-19 | Azetidinylphenyl, pyridyl, or pyrazinylcarboxamide derivatives as JAK inhibitors |
EP12735369.6A EP2721028B1 (en) | 2011-06-20 | 2012-06-19 | Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as jak inhibitors |
UAA201400439A UA110978C2 (en) | 2011-06-20 | 2012-06-19 | Azetidinylphenyl, pyridyl or pyrazinylcarboxamide derivatives as JAK inhibitors |
CA2839767A CA2839767A1 (en) | 2011-06-20 | 2012-06-19 | Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as jak inhibitors |
KR1020147001320A KR20140040819A (en) | 2011-06-20 | 2012-06-19 | Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as jak inhibitors |
ES12735369.6T ES2560611T3 (en) | 2011-06-20 | 2012-06-19 | Phenyl azetidinyl, pyridyl or pyrazinyl carboxamide derivatives as JAK inhibitors |
IL230008A IL230008A (en) | 2011-06-20 | 2013-12-17 | Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as jak inhibitors |
HK14110258.0A HK1197056A1 (en) | 2011-06-20 | 2014-10-14 | Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as jak inhibitors jak |
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US201161498942P | 2011-06-20 | 2011-06-20 | |
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US (5) | US8691807B2 (en) |
EP (1) | EP2721028B1 (en) |
JP (1) | JP5876146B2 (en) |
KR (1) | KR20140040819A (en) |
CN (1) | CN103797010B (en) |
AR (1) | AR086983A1 (en) |
AU (1) | AU2012273164B2 (en) |
BR (1) | BR112013032720A2 (en) |
CA (1) | CA2839767A1 (en) |
CL (1) | CL2013003647A1 (en) |
CO (1) | CO6821966A2 (en) |
CR (1) | CR20130668A (en) |
EA (1) | EA201490042A1 (en) |
EC (1) | ECSP14013148A (en) |
ES (1) | ES2560611T3 (en) |
HK (1) | HK1197056A1 (en) |
IL (1) | IL230008A (en) |
MX (1) | MX344479B (en) |
MY (1) | MY165963A (en) |
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