BR112018015501B1 - PYRAZOLO[1,5-A]PYRAZIN-4-YL DERIVATIVES AS JAK INHIBITORS, THEIR USE AND PHARMACEUTICAL COMPOSITION COMPRISING THEM - Google Patents
PYRAZOLO[1,5-A]PYRAZIN-4-YL DERIVATIVES AS JAK INHIBITORS, THEIR USE AND PHARMACEUTICAL COMPOSITION COMPRISING THEM Download PDFInfo
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- BR112018015501B1 BR112018015501B1 BR112018015501-2A BR112018015501A BR112018015501B1 BR 112018015501 B1 BR112018015501 B1 BR 112018015501B1 BR 112018015501 A BR112018015501 A BR 112018015501A BR 112018015501 B1 BR112018015501 B1 BR 112018015501B1
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- Prior art keywords
- mmol
- pyrazol
- mixture
- preparation
- methyl
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 15
- -1 PYRAZOLO[1,5-A]PYRAZIN-4-YL Chemical class 0.000 title abstract description 55
- 229940122245 Janus kinase inhibitor Drugs 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 309
- 150000003839 salts Chemical class 0.000 claims abstract description 70
- 238000002360 preparation method Methods 0.000 claims description 271
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 84
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 40
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 31
- 208000006673 asthma Diseases 0.000 claims description 17
- 201000010099 disease Diseases 0.000 claims description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- 208000023275 Autoimmune disease Diseases 0.000 claims description 11
- 230000001363 autoimmune Effects 0.000 claims description 10
- 206010061218 Inflammation Diseases 0.000 claims description 8
- 230000004054 inflammatory process Effects 0.000 claims description 8
- 206010025135 lupus erythematosus Diseases 0.000 claims description 8
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 claims description 7
- 208000012654 Primary biliary cholangitis Diseases 0.000 claims description 7
- 201000008937 atopic dermatitis Diseases 0.000 claims description 7
- 208000024827 Alzheimer disease Diseases 0.000 claims description 6
- 208000003251 Pruritus Diseases 0.000 claims description 6
- 201000004681 Psoriasis Diseases 0.000 claims description 6
- 208000024891 symptom Diseases 0.000 claims description 6
- 206010002556 Ankylosing Spondylitis Diseases 0.000 claims description 5
- 208000033222 Biliary cirrhosis primary Diseases 0.000 claims description 5
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 5
- 208000011231 Crohn disease Diseases 0.000 claims description 5
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 5
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 5
- 102000002227 Interferon Type I Human genes 0.000 claims description 5
- 108010014726 Interferon Type I Proteins 0.000 claims description 5
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 5
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 5
- 206010047642 Vitiligo Diseases 0.000 claims description 5
- 208000027866 inflammatory disease Diseases 0.000 claims description 5
- 201000006417 multiple sclerosis Diseases 0.000 claims description 5
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 5
- 230000002018 overexpression Effects 0.000 claims description 5
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 5
- 208000033237 Aicardi-Goutières syndrome Diseases 0.000 claims description 4
- 206010008609 Cholangitis sclerosing Diseases 0.000 claims description 4
- 208000024556 Mendelian disease Diseases 0.000 claims description 4
- 201000001263 Psoriatic Arthritis Diseases 0.000 claims description 4
- 208000036824 Psoriatic arthropathy Diseases 0.000 claims description 4
- 206010039710 Scleroderma Diseases 0.000 claims description 4
- 208000029265 Type 1 interferonopathy Diseases 0.000 claims description 4
- 201000009961 allergic asthma Diseases 0.000 claims description 4
- 208000007118 chronic progressive multiple sclerosis Diseases 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 208000005987 polymyositis Diseases 0.000 claims description 4
- 201000000742 primary sclerosing cholangitis Diseases 0.000 claims description 4
- 208000010157 sclerosing cholangitis Diseases 0.000 claims description 4
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 4
- 208000006547 Central Nervous System Lupus Vasculitis Diseases 0.000 claims description 3
- 208000005777 Lupus Nephritis Diseases 0.000 claims description 3
- 208000036110 Neuroinflammatory disease Diseases 0.000 claims description 3
- 208000011235 central nervous system lupus Diseases 0.000 claims description 3
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 claims description 3
- 230000003959 neuroinflammation Effects 0.000 claims description 3
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 3
- 206010063401 primary progressive multiple sclerosis Diseases 0.000 claims description 3
- 201000005671 spondyloarthropathy Diseases 0.000 claims description 3
- 208000007400 Relapsing-Remitting Multiple Sclerosis Diseases 0.000 claims description 2
- 230000007803 itching Effects 0.000 claims description 2
- 208000004631 alopecia areata Diseases 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 66
- 239000012453 solvate Substances 0.000 abstract description 18
- 238000011282 treatment Methods 0.000 abstract description 15
- 239000003814 drug Substances 0.000 abstract description 3
- 229940124597 therapeutic agent Drugs 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 310
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 182
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 154
- 238000005160 1H NMR spectroscopy Methods 0.000 description 146
- 239000000243 solution Substances 0.000 description 139
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 134
- 239000007787 solid Substances 0.000 description 115
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 111
- 238000004587 chromatography analysis Methods 0.000 description 100
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 84
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 82
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- 238000006243 chemical reaction Methods 0.000 description 62
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 60
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 57
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 52
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- 239000007832 Na2SO4 Substances 0.000 description 48
- 229910052938 sodium sulfate Inorganic materials 0.000 description 48
- 235000011152 sodium sulphate Nutrition 0.000 description 48
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 47
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 47
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 47
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 46
- 239000002024 ethyl acetate extract Substances 0.000 description 36
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 36
- 229910052757 nitrogen Inorganic materials 0.000 description 34
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 31
- 238000000746 purification Methods 0.000 description 31
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 28
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- 239000012391 XPhos Pd G2 Substances 0.000 description 27
- RSLSVURFMXHEEU-UHFFFAOYSA-M chloropalladium(1+);dicyclohexyl-[3-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane;2-phenylaniline Chemical compound [Pd+]Cl.NC1=CC=CC=C1C1=CC=CC=[C-]1.CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC(P(C2CCCCC2)C2CCCCC2)=C1 RSLSVURFMXHEEU-UHFFFAOYSA-M 0.000 description 27
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 27
- 239000012071 phase Substances 0.000 description 27
- 238000004128 high performance liquid chromatography Methods 0.000 description 25
- 239000002904 solvent Substances 0.000 description 25
- 239000003921 oil Substances 0.000 description 24
- 229910052786 argon Inorganic materials 0.000 description 23
- 101000844245 Homo sapiens Non-receptor tyrosine-protein kinase TYK2 Proteins 0.000 description 22
- 102100032028 Non-receptor tyrosine-protein kinase TYK2 Human genes 0.000 description 22
- 125000001475 halogen functional group Chemical group 0.000 description 22
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 22
- 239000002244 precipitate Substances 0.000 description 22
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
- 239000008346 aqueous phase Substances 0.000 description 20
- 239000012267 brine Substances 0.000 description 20
- 239000000706 filtrate Substances 0.000 description 20
- 125000000623 heterocyclic group Chemical group 0.000 description 20
- 229920006395 saturated elastomer Polymers 0.000 description 20
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 20
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 19
- 239000002027 dichloromethane extract Substances 0.000 description 19
- 125000001072 heteroaryl group Chemical group 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
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- 229910000027 potassium carbonate Inorganic materials 0.000 description 18
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 18
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 17
- 235000015320 potassium carbonate Nutrition 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 16
- 108091082332 JAK family Proteins 0.000 description 16
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- 229910052799 carbon Inorganic materials 0.000 description 14
- 208000035475 disorder Diseases 0.000 description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 14
- 239000003112 inhibitor Substances 0.000 description 14
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 13
- 239000002253 acid Substances 0.000 description 13
- 239000012230 colorless oil Substances 0.000 description 13
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 13
- 229910052739 hydrogen Inorganic materials 0.000 description 13
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 13
- 239000000725 suspension Substances 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 13
- 101000997832 Homo sapiens Tyrosine-protein kinase JAK2 Proteins 0.000 description 12
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- 238000003756 stirring Methods 0.000 description 12
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 12
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- MXQOYLRVSVOCQT-UHFFFAOYSA-N palladium;tritert-butylphosphane Chemical compound [Pd].CC(C)(C)P(C(C)(C)C)C(C)(C)C.CC(C)(C)P(C(C)(C)C)C(C)(C)C MXQOYLRVSVOCQT-UHFFFAOYSA-N 0.000 description 10
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- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- NDFBBDUBZDNHGS-UHFFFAOYSA-N 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine Chemical compound ClC=1C=2N(C=C(N=1)C=1C=NN(C=1)C)N=CC=2 NDFBBDUBZDNHGS-UHFFFAOYSA-N 0.000 description 8
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- ZSMFWODFQGCAKW-UHFFFAOYSA-N 4,6-dichloropyrazolo[1,5-a]pyrazine Chemical compound ClC=1C=2N(C=C(N=1)Cl)N=CC=2 ZSMFWODFQGCAKW-UHFFFAOYSA-N 0.000 description 7
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- FCZCIXQGZOUIDN-UHFFFAOYSA-N ethyl 2-diethoxyphosphinothioyloxyacetate Chemical compound CCOC(=O)COP(=S)(OCC)OCC FCZCIXQGZOUIDN-UHFFFAOYSA-N 0.000 description 7
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 7
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- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 5
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Abstract
Um composto derivado de pirazolo[1,5-a]pirazin-4-ila tendo a estrutura (I) ou um sal farmaceuticamente aceitável do mesmo, ou um solvato farmaceuticamente aceitável do referido composto ou sal farmaceuticamente aceitável, seu uso, bem como métodos de tratamento como inibidores de Janus Cinase e composições farmacêuticas contendo os compostos da invenção e combinaçãos dos mesmos com outros agentes terapêuticos. (I)A pyrazolo[1,5-a]pyrazin-4-yl derivative compound having structure (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, its use, as well as methods treatments such as Janus Kinase inhibitors and pharmaceutical compositions containing the compounds of the invention and combinations thereof with other therapeutic agents. (I)
Description
[001] A presente invenção fornece análogos e ligantes de TYK2 de pirazolo[1,5-a]pirazin-4-ila farmaceuticamente ativos. Tais compostos são úteis para inibir Janus Kinases (JAKs). Esta invenção também é direcionada a composições compreendendo métodos para fabricar tais compostos, e métodos para tratar e prevenir condições mediadas por JAK.[001] The present invention provides pharmaceutically active pyrazolo[1,5-a]pyrazin-4-yl TYK2 analogs and ligands. Such compounds are useful for inhibiting Janus Kinases (JAKs). This invention is also directed to compositions comprising methods for making such compounds, and methods for treating and preventing JAK-mediated conditions.
[002] Proteína cinases são famílias de enzimas que catalisam a fosforilação de resíduos específicos em proteínas, amplamente classificadas em tirosina e serina/treonina cinases. A atividade inapropriada de cinase, decorrente de mutação, superexpressão ou regulação inadequada, desregulação(dys-regulation) ou desregulação(de-regulation), assim como super ou subprodução de fatores de crescimento ou citocinas, tem sido implicada em muitas doenças, incluindo, porém, não se limitando a, câncer, doenças cardiovasculares, alergias, asma e outras doenças respiratórias, doenças autoimunes, doenças inflamatórias, doenças ósseas, distúrbios metabólicos e distúrbios neurológicos e neurodegenerativos, tais como a doença de Alzheimer. A atividade de cinase inapropriada desencadeia uma variedade de respostas celulares biológicas relacionadas com o crescimento celular, diferenciação celular, função celular, sobrevivência, apoptose e mobilidade celular implicadas nas doenças acima mencionadas e relacionadas.[002] Protein kinases are families of enzymes that catalyze the phosphorylation of specific residues in proteins, broadly classified into tyrosine and serine/threonine kinases. Inappropriate kinase activity, resulting from mutation, overexpression or inappropriate regulation, dysregulation or de-regulation, as well as over- or underproduction of growth factors or cytokines, has been implicated in many diseases, including, however, not limited to, cancer, cardiovascular diseases, allergies, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders and neurological and neurodegenerative disorders, such as Alzheimer's disease. Inappropriate kinase activity triggers a variety of biological cellular responses related to cell growth, cell differentiation, cell function, survival, apoptosis, and cell motility implicated in the above-mentioned and related diseases.
[003] Assim, as proteína cinases emergiram como uma classe importante de enzimas como alvos para a intervenção terapêutica. Em particular, a família JAK de proteína tirosina cinase celular (JAK1, JAK2, JAK3 e Tyk2) desempenham um papel central na sinalização de citocina (Kisseleva et al, Gene, 2002, 285, 1; Yamaoka et al, Genome Biology 2004, 5, 253)). Na ligação aos seus receptores, as citocinas ativam JAK que em seguida fosforila o receptor de citoquina, criando desse modo sítios de ancoragem para moléculas de sinalização, nomeadamente, membros da família de transdutor de sinal e ativador de transcrição (STAT) que conduzem finalmente à expressão de gene. Sabe-se que numerosas citocinas ativam a família JAK. Estas citocinas incluem a família de interferon (IFN) (IFN-alfa, IFN-beta, IFN- ômega, Limitina, IFN-gama, IL-10, IL-19, IL-20, IL-22), a família gp130 (IL-6, IL-11, OSM, LIF, CNTF, NNT-1/BSF-3, G-CSF, CT-1, leptina, IL- 12, IL-23), família gama C (IL-2, IL -7, TSLP, IL-9, IL-15, IL-21, IL-4, IL- 13), família IL-3 (IL-3, IL-5, GM-CSF), família de cadeia única (EPO, GH, PRL, TPO), recetores de tirosina cinases (EGF, PDGF, CSF-1, HGF) e receptores acoplados à protease G (AT1).[003] Thus, protein kinases have emerged as an important class of enzymes as targets for therapeutic intervention. In particular, the JAK family of cellular protein tyrosine kinases (JAK1, JAK2, JAK3 and Tyk2) play a central role in cytokine signaling (Kisseleva et al, Gene, 2002, 285, 1; Yamaoka et al, Genome Biology 2004, 5 , 253)). Upon binding to their receptors, cytokines activate JAK, which then phosphorylates the cytokine receptor, thereby creating docking sites for signaling molecules, namely, members of the signal transducer and activator of transcription (STAT) family, which ultimately lead to gene expression. Numerous cytokines are known to activate the JAK family. These cytokines include the interferon (IFN) family (IFN-alpha, IFN-beta, IFN-omega, Limitin, IFN-gamma, IL-10, IL-19, IL-20, IL-22), the gp130 family ( IL-6, IL-11, OSM, LIF, CNTF, NNT-1/BSF-3, G-CSF, CT-1, leptin, IL-12, IL-23), gamma family C (IL-2, IL -7, TSLP, IL-9, IL-15, IL-21, IL-4, IL-13), IL-3 family (IL-3, IL-5, GM-CSF), single-chain family (EPO , GH, PRL, TPO), tyrosine kinase receptors (EGF, PDGF, CSF-1, HGF) and G protease-coupled receptors (AT1).
[004] Permanece a necessidade de novos compostos que eficazmente e seletivamente inibam as enzimas JAK específicas: TYK2 em particular. TYK2 é um membro da família JAK cinase e é importante na sinalização dos interferons tipo I (incluindo IFNalfa, INFbeta), IL-6, IL-10, IL-12 e IL-23 (Liang, Y. et al., Expert Opinion on Therapeutics Targets, 18, 5, 571-580 (2014)). Como tal, TYK2 sinaliza com outros membros da família JAK cinase nas seguintes combinações: TYK2/JAK1, TYK2/JAK2, TYK2/JAK1/JAK2. Demonstrou-se que a TYK2 é importante na diferenciação e função de vários tipos de células importantes na doença inflamatória e na doença autoimune, incluindo células exterminadoras naturais, células B e tipos de células T auxiliares. A expressão de TYK2 aberrante é associada com múltiplos estados autoimunes ou inflamatórios. A modulação da atividade imune através da inibição da atividade da TYK2 cinase pode revelar-se útil no tratamento de vários distúrbios imunes (O'Shea JJ, Plenge R, Immunity, 36, 542-50 (2012); Murray, P. J., J. Immunol., 178, 2623-2629 (2007), Kisseleva, T., et al., Gene, 285, 1-24 (2002)) enquanto evitando a sinalização da eritropoietina dependente de JAK2 (EPO) e trombopoietina (TPO) (Neubauer H., et al., Cell, 93 (3), 397409 (1998), Parganas E., et al., Cell, 93 (3), 385-95 (1998)).[004] There remains a need for new compounds that effectively and selectively inhibit specific JAK enzymes: TYK2 in particular. TYK2 is a member of the JAK kinase family and is important in the signaling of type I interferons (including IFNalpha, INFbeta), IL-6, IL-10, IL-12 and IL-23 (Liang, Y. et al., Expert Opinion on Therapeutics Targets, 18, 5, 571-580 (2014)). As such, TYK2 signals with other members of the JAK kinase family in the following combinations: TYK2/JAK1, TYK2/JAK2, TYK2/JAK1/JAK2. TYK2 has been shown to be important in the differentiation and function of several cell types important in inflammatory disease and autoimmune disease, including natural killer cells, B cells, and T helper cell types. Aberrant TYK2 expression is associated with multiple autoimmune or inflammatory states. Modulation of immune activity through inhibition of TYK2 kinase activity may prove useful in the treatment of several immune disorders (O'Shea JJ, Plenge R, Immunity, 36, 542-50 (2012); Murray, P. J., J. Immunol., 178, 2623-2629 (2007), Kisseleva, T., et al., Gene, 285, 1-24 (2002)) while preventing JAK2-dependent erythropoietin (EPO) and thrombopoietin (TPO) signaling ( Neubauer H., et al., Cell, 93 (3), 397409 (1998), Parganas E., et al., Cell, 93 (3), 385-95 (1998)).
[005] A presente invenção fornece um composto de fórmula I tendo a estrutura: [005] The present invention provides a compound of formula I having the structure:
[006] ou um sal farmaceuticamente aceitável do mesmo, ou um solvato farmaceuticamente aceitável do referido composto ou sal far- maceuticamente aceitável, em que: A, A’ e A’’ são independentemente O, C=O, C-R’ ou N-R’’, onde R’ e R’’ podem independentemente ser H, amino, -NR7COR6, COR6, -CONR7R8, C1-C6 alquila, ou hidróxi(C1-C6 alquil), e R’’ pode estar presente ou ausente, e está presente onde as regras de valência permitem, e quando não mais do que um dentre A, A’ e A’’ é O ou C=O; R0 e R são independentemente H, Br, Cl, F, ou C1-C6 alquila; R1 é H, C1-C6 alquila, ou hidróxi(C1-C6 alquil); R2 é selecionado a partir do grupo consistindo em H, C1-C6 alquila, C1-C6 alcóxi, hidróxi(C1-C6 alquil), fenil(C1-C6 alquil), formila, heteroarila, heterocícli- co, -COR6, -OCOR6, -COOR6, -NR7COR6, -CONR7R8, e -(CH2)n-W, onde W é ciano, hidróxi, C3-C8 cicloalquila, -SO2NR7R8, e -SO2-R9, on- de R9 é C1-C6 alquila, C3-C8 cicloalquila, heteroarila, ou heterocíclico; em que cada dentre a referida alquila, cicloalquila, heterocíclico, ou heteroarila pode ser não substituído ou substituído por halo, ciano, hi- dróxi, ou C1-C6 alquila; X é C-R3 ou N, onde R3 pode ser H ou C1-C6 alquila; R4 e R5 são independentemente H, amino, C1-C6 alquila, ou hi- dróxi(C1-C6 alquil); R6, R7 e R8 são cada qual independentemente H, C1-C6 alquila, C1-C4 alcóxi(C1-C6 alquil), ou C3-C8 cicloalquila, a referida C1-C6 alquila é opcionalmente substituída por halo, CN ou hidróxi; ou, R7 e R8 juntamente com o átomo ligado a estes formam um anel de 5 ou 6 membros, o referido anel sendo opcionalmente substituído por halo, hidróxi, CN, ou C1-C6 alquila; e, n é 0, 1, 2 ou 3.[006] or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein: A, A' and A'' are independently O, C=O, C-R' or N-R'', where R' and R'' may independently be H, amino, -NR7COR6, COR6, -CONR7R8, C1-C6 alkyl, or hydroxy(C1-C6 alkyl), and R'' may be present or absent, and is present where valence rules allow, and when no more than one of A, A' and A'' is O or C=O; R0 and R are independently H, Br, Cl, F, or C1-C6 alkyl; R1 is H, C1-C6 alkyl, or hydroxy(C1-C6 alkyl); R2 is selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, hydroxy(C1-C6 alkyl), phenyl(C1-C6 alkyl), formyl, heteroaryl, heterocyclic, -COR6, -OCOR6 , -COOR6, -NR7COR6, -CONR7R8, and -(CH2)n-W, where W is cyano, hydroxy, C3-C8 cycloalkyl, -SO2NR7R8, and -SO2-R9, where- of R9 is C1-C6 alkyl, C3- C8 cycloalkyl, heteroaryl, or heterocyclic; wherein each of said alkyl, cycloalkyl, heterocyclic, or heteroaryl may be unsubstituted or substituted by halo, cyano, hydroxy, or C1-C6 alkyl; X is C-R3 or N, where R3 can be H or C1-C6 alkyl; R4 and R5 are independently H, amino, C1-C6 alkyl, or hydroxy(C1-C6 alkyl); R6, R7 and R8 are each independently H, C1-C6 alkyl, C1-C4 alkoxy (C1-C6 alkyl), or C3-C8 cycloalkyl, said C1-C6 alkyl is optionally substituted by halo, CN or hydroxy; or, R7 and R8 together with the atom bonded thereto form a 5- or 6-membered ring, said ring being optionally substituted by halo, hydroxy, CN, or C1-C6 alkyl; and, n is 0, 1, 2 or 3.
[007] Em outros aspectos, a presente invenção da mesma forma fornece:[007] In other aspects, the present invention likewise provides:
[008] composições farmacêuticas as quais compreendem um ve ículo farmaceuticamente aceitável e um composto de fórmula I;[008] pharmaceutical compositions which comprise a pharmaceutically acceptable carrier and a compound of formula I;
[009] métodos para tratar condições ou distúrbios incluindo infla mação, doença autoimune, lúpus eritematoso sistêmico, nefrite por lúpus, lúpus discoide, lúpus cutâneo, lúpus do sistema nervoso central, artrite reumatoide, artrite psoriática, doença intestinal inflamatória, doença de Crohn, colite ulcerativa, asma, asma alérgica, diabetes Tipo I, polimiosite, dermatomoiosite, interferonopatias tipo I incluindo síndro- me de Aicardi-Goutières e outras doenças mendelianas de superex- pressão de interferon tipo I, esclerose múltipla, esclerose múltipla progressiva primária, esclerose múltipla remitente reincidente, cirrose biliar primária da mesma forma conhecida como colangite biliar primária, colangite esclerosante primária, hetatite autoimune, doença da estea- tose hepática não alcoólica, esteatohepatite não alcoólica, psoríase, dermatomoiosite, escleroderma, dermatite atópica, vitiligo, alopecia em áreas, espondilopatia, espondilite ancilosante, doença de Alzheimer, miosite por neuroinflamação, vasculite, pênfigo, doença de Crohn, lú- pus, nefrite, psoríase, esclerose múltipla, transtorno depressivo maior, alergia, asma, doença de Sjogren, síndrome do olho seco, rejeição ao transplante, câncer, doença intestinal inflamatória, choque séptico, disfunção cardiopulmonar, vitiligo, alopecia, doença respiratória aguda, espondilite ancilosante, hetatite autoimune, colangite esclerosante primária, cirrose biliar primária, doença de Alzheimer, ou cachexia administrando-se a um indivíduo em necessidade, uma quantidade tera- peuticamente eficaz de um composto de fórmula I ou um sal farmaceu- ticamente aceitável do mesmo;[009] methods for treating conditions or disorders including inflammation, autoimmune disease, systemic lupus erythematosus, lupus nephritis, discoid lupus, cutaneous lupus, central nervous system lupus, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, asthma, allergic asthma, Type I diabetes, polymyositis, dermatomoiositis, type I interferonopathies including Aicardi-Goutières syndrome and other type I interferon overexpression Mendelian diseases, multiple sclerosis, primary progressive multiple sclerosis, multiple sclerosis relapsing remitting, primary biliary cirrhosis also known as primary biliary cholangitis, primary sclerosing cholangitis, autoimmune hetatitis, non-alcoholic hepatic steatosis disease, non-alcoholic steatohepatitis, psoriasis, dermatomoiositis, scleroderma, atopic dermatitis, vitiligo, area alopecia, spondylopathy, ankylosing spondylitis, Alzheimer's disease, neuroinflammation myositis, vasculitis, pemphigus, Crohn's disease, lupus, nephritis, psoriasis, multiple sclerosis, major depressive disorder, allergy, asthma, Sjogren's disease, dry eye syndrome, rejection transplantation, cancer, inflammatory bowel disease, septic shock, cardiopulmonary dysfunction, vitiligo, alopecia, acute respiratory disease, ankylosing spondylitis, autoimmune hetatitis, primary sclerosing cholangitis, primary biliary cirrhosis, Alzheimer's disease, or cachexia administered to an individual in necessity, a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof;
[0010] Métodos para tratar condições ou distúrbios incluindo der matite atópica, eczema, psoríase, escleroderma, lúpus, prurido, fadiga, outras condições pruríticas, reações alérgicas incluindo dermatite alérgica em mamífero, doenças alérgicas do cavalo incluindo hipersensibi- lidade à mordida, eczema de verão, coceira doce em cavalos, vômitos, doença das vias aéreas inflamatórias, obstrução das vias aéreas recorrentes, hipersensibilidade das vias áereas, e doença pulmonar obstrutiva crônica administrando-se a um mamífero em necessidade, uma quantidade terapeuticamente eficaz de um composto de fórmula I, ou um sal farmaceuticamente aceitável do mesmo; e, métodos para a preparação de compostos da presente invenção.[0010] Methods for treating conditions or disorders including atopic dermatitis, eczema, psoriasis, scleroderma, lupus, pruritus, fatigue, other pruritic conditions, allergic reactions including mammalian allergic dermatitis, horse allergic diseases including bite hypersensitivity, eczema of summer, sweet itch in horses, vomiting, inflammatory airway disease, recurrent airway obstruction, airway hypersensitivity, and chronic obstructive pulmonary disease by administering to a mammal in need, a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof; and, methods for preparing compounds of the present invention.
[0011] A presente invenção será também entendida a partir da se guinte descrição dada apenas por meio de exemplo. A presente invenção é direcionada a uma classe de derivados de pirazolo[1,5-a]pirazin- 4-ila. Em particular, a presente invenção é direcionada a ompostos de pirazolo[1,5-a]pirazin-4-ila úteis como inibitores de JAKs, e particularmente TYK2. Enquanto presente invenção não é tão limitada, uma apreciação de vários aspectos da invenção será ganha através da seguinte discussão, e os exemplos.[0011] The present invention will also be understood from the following description given by way of example only. The present invention is directed to a class of pyrazolo[1,5-a]pyrazin-4-yl derivatives. In particular, the present invention is directed to pyrazolo[1,5-a]pyrazin-4-yl compounds useful as inhibitors of JAKs, and particularly TYK2. While the present invention is not so limited, an appreciation of various aspects of the invention will be gained through the following discussion, and examples.
[0012] O termo "alquila", sozinho ou em combinação, significa um grupo hidrocarbonoeto acíclico, saturado da fórmula CnH2n+1 o qual pode ser linear ou ramificado. Exemplos de tais grupos incluem metila, etila, n-propila, isopropila, n-butila, isobutila, sec-butila, terc-butila, pentila, iso-amila e hexila. A menos que de outra maneira especificado, um grupo alquila compreende a partir de 1 a 6 átomos de carbonoo. O teor de átomo de carbonoo de alquila e várias outras porções contendo hidrocarbonoeto é indicado por um prefixo designando um número menor e maior de átomos de carbonoo na porção, isto é, o prefixo Ci- Cj indica uma porção do número inteiro "i" ao número inteiro "j" átomos de carbonoo, inclusive. Desse modo, por exemplo, C1-C6 alquila refere- se à alquila de um a seis átomos de carbonoo, inclusive.[0012] The term "alkyl", alone or in combination, means an acyclic, saturated hydrocarbon group of the formula CnH2n+1 which can be linear or branched. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl and hexyl. Unless otherwise specified, an alkyl group comprises from 1 to 6 carbon atoms. The carbon atom content of alkyl and various other hydrocarbon-containing moieties is indicated by a prefix designating a smaller and larger number of carbon atoms in the moiety, that is, the prefix Ci-Cj indicates a portion of the integer "i" to the whole number "j" carbon atoms, inclusive. Thus, for example, C1-C6 alkyl refers to alkyl of one to six carbon atoms, inclusive.
[0013] O termo "hidróxi," quando aqui usado, significa um grupo OH. O termo "heterocíclico" refere-se a um heterociclo saturado ou parcialmente saturado (isto é, não aromático) o qual contém três a dez átomos no anel onde um ou mais, preferivelmente, um, dois ou três átomos no anel, são heterátomo(s) selecionado(s) a partir de N, O e S, o restante sendo carbono, e os quais podem ser ligados por meio de um átomo de nitrogênio no anel ou um átomo de carbono no anel. Igualmente, quando substituído, o substituinte pode estar localizado em um átomo de nitrogênio no anel (se o substituinte for unido através de um átomo de carbono) ou um átomo de carbono no anel (em todos os cases). Exemplos específicos incluem oxiranila, aziridinila, oxetanila, azetidinila, tetra-hidrofuranila, pirrolidinila, tetra-hidropiranila, piperidinila, 1,4-dioxanila, morfolinila, pipe- razinila, azepanila, oxepanila, oxazepanila e diazepinila.[0013] The term "hydroxy," when used herein, means an OH group. The term "heterocyclic" refers to a saturated or partially saturated (i.e., non-aromatic) heterocycle which contains three to ten ring atoms where one or more, preferably one, two or three ring atoms, are heteroatoms ( s) selected from N, O and S, the remainder being carbon, and which may be bonded through a ring nitrogen atom or a ring carbon atom. Likewise, when substituted, the substituent can be located on a nitrogen atom in the ring (if the substituent is joined through a carbon atom) or a carbon atom in the ring (in all cases). Specific examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, piperazinyl, azepanil, oxepanil, oxazepanil and diazepinil.
[0014] O termo "arila" refere-se a um hidrocarboneto aromático monocíclico ou bicíclico contendo seis a dez átomos de carbono no anel os quais podem ser ligados por meio de um dos átomos de carbono no anel. Igualmente, quando substituído, o substituinte pode estar localizado em um átomo de carbono no anel. Exemplos específicos incluem, porém, não são limitados à, fenila, tolila, xilila, trimetilfenila e naftila. Exemplos de substituintes de arila incluem, porém não são limi- tados à, alquila, hidroxila, halo, nitrila, alcóxi, trifluorometila, carboxa- mido, SO2Me, benzila, e benzila substituída.[0014] The term "aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon containing six to ten ring carbon atoms which can be bonded through one of the ring carbon atoms. Likewise, when substituted, the substituent may be located on a carbon atom in the ring. Specific examples include, but are not limited to, phenyl, tolyl, xylyl, trimethylphenyl and naphthyl. Examples of aryl substituents include, but are not limited to, alkyl, hydroxyl, halo, nitrile, alkoxy, trifluoromethyl, carboxamido, SO2Me, benzyl, and substituted benzyl.
[0015] O termo "heteroarila" refere-se a um heterociclo monova lente aromático monocíclico ou bicíclico de cinco a dez átomos no anel onde um ou mais, preferivelmente, um, dois ou três átomos no anel, são heterátomo(s) selecionado(s) a partir de N, O e S, o restante sendo carbono, e os quais podem ser ligados por meio de um átomo de carbono no anel ou um átomo de nitrogênio no anel com uma valência apropriada. Igualmente, quando substituído, o substituinte pode estar localizado em um átomo de carbono no anel ou um átomo de nitrogênio no anel com uma valência apropriada. Exemplos específicos incluem, porém não são limitados à, tienila, furanila, pirrolila, pirazolila, imi- dazolila, oxazolila, isoxazolila, tiazolila, isotiazolila, triazolila, oxadiazolila, tiadiazolila, tetrazolila, piridila, piridazinila, pirimidinila e pirazini- la. O termo "cicloalquila" significa um grupo hidrocarboneto monocícli- co, saturado da fórmula CnH2n-1. Exemplos incluem, porém não são limitados à, ciclopropila, ciclobutila, ciclopentila, ciclo-hexila, e ciclo- heptila. A menos que de outra maneira especificado, um grupo cicloal- quila compreende a partir de 3 a 8 átomos de carbonoo.[0015] The term "heteroaryl" refers to a monovalent aromatic monocyclic or bicyclic heterocycle of five to ten ring atoms where one or more, preferably one, two or three ring atoms, are selected heteroatom(s). s) from N, O and S, the remainder being carbon, and which may be bonded through a ring carbon atom or a ring nitrogen atom with an appropriate valence. Likewise, when substituted, the substituent may be located on a ring carbon atom or a ring nitrogen atom with an appropriate valence. Specific examples include, but are not limited to, thienyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl. The term "cycloalkyl" means a monocyclic, saturated hydrocarbon group of the formula CnH2n-1. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Unless otherwise specified, a cycloalkyl group comprises from 3 to 8 carbon atoms.
[0016] Os termos "halo" e "halogênio" refere-se a fluoreto (F), clo reto (Cl), brometo (Br) ou iodeto (I).[0016] The terms "halo" and "halogen" refer to fluoride (F), chloride (Cl), bromide (Br) or iodide (I).
[0017] O termo "mamífero" refere-se a humanos, gado ou animais de companhia.[0017] The term "mammal" refers to humans, livestock or companion animals.
[0018] O termo "animal de companhia" ou "animais de companhia" refere-se a animais mantidos como animais de estimação ou animais domésticos. Exemplos de animais de companhia incluem cães, gatos e roedores incluindo hamsters, porquinhos-da-índia, gerbos, e similares, coelhos, furões e aves.[0018] The term "companion animal" or "companion animals" refers to animals kept as pets or domestic animals. Examples of companion animals include dogs, cats and rodents including hamsters, guinea pigs, gerbils, and the like, rabbits, ferrets and birds.
[0019] O termo "criação" refere-se a animais criados ou originados em um ambiente agrícola para produzir produtos tais como alimentos ou fibras, ou para o seu trabalho. Em algumas modalidades, a criação é adequada para consumo por mamíferos, por exemplo humanos. Exemplos de animais de criação incluem bovinos, cabras, cavalos, porcos, ovelhas, incluindo cordeiros e coelhos, bem como aves, tais como galinhas, patos e perus.[0019] The term "farmed" refers to animals raised or originated in an agricultural environment to produce products such as food or fiber, or for their work. In some embodiments, the creation is suitable for consumption by mammals, for example humans. Examples of farm animals include cattle, goats, horses, pigs, sheep including lambs and rabbits, as well as poultry such as chickens, ducks and turkeys.
[0020] O termo "tratando" ou "tratamento" significa um alívio dos sintomas associados a uma doença, distúrbio ou condição, ou interrupção de outro progresso ou agravamento desses sintomas. Dependendo da doença e condição do paciente, o termo "tratamento" quando aqui usado pode incluir um ou mais dentre tratamento curativo, paliativo e profilático. O tratamento também pode incluir a administração de uma formulação farmacêutica da presente invenção em combinação com outras terapias.[0020] The term "treating" or "treatment" means a relief of symptoms associated with a disease, disorder or condition, or interruption of further progress or worsening of these symptoms. Depending on the disease and condition of the patient, the term "treatment" when used herein may include one or more of curative, palliative and prophylactic treatment. Treatment may also include administration of a pharmaceutical formulation of the present invention in combination with other therapies.
[0021] O termo "terapeuticamente eficaz" indica a capacidade de um agente para prevenir ou melhorar a gravidade do distúrbio. A frase "terapeuticamente eficaz" deve ser entendida como equivalente à frase "eficaz para o tratamento, prevenção ou melhoria", e ambas pretendem qualificar a quantidade de um agente - que atingirá a meta de melhoria na gravidade do câncer, doença cardiovascular, ou dor e inflamação e a frequência de incidência sobre o tratamento de cada agente por si próprio.[0021] The term "therapeutically effective" indicates the ability of an agent to prevent or improve the severity of the disorder. The phrase "therapeutically effective" should be understood as equivalent to the phrase "effective for the treatment, prevention, or amelioration", and both are intended to qualify the quantity of an agent - which will achieve the goal of improvement in the severity of cancer, cardiovascular disease, or pain and inflammation and the frequency of incidence on the treatment of each agent on its own.
[0022] "Farmaceuticamente aceitável" significa adequado para uso em mamíferos, animais de companhia ou animais de criação.[0022] "Pharmaceutically acceptable" means suitable for use in mammals, companion animals or farm animals.
[0023] Se os substituintes são descritos como sendo "independen temente selecionados" a partir de um grupo, cada substituinte é selecionado independentemente do outro. Cada substituinte pode, portanto, ser idêntico ou diferente do(s) outro(s) substituinte(s).[0023] If substituents are described as being "independently selected" from a group, each substituent is selected independently of the other. Each substituent can therefore be identical or different from the other substituent(s).
[0024] A presente invenção refere-se a novos compostos que são moduladores de TYK2 úteis para o tratamento de doenças e condições associadas à desregulação de TYK2. A presente invenção proporciona ainda composições farmacêuticas compreendendo tais moduladores da enzima JAK, bem como métodos de tratamento e/ou prevenção de tais doenças e condições. Por conseguinte, a presente invenção fornece um composto de fórmula I como representado acima tendo a estrutura (I): [0024] The present invention relates to new compounds that are TYK2 modulators useful for the treatment of diseases and conditions associated with TYK2 deregulation. The present invention further provides pharmaceutical compositions comprising such JAK enzyme modulators, as well as methods of treating and/or preventing such diseases and conditions. Therefore, the present invention provides a compound of formula I as represented above having the structure (I):
[0025] A invenção da mesma forma fornece um composto tendo a estrutura (Ia): [0025] The invention likewise provides a compound having the structure (Ia):
[0026] ou um sal farmaceuticamente aceitável do mesmo, ou um solvato farmaceuticamente aceitável do referido composto ou sal far- maceuticamente aceitável, em que: A, A’ e A’’ são independentemente O, C=O, C-R’ ou N-R’’, onde R’ e R’’ podem independentemente ser H, amino, -NR7COR6, COR6, -CONR7R8, C1-C6 alquil-, ou hidróxi(C1-C6 alquil)-, e R’’ pode estar presente ou ausente, e está presente onde as regras de valência permitem, e quando não mais do que um dentre A, A’ e A’’ é O ou C=O; R0 e R são independentemente H, Br, Cl, F, ou C1-C6 alquila; R1 é H, C1-C6 alquila, ou hidróxi(C1-C6 alquil)-; R2 é selecionado a partir do grupo consistindo em H, C1-C6 alquila, C1-C6 alcóxi- , hidróxi(C1-C6 alquil)-, fenil(C1-C6 alquil)-, formila, heteroarila, hetero- cíclico, -COR6, -OCOR6, -COOR6, -NR7COR6, -CONR7R8, e -(CH2)n-W, onde W é ciano, hidróxi, C3-C8 cicloalquila, -SO2NR7R8, e -SO2-R9, onde R9 é C1-C6 alquila, C3-C8 cicloalquila, heteroarila, ou heterocíclico; em que cada dentre a referida alquila, cicloalquila, heterocíclico, ou heteroarila pode ser não substituído ou substituído por halo, ciano, hi- dróxi, ou C1-C6 alquila; R3 pode ser H ou C1-C6 alquila; R4 e R5 são in-dependentemente H, amino, C1-C6 alquila, ou hidróxi(C1-C6 alquil); R6, R7 e R8 são cada qual independentemente H, C1-C6 alquila, C1-C4 alcóxi(C1-C6 alquil), ou C3-C8 cicloalquila, a referida C1-C6 alquila é opcionalmente substituída por halo, CN ou hidróxi; ou, R7 e R8 juntamente com o átomo ligado a estes formam um anel de 5 ou 6 membros, o referido anel sendo opcionalmente substituído por halo, hidróxi, CN, ou C1-C6 alquila; e, n é 0, 1, 2 ou 3.[0026] or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein: A, A' and A'' are independently O, C=O, C-R' or N-R'', where R' and R'' may independently be H, amino, -NR7COR6, COR6, -CONR7R8, C1-C6 alkyl-, or hydroxy(C1-C6 alkyl)-, and R'' may be present or absent, and is present where valence rules allow, and when no more than one of A, A' and A'' is O or C=O; R0 and R are independently H, Br, Cl, F, or C1-C6 alkyl; R1 is H, C1-C6 alkyl, or hydroxy(C1-C6 alkyl)-; R2 is selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy-, hydroxy(C1-C6 alkyl)-, phenyl(C1-C6 alkyl)-, formyl, heteroaryl, heterocyclic, -COR6 , -OCOR6, -COOR6, -NR7COR6, -CONR7R8, and -(CH2)n-W, where W is cyano, hydroxy, C3-C8 cycloalkyl, -SO2NR7R8, and -SO2-R9, where R9 is C1-C6 alkyl, C3 -C8 cycloalkyl, heteroaryl, or heterocyclic; wherein each of said alkyl, cycloalkyl, heterocyclic, or heteroaryl may be unsubstituted or substituted by halo, cyano, hydroxy, or C1-C6 alkyl; R3 can be H or C1-C6 alkyl; R4 and R5 are independently H, amino, C1-C6 alkyl, or hydroxy (C1-C6 alkyl); R6, R7 and R8 are each independently H, C1-C6 alkyl, C1-C4 alkoxy (C1-C6 alkyl), or C3-C8 cycloalkyl, said C1-C6 alkyl is optionally substituted by halo, CN or hydroxy; or, R7 and R8 together with the atom bonded thereto form a 5- or 6-membered ring, said ring being optionally substituted by halo, hydroxy, CN, or C1-C6 alkyl; and, n is 0, 1, 2 or 3.
[0027] A invenção também fornece um composto tendo a estrutura (Ib): [0027] The invention also provides a compound having the structure (Ib):
[0028] ou um sal farmaceuticamente aceitável do mesmo, ou um solvato farmaceuticamente aceitável do referido composto ou sal far- maceuticamente aceitável, em que: R’’ é H, -COR6, -CONR7R8, C1-C6 alquil-, ou hidróxi(C1-C6 alquil)-; R0 e R são independentemente H, Br, Cl, F, ou C1-C6 alquila; R1 é H, C1-C6 alquila, ou hidróxi(C1-C6 alquil); R2 é selecionado a partir do grupo consistindo em H, C1-C6 alquila, C1C6 alcóxi, hidróxi(C1-C6 alquil), fenil(C1-C6 alquil), formila, heteroarila, heterocíclico, -COR6, -OCOR6, -COOR6, -NR7COR6, -CONR7R8, e - (CH2)n-W, onde W é ciano, hidróxi, C3-C8 cicloalquila, -SO2NR7R8, e - SO2-R9, onde R9 é C1-C6 alquila, C3-C8 cicloalquila, heteroarila, ou he- terocíclico; em que cada dentre a referida alquila, cicloalquila, hetero- cíclico, ou heteroarila pode ser não substituído ou substituído por halo, ciano, hidróxi, ou C1-C6 alquila; R3 pode ser H ou C1-C6 alquila; R5 é H, amino, C1-C6 alquila, ou hidróxi(C1-C6 alquil); R6, R7 e R8 são cada qual independentemente H, C1-C6 alquila, C1-C4 alcóxi(C1-C6 alquil), ou C3C8 cicloalquila, a referida C1-C6 alquila é opcionalmente substituída por halo, CN ou hidróxi; ou, R7 e R8 juntamente com o átomo ligado a estes formam um anel de 5 ou 6 membros, o referido anel sendo opcionalmente substituído por halo, hidróxi, CN, ou C1-C6 alquila; e, n é 0, 1, 2 ou 3.[0028] or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein: R'' is H, -COR6, -CONR7R8, C1-C6 alkyl-, or hydroxy( C1-C6 alkyl)-; R0 and R are independently H, Br, Cl, F, or C1-C6 alkyl; R1 is H, C1-C6 alkyl, or hydroxy(C1-C6 alkyl); R2 is selected from the group consisting of H, C1-C6 alkyl, C1C6 alkoxy, hydroxy(C1-C6 alkyl), phenyl(C1-C6 alkyl), formyl, heteroaryl, heterocyclic, -COR6, -OCOR6, -COOR6, -NR7COR6, -CONR7R8, and - (CH2)n-W, where W is cyano, hydroxy, C3-C8 cycloalkyl, -SO2NR7R8, and - SO2-R9, where R9 is C1-C6 alkyl, C3-C8 cycloalkyl, heteroaryl, or heterocyclic; wherein each of said alkyl, cycloalkyl, heterocyclic, or heteroaryl may be unsubstituted or substituted by halo, cyano, hydroxy, or C1-C6 alkyl; R3 can be H or C1-C6 alkyl; R5 is H, amino, C1-C6 alkyl, or hydroxy(C1-C6 alkyl); R6, R7 and R8 are each independently H, C1-C6 alkyl, C1-C4 alkoxy (C1-C6 alkyl), or C3C8 cycloalkyl, said C1-C6 alkyl is optionally substituted by halo, CN or hydroxy; or, R7 and R8 together with the atom bonded thereto form a 5- or 6-membered ring, said ring being optionally substituted by halo, hydroxy, CN, or C1-C6 alkyl; and, n is 0, 1, 2 or 3.
[0029] A invenção da mesma forma fornece um composto tendo a estrutura (Ic): [0029] The invention likewise provides a compound having the structure (Ic):
[0030] ou um sal farmaceuticamente aceitável do mesmo, ou um solvato farmaceuticamente aceitável do referido composto ou sal far- maceuticamente aceitável, em que: R’’ é H, -COR6, -CONR7R8, C1-C6 alquila, ou hidróxi(C1-C6 alquil); R2 é selecionado a partir do grupo consistindo em H, C1-C6 alquil-, C1-C6 alcóxi-, hidróxi(C1-C6 alquil)-, fenil(C1-C6 alquil)-, formila, heteroarila, heterocíclico, -COR6, -OCOR6, - COOR6, -NR7COR6, -CONR7R8, e -(CH2)n-W, onde W é ciano, hidróxi, C3-C8 cicloalquila, -SO2NR7R8, e -SO2-R9, onde R9 é C1-C6 alquila, C3C8 cicloalquila, heteroarila, ou heterocíclico; em que cada dentre a referida alquila, cicloalquila, heterocíclico, ou heteroarila pode ser não substituído ou substituído por halo, ciano, hidróxi, ou C1-C6 alquila; R3 é H ou C1-C6 alquila; R5 é H, amino, C1-C6 alquil-, ou hidróxi(C1-C6 al- quil)-; R6, R7 e R8 são cada qual independentemente H, C1-C6 alquil-, C1-C4 alcóxi(C1-C6 alquil)-, ou C3-C8 cicloalquila, a referida C1-C6 alquila é opcionalmente substituída por halo, CN ou hidróxi; ou, R7 e R8 juntamente com o átomo ligado a estes formam um anel de 5 ou 6 membros, o referido anel sendo opcionalmente substituído por halo, hidróxi, CN, ou C1-C6 alquila; e, n é 1, 2 ou 3. Em uma modalidade particular, a invenção fornece o referido composto em que R’’ é C1-C6 alquila e R5 é H.[0030] or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein: R'' is H, -COR6, -CONR7R8, C1-C6 alkyl, or hydroxy(C1 -C6 alkyl); R2 is selected from the group consisting of H, C1-C6 alkyl-, C1-C6 alkoxy-, hydroxy(C1-C6 alkyl)-, phenyl(C1-C6 alkyl)-, formyl, heteroaryl, heterocyclic, -COR6, -OCOR6, -COOR6, -NR7COR6, -CONR7R8, and -(CH2)n-W, where W is cyano, hydroxy, C3-C8 cycloalkyl, -SO2NR7R8, and -SO2-R9, where R9 is C1-C6 alkyl, C3C8 cycloalkyl , heteroaryl, or heterocyclic; wherein each of said alkyl, cycloalkyl, heterocyclic, or heteroaryl may be unsubstituted or substituted by halo, cyano, hydroxy, or C1-C6 alkyl; R3 is H or C1-C6 alkyl; R5 is H, amino, C1-C6 alkyl-, or hydroxy(C1-C6 alkyl)-; R6, R7 and R8 are each independently H, C1-C6 alkyl-, C1-C4 alkoxy(C1-C6 alkyl)-, or C3-C8 cycloalkyl, said C1-C6 alkyl is optionally substituted by halo, CN or hydroxy ; or, R7 and R8 together with the atom bonded thereto form a 5- or 6-membered ring, said ring being optionally substituted by halo, hydroxy, CN, or C1-C6 alkyl; and, n is 1, 2 or 3. In a particular embodiment, the invention provides said compound in which R'' is C1-C6 alkyl and R5 is H.
[0031] A invenção da mesma forma fornece um composto tendo a estrutura (Id): [0031] The invention likewise provides a compound having the structure (Id):
[0032] ou um sal farmaceuticamente aceitável do mesmo, ou um solvato farmaceuticamente aceitável do referido composto ou sal far- maceuticamente aceitável, em que: R’’ é H, -COR6, -CONR7R8, C1-C6 alquila, ou hidróxi(C1-C6 alquil); R2 é selecionado a partir do grupo consistindo em H, C1-C6 alquila, C1-C6 alcóxi, hidróxi(C1-C6 alquil), fe- nil(C1-C6 alquil), formila, heteroarila, heterocíclico, -COR6, -OCOR6, - COOR6, -NR7COR6, -CONR7R8, e -(CH2)n-W, onde W é ciano, hidróxi, C3-C8 cicloalquila, -SO2NR7R8, e -SO2-R9, onde R9 é C1-C6 alquila, C3C8 cicloalquila, heteroarila, ou heterocíclico; em que cada dentre a referida alquila, cicloalquila, heterocíclico, ou heteroarila pode ser não substituído ou substituído por halo, ciano, hidróxi, ou C1-C6 alquila; R5 é H, amino, C1-C6 alquil-, ou hidróxi(C1-C6 alquil)-; R6, R7 e R8 são cada qual independentemente H, C1-C6 alquila, C1-C4 alcóxi(C1-C6 alquil), ou C3-C8 cicloalquila, a referida C1-C6 alquila é opcionalmente substituída por halo, CN ou hidróxi; ou, R7 e R8 juntamente com o átomo ligado a estes formam um anel de 5 ou 6 membros, o referido anel sendo opcionalmente substituído por halo, hidróxi, CN, ou C1-C6 alquila; e, n é 1, 2 ou 3. Em uma modalidade particular, a invenção fornece o referido composto em que R’’ é C1-C6 alquila e R5 é H.[0032] or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein: R'' is H, -COR6, -CONR7R8, C1-C6 alkyl, or hydroxy(C1 -C6 alkyl); R2 is selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, hydroxy(C1-C6 alkyl), phenyl(C1-C6 alkyl), formyl, heteroaryl, heterocyclic, -COR6, -OCOR6 , -COOR6, -NR7COR6, -CONR7R8, and -(CH2)n-W, where W is cyano, hydroxy, C3-C8 cycloalkyl, -SO2NR7R8, and -SO2-R9, where R9 is C1-C6 alkyl, C3C8 cycloalkyl, heteroaryl , or heterocyclic; wherein each of said alkyl, cycloalkyl, heterocyclic, or heteroaryl may be unsubstituted or substituted by halo, cyano, hydroxy, or C1-C6 alkyl; R5 is H, amino, C1-C6 alkyl-, or hydroxy(C1-C6 alkyl)-; R6, R7 and R8 are each independently H, C1-C6 alkyl, C1-C4 alkoxy (C1-C6 alkyl), or C3-C8 cycloalkyl, said C1-C6 alkyl is optionally substituted by halo, CN or hydroxy; or, R7 and R8 together with the atom bonded thereto form a 5- or 6-membered ring, said ring being optionally substituted by halo, hydroxy, CN, or C1-C6 alkyl; and, n is 1, 2 or 3. In a particular embodiment, the invention provides said compound in which R'' is C1-C6 alkyl and R5 is H.
[0033] A invenção da mesma forma fornece um composto tendo a estrutura (Ie): [0033] The invention likewise provides a compound having the structure (Ie):
[0034] ou um sal farmaceuticamente aceitável do mesmo, ou um solvato farmaceuticamente aceitável do referido composto ou sal farma- ceuticamente aceitável, em que: R2 é selecionado a partir do grupo consistindo em H, C1-C6 alquil-, C1-C6 alcóxi-, hidróxi(C1-C6 alquil)-, fenil(C1- C6 alquil)-, formila, heteroarila, heterocíclico, -COR6, -OCOR6, -COOR6, -CONR7R8, e -(CH2)n-W, onde W é ciano, hidróxi, C3-C8 cicloalquila, - SO2NR7R8, e -SO2-R’, onde R’ é C1-C6 alquila, C3-C8 cicloalquila, hete- roarila, ou heterocíclico; em que cada dentre a referida alquila, cicloal- quila, heterocíclico, ou heteroarila pode ser não substituído ou substituído por halo, ciano, hidróxi, ou C1-C6 alquila; R6, R7 e R8 são cada qual independentemente H, C1-C6 alquil-, C1-C4 alcóxi(C1-C6 alquil)- ou C3-C8 cicloalquila, a referida C1-C6 alquila é opcionalmente substituída por halo, CN ou hidróxi; ou, R7 e R8 juntamente com o átomo ligado a estes formam um anel de 5 ou 6 membros, o referido anel sendo opcionalmente substituído por halo, hidróxi, CN, ou C1-C6 alquila; e, n é 1, 2 ou 3. Em uma modalidade particular, a invenção fornece o referido composto em que R2 é -(CH2)n-W, onde W é ciano e n é 1, 2 ou 3.[0034] or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein: R2 is selected from the group consisting of H, C1-C6 alkyl-, C1-C6 alkoxy -, hydroxy(C1-C6 alkyl)-, phenyl(C1- C6 alkyl)-, formyl, heteroaryl, heterocyclic, -COR6, -OCOR6, -COOR6, -CONR7R8, and -(CH2)n-W, where W is cyano, hydroxy, C3-C8 cycloalkyl, -SO2NR7R8, and -SO2-R', where R' is C1-C6 alkyl, C3-C8 cycloalkyl, heteroaryl, or heterocyclic; wherein each of said alkyl, cycloalkyl, heterocyclic, or heteroaryl may be unsubstituted or substituted by halo, cyano, hydroxy, or C1-C6 alkyl; R6, R7 and R8 are each independently H, C1-C6 alkyl-, C1-C4 alkoxy (C1-C6 alkyl)- or C3-C8 cycloalkyl, said C1-C6 alkyl is optionally substituted by halo, CN or hydroxy; or, R7 and R8 together with the atom bonded thereto form a 5- or 6-membered ring, said ring being optionally substituted by halo, hydroxy, CN, or C1-C6 alkyl; and, n is 1, 2 or 3. In a particular embodiment, the invention provides said compound wherein R2 is -(CH2)n-W, where W is cyano and n is 1, 2 or 3.
[0035] A invenção da mesma forma fornece um composto tendo a estrutura (If): [0035] The invention likewise provides a compound having the structure (If):
[0036] ou um sal farmaceuticamente aceitável do mesmo, ou um solvato farmaceuticamente aceitável do referido composto ou sal far- maceuticamente aceitável, em que: R’’ é H, -COR6, -CONR7R8, C1-C6 alquil-, ou hidróxi(C1-C6 alquil)-; R5 é H, amino, C1-C6 alquil-, ou hidró- xi(C1-C6 alquil)-; R6, R7 e R8 são cada qual independentemente H, C1C6 alquil-, C1-C4 alcóxi(C1-C6 alquil)-, ou C3-C8 cicloalquila, a referida C1-C6 alquila é opcionalmente substituída por halo, CN ou hidróxi; ou, R7 e R8 juntamente com o átomo ligado a estes formam um anel de 5 ou 6 membros, o referido anel sendo opcionalmente substituído por halo, hidróxi, CN, ou C1-C6 alquila; e, n é 0, 1, 2 ou 3. Em uma modalidade particular, a invenção fornece o referido composto em que R’’ é C1-C6 alquila. Em outra modalidade particular, a invenção fornece o referido composto em que R’’ é metila.[0036] or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein: R'' is H, -COR6, -CONR7R8, C1-C6 alkyl-, or hydroxy( C1-C6 alkyl)-; R5 is H, amino, C1-C6 alkyl-, or hydroxy(C1-C6 alkyl)-; R6, R7 and R8 are each independently H, C1-C6 alkyl-, C1-C4 alkoxy(C1-C6 alkyl)-, or C3-C8 cycloalkyl, said C1-C6 alkyl is optionally substituted by halo, CN or hydroxy; or, R7 and R8 together with the atom bonded thereto form a 5- or 6-membered ring, said ring being optionally substituted by halo, hydroxy, CN, or C1-C6 alkyl; and, n is 0, 1, 2 or 3. In a particular embodiment, the invention provides said compound wherein R'' is C1-C6 alkyl. In another particular embodiment, the invention provides said compound in which R'' is methyl.
[0037] Em certas modalidades preferidas, a invenção fornece um composto selecionado a partir do grupo consistindo em: (1r,3r)-3-(4-(6-(3-amino-1-metil-1H-pirazol-4-il)pirazolo[1,5- a]pirazin-4-il)-1H-pirazol-1-il)-3-(cianometil)ciclobutano-1-carbonitrila; 2,2'-(3-(4-(6-(1-metil-1H-pirazol-4-il)pirazolo[1,5-a]pirazin-4- il)-1H-pirazol-1-il)azetidina-1,3-diil)diacetonitrila; 2-((1s,3r)-1-(4-(6-(5-(hidroximetil)-1H-pirazol-3- il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)-3- metoxiciclobutil)acetonitrila; 5-(4-(1-((1s,3r)-1-(cianometil)-3-metoxiciclobutil)-1H-pirazol- 4-il)pirazolo[1,5-a]pirazin-6-il)-1H-pirazol-3-carboxamida; (1s,3s)-3-(cianometil)-3-(4-(6-(5-(hidroximetil)isoxazol-3- il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)ciclobutano-1-carbonitrila; (1r,3r)-3-(cianometil)-3-(4-(6-(1-metil-1H-pirazol-4- il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)ciclobutano-1-carbonitrila; (1s,3s)-3-(cianometil)-3-(4-(6-(1-metil-1H-pirazol-4- il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)ciclobutano-1-carbonitrila; (1r,3r)-3-(cianometil)-3-(4-(3-metil-6-(1-metil-1H-pirazol-4- il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)ciclobutano-1-carbonitrila; 2-((1r,3s)-1-(4-(6-(3-amino-1H-pirazol-5-il)pirazolo[1,5- a]pirazin-4-il)-1H-pirazol-1-il)-3-metoxiciclobutil)acetonitrila; (1r,3r)-3-(cianometil)-3-(4-(6-(1-(hidroximetil)-1H-pirazol-4- il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)ciclobutano-1-carbonitrila; e, 2-(1-etil-3-(4-(6-(5-(hidroximetil)-1H-pirazol-3-il)pirazolo[1,5- a]pirazin-4-il)-1H-pirazol-1-il)azetidin-3-il)acetonitrila, ou, um sal farma- ceuticamente aceitável do mesmo.[0037] In certain preferred embodiments, the invention provides a compound selected from the group consisting of: (1r,3r)-3-(4-(6-(3-amino-1-methyl-1H-pyrazol-4- il)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)cyclobutane-1-carbonitrile; 2,2'-(3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl) azetidine-1,3-diyl)diacetonitrile; 2-((1s,3r)-1-(4-(6-(5-(hydroxymethyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazole -1-yl)-3-methoxycyclobutyl)acetonitrile; 5-(4-(1-((1s,3r)-1-(cyanomethyl)-3-methoxycyclobutyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H -pyrazole-3-carboxamide; (1s,3s)-3-(cyanomethyl)-3-(4-(6-(5-(hydroxymethyl)isoxazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazole -1-yl)cyclobutane-1-carbonitrile; (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H- pyrazol-1-yl)cyclobutane-1-carbonitrile; (1s,3s)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H- pyrazol-1-yl)cyclobutane-1-carbonitrile; (1r,3r)-3-(cyanomethyl)-3-(4-(3-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl )-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile; 2-((1r,3s)-1-(4-(6-(3-amino-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1 -yl)-3-methoxycyclobutyl)acetonitrile; (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-(hydroxymethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)- 1H-pyrazol-1-yl)cyclobutane-1-carbonitrile; and, 2-(1-ethyl-3-(4-(6-(5-(hydroxymethyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazole -1-yl)azetidin-3-yl)acetonitrile, or, a pharmaceutically acceptable salt thereof.
[0038] Em uma certa modalidade, a invenção fornece um composto que é (1r,3r)-3-(4-(6-(3-amino-1-metil-1H-pirazol-4-il)pirazolo[1,5- a]pirazin-4-il)-1H-pirazol-1-il)-3-(cianometil)ciclo-butano-1-carbonitrila, ou um sal farmaceuticamente aceitável do mesmo.[0038] In a certain embodiment, the invention provides a compound that is (1r,3r)-3-(4-(6-(3-amino-1-methyl-1H-pyrazol-4-yl)pyrazolo[1, 5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof.
[0039] Em uma certa modalidade, a invenção fornece um compos to que é 2,2'-(3-(4-(6-(1-metil-1H-pirazol-4-il)pirazolo[1,5-a]pirazin-4-il)- 1H-pirazol-1-il)azetidina-1,3-diil)diacetonitrila, ou um sal farmaceutica- mente aceitável do mesmo.[0039] In a certain embodiment, the invention provides a compound that is 2,2'-(3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a ]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidine-1,3-diyl)diacetonitrile, or a pharmaceutically acceptable salt thereof.
[0040] Em uma certa modalidade, a invenção fornece um compos to que é 2-((1s,3r)-1-(4-(6-(5-(hidroximetil)-1H-pirazol-3-il)pirazolo[1,5- a]pirazin-4-il)-1H-pirazol-1-il)-3-metoxiciclo-butil)acetonitrila, ou um sal farmaceuticamente aceitável do mesmo.[0040] In a certain embodiment, the invention provides a compound that is 2-((1s,3r)-1-(4-(6-(5-(hydroxymethyl)-1H-pyrazol-3-yl)pyrazolo[ 1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclo-butyl)acetonitrile, or a pharmaceutically acceptable salt thereof.
[0041] Em uma certa modalidade, a invenção fornece um compos to que é 5-(4-(1-((1s,3r)-1-(cianometil)-3-metoxiciclobutil)-1H-pirazol-4- il)pirazolo[1,5-a]pirazin-6-il)-1H-pirazol-3-carboxamida, ou um sal far- maceuticamente aceitável do mesmo.[0041] In a certain embodiment, the invention provides a compound that is 5-(4-(1-((1s,3r)-1-(cyanomethyl)-3-methoxycyclobutyl)-1H-pyrazol-4-yl) pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-3-carboxamide, or a pharmaceutically acceptable salt thereof.
[0042] Em uma certa modalidade, a invenção fornece um composto que é (1s,3s)-3-(cianometil)-3-(4-(6-(5-(hidroximetil)isoxazol-3- il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)ciclobutano-1-carbonitrila, ou um sal farmaceuticamente aceitável do mesmo.[0042] In a certain embodiment, the invention provides a compound that is (1s,3s)-3-(cyanomethyl)-3-(4-(6-(5-(hydroxymethyl)isoxazol-3-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof.
[0043] Em uma certa modalidade, a invenção fornece um composto que é (1r,3r)-3-(cianometil)-3-(4-(6-(1-metil-1H-pirazol-4-il)pirazolo[1,5- a]pirazin-4-il)-1H-pirazol-1-il)ciclobutano-1-carbonitrila, ou um sal farma- ceuticamente aceitável do mesmo.[0043] In a certain embodiment, the invention provides a compound that is (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[ 1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof.
[0044] Em outra certa modalidade, a invenção fornece um composto que é (1s,3s)-3-(cianometil)-3-(4-(6-(1-metil-1H-pirazol-4-il)pirazolo[1,5- a]pirazin-4-il)-1H-pirazol-1-il)ciclobutano-1-carbonitrila, ou um sal farma- ceuticamente aceitável do mesmo.[0044] In another certain embodiment, the invention provides a compound that is (1s,3s)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[ 1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof.
[0045] Em ainda outra modalidade, a invenção fornece um com posto que é (1r,3r)-3-(cianometil)-3-(4-(3-metil-6-(1-metil-1H-pirazol-4- il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)ciclobutano-1-carbonitrila, ou um sal farmaceuticamente aceitável do mesmo.[0045] In yet another embodiment, the invention provides a compound that is (1r,3r)-3-(cyanomethyl)-3-(4-(3-methyl-6-(1-methyl-1H-pyrazol-4 - il)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof.
[0046] Em uma certa outra modalidade, a invenção fornece um composto que é 2-((1r,3s)-1-(4-(6-(3-amino-1H-pirazol-5-il)pirazolo[1,5- a]pirazin-4-il)-1H-pirazol-1-il)-3-metoxiciclobutil)acetonitrila, ou um sal farmaceuticamente aceitável do mesmo.[0046] In a certain other embodiment, the invention provides a compound that is 2-((1r,3s)-1-(4-(6-(3-amino-1H-pyrazol-5-yl)pyrazolo[1, 5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile, or a pharmaceutically acceptable salt thereof.
[0047] Em outra certa modalidade, a invenção fornece um composto que é 2-(1-etil-3-(4-(6-(5-(hidroximetil)-1H-pirazol-3- il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)azetidin-3-il)acetonitrila, ou, um sal farmaceuticamente aceitável do mesmo.[0047] In another certain embodiment, the invention provides a compound that is 2-(1-ethyl-3-(4-(6-(5-(hydroxymethyl)-1H-pyrazol-3-yl)pyrazolo[1.5 -a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile, or, a pharmaceutically acceptable salt thereof.
[0048] A invenção também fornece uma composição farmacêutica ou veterinária compreendendo um composto de fórmula I e Ia-f ou um sal farmaceuticamente aceitável do mesmo, e um veículo farmaceuti- camente aceitável.[0048] The invention also provides a pharmaceutical or veterinary composition comprising a compound of formula I and Ia-f or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
[0049] A invenção da mesma forma fornece um método de tratar uma doença ou condição para a qual um inibidor de Tyk2 é indicado, em um indivíduo em necessidade de tal tratamento, compreendendo administrar ao indivíduo uma quantidade terapeuticamente eficaz de um composto de fórmula I ou Ia-f, ou um sal farmaceuticamente aceitável do mesmo, ou um solvato farmaceuticamente aceitável do referido composto ou sal.[0049] The invention likewise provides a method of treating a disease or condition for which a Tyk2 inhibitor is indicated, in an individual in need of such treatment, comprising administering to the individual a therapeutically effective amount of a compound of formula I or Ia-f, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt.
[0050] A invenção da mesma forma fornece um método para tratar ou prevenir um distúrbio ou condição selecionado a partir de rinite alérgica, congestão nasal, rinorreia, rinite perene, inflamação nasal, asma de todos os tipos, doença pulmonar obstrutiva crônica, broncoconstrição crônica ou aguda, bronquite crônica, obstrução das vias aéreas pequenas, enfisema, pneumonia eosinofílica crônica, síndrome da angústia respiratória do adulto, exacerbação daa hiper- reatividade das vias aéreas consequente a outra terapia medicamentosa, doença vascular pulmonar, hipertensão arterial pulmonar, lesão pulmonar aguda, bronquiectasia, sinusite, conjuntivite alérgica, fibrose pulmonar idiopática ou dermatite atópica, compreendendo administrar ao indivíduo uma quantidade terapeuticamente eficaz de um composto de fórmula I e Ia-f, ou um sal farmaceuticamente aceitável do mesmo, ou um solvato farmaceuticamente aceitável do referido composto ou sal.[0050] The invention likewise provides a method for treating or preventing a disorder or condition selected from allergic rhinitis, nasal congestion, rhinorrhea, perennial rhinitis, nasal inflammation, asthma of all types, chronic obstructive pulmonary disease, chronic bronchoconstriction or acute, chronic bronchitis, small airway obstruction, emphysema, chronic eosinophilic pneumonia, adult respiratory distress syndrome, exacerbation of airway hyperreactivity resulting from other drug therapy, pulmonary vascular disease, pulmonary arterial hypertension, acute lung injury , bronchiectasis, sinusitis, allergic conjunctivitis, idiopathic pulmonary fibrosis or atopic dermatitis, comprising administering to the subject a therapeutically effective amount of a compound of formula I and Ia-f, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt.
[0051] A invenção da mesma forma fornece um método de tratar cirrose biliar primária compreendendo administrar ao indivíduo uma quantidade terapeuticamente eficaz de um composto de fórmula I ou Ia-f, ou um sal farmaceuticamente aceitável do mesmo, ou um solvato farmaceuticamente aceitável do referido composto ou sal.[0051] The invention likewise provides a method of treating primary biliary cirrhosis comprising administering to the individual a therapeutically effective amount of a compound of formula I or Ia-f, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt.
[0052] A invenção da mesma forma fornece um método de tratar uma doença ou condição selecionada a partir de inflamação, inflamação, doença autoimune, lúpus eritematoso sistêmico, nefrite por lúpus, lúpus discoide, lúpus cutâneo, lúpus do sistema nervoso central, artrite reumatoide, artrite psoriática, doença intestinal inflamatória, doença de Crohn, colite ulcerativa, asma, asma alérgica, diabetes Tipo I, polimio- site, dermatomoiosite, interferonopatias tipo I incluindo síndrome de Aicardi-Goutières e outras doenças mendelianas de superexpressão de interferon tipo I, esclerose múltipla, esclerose múltipla progressiva primária, esclerose múltipla remitente reincidente, cirrose biliar primária da mesma forma conhecida como colangite biliar primária, colangite esclerosante primária, hetatite autoimune, doença da esteatose hepática não alcoólica, esteatohepatite não alcoólica, psoríase, dermato- moiosite, escleroderma, dermatite atópica, vitiligo, alopecia em áreas, espondilopatia, espondilite ancilosante, doença de Alzheimer, neuroin- flamação compreendendo administrar ao indivíduo uma quantidade terapeuticamente eficaz de um composto de fórmula I ou Ia-f, ou um sal farmaceuticamente aceitável do mesmo, ou um solvato farmaceuti- camente aceitável do referido composto ou sal.[0052] The invention likewise provides a method of treating a disease or condition selected from inflammation, inflammation, autoimmune disease, systemic lupus erythematosus, lupus nephritis, discoid lupus, cutaneous lupus, central nervous system lupus, rheumatoid arthritis , psoriatic arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, asthma, allergic asthma, Type I diabetes, polymyositis, dermatomoiositis, type I interferonopathies including Aicardi-Goutières syndrome and other Mendelian diseases of type I interferon overexpression, MS , atopic dermatitis, vitiligo, patchy alopecia, spondylopathy, ankylosing spondylitis, Alzheimer's disease, neuroinflammation comprising administering to the subject a therapeutically effective amount of a compound of formula I or Ia-f, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt.
[0053] A invenção da mesma forma fornece um método de tratar os sintomas de doença inflamatória ou autoimune, incluindo prurido e fadiga.[0053] The invention also provides a method of treating symptoms of inflammatory or autoimmune disease, including itching and fatigue.
[0054] Em certas modalidades, a quantidade terapeuticamente efi caz usada de acordo com o método é a partir de 0,01 mg/kg de peso corporal/dia a 100 mg/kg de peso corporal/dia. Em certas outras modalidades, a quantidade terapeuticamente eficaz usada de acordo com o método é em que a quantidade terapeuticamente eficaz é a partir de 0,1 mg/kg de peso corporal/dia a 10 mg/kg de peso corporal/dia.[0054] In certain embodiments, the therapeutically effective amount used according to the method is from 0.01 mg/kg of body weight/day to 100 mg/kg of body weight/day. In certain other embodiments, the therapeutically effective amount used in accordance with the method is wherein the therapeutically effective amount is from 0.1 mg/kg of body weight/day to 10 mg/kg of body weight/day.
[0055] Compostos da invenção que têm a mesma fórmula molecu lar, porém, diferem-se na natureza ou sequência de ligação de seus átomos ou a disposição de seus átomos no espaço são chamados "isômeros". Isômeros que se diferem na disposição de seus átomos no espaço são chamados "estereoisômeros". Será apreciado por aqueles versados na técnica que o composto de fórmula I pode existir como diastereômeros aquirais cis- e trans-. Incluídos dentro do escopo dos compostos descritos são todos os isômeros (por exemplo, cis-, trans-, ou diastereômeros) dos compostos descritos aqui sozinhos bem como quaisquer misturas. Todas destas formas, incluindo enantiômeros, di- astereômeros, cis, trans, syn, anti, solvatos (incluindo hidratos), tautô- meros, e misturas dos mesmos, são incluídos nos compostos descritos. Misturas estereoisoméricas, por exemplo, misturas de diastereômeros, podem ser separadas nos seus isômeros correspondentes de uma maneira conhecida por meio de modos de separação adequados. As misturas diastereoméricas, por exemplo, podem ser separadas nos seus diastereômeros individuais por meio de cristalização fracionada, cromatografia, distribuição de solvente e procedimentos similares. Esta separação pode ocorrer quer ao nível de um dos compostos de partida quer em um composto de fórmula I em si. Os enantiômeros podem ser separados através da formação de sais diastereoméricos, por exemplo, por formação de sais com um ácido quiral enantiomericamente puro ou por meio de cromatografia, por exemplo por HPLC, usando substratos cromatográficos com ligantes quirais. A presente invenção inclui todos os compostos de marcados isotopicamente farmaceuticamente aceitáveis de fórmula I em que um ou mais átomos são substituídos por átomos tendo o mesmo número atômico, mas uma massa atômica ou número de massa diferente da massa atômica ou número de massa que predomina na natureza.[0055] Compounds of the invention that have the same molecular formula, however, differ in the nature or sequence of bonds of their atoms or the arrangement of their atoms in space are called "isomers". Isomers that differ in the arrangement of their atoms in space are called "stereoisomers". It will be appreciated by those skilled in the art that the compound of formula I can exist as achiral cis- and trans- diastereomers. Included within the scope of the compounds described are all isomers (e.g., cis-, trans-, or diastereomers) of the compounds described herein alone as well as any mixtures. All of these forms, including enantiomers, diastereomers, cis, trans, syn, anti, solvates (including hydrates), tautomers, and mixtures thereof, are included in the described compounds. Stereoisomeric mixtures, for example mixtures of diastereomers, can be separated into their corresponding isomers in a known manner by means of suitable separation modes. Diastereomeric mixtures, for example, can be separated into their individual diastereomers by fractional crystallization, chromatography, solvent distribution, and similar procedures. This separation can occur either at the level of one of the starting compounds or at a compound of formula I itself. Enantiomers can be separated through the formation of diastereomeric salts, for example by salt formation with an enantiomerically pure chiral acid or by means of chromatography, for example by HPLC, using chromatographic substrates with chiral ligands. The present invention includes all pharmaceutically acceptable isotopically labeled compounds of formula I in which one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number that predominates in the nature.
[0056] Exemplos de isótopos adequados para inclusão nos compostos da invenção incluem isótopos de hidrogênio, tais como 2H e 3H, carbono, tais como 11C, 13C e 14C, cloro, tal como 36Cl, flúor, tal como 18F, iodo, tal como 123I e 125I, nitrogênio, tais como 13N e 15N, oxigênio, tais como 15O, 17O e 18O, fósforo, tal como 32P, e enxofre, tal como 35S.[0056] Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36Cl, fluorine, such as 18F, iodine, such as 123I and 125I, nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 32P, and sulfur, such as 35S.
[0057] Certos compostos marcados isotopicamente de fórmula I, por exemplo, aqueles que incorporam um isótopo radioativo, são úteis em estudos de distribuição tecido de substrato e/ou fármaco. Os isótopos radioativos trício, isto é, 3H, e carbono-14, isto é, 14C, são particularmente úteis para este fim, tendo em vista a sua facilidade de incorporação e meios de detecção prontos.[0057] Certain isotopically labeled compounds of formula I, for example, those that incorporate a radioactive isotope, are useful in substrate and/or drug tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
[0058] A substituição com isótopos mais pesados, tal como deutério, isto é, 2H, pode proporcionar certas vantagens terapêuticas resultantes de maior estabilidade metabólica, por exemplo, meia-vida in vivo aumentada ou requisitos de dosagem reduzidos e, portanto, pode ser preferida em algumas circunstâncias. A substituição com isótopos emissores de pósitrons, tais como 11C, 18F, 15O e 13N, pode ser útil em estudos de Topografia por Emissão de Pósitrons (PET) para examinar a ocupação de receptores de substratos. Os compostos marcados isotopicamente de fórmula I podem geralmente ser preparados por técnicas convencionais conhecidas por aqueles versados na técnica ou por processos análogos aos descritos nos Exemplos e Preparações acompanhantes usando um reagente marcado isotopicamente apropriado em vez do reagente não marcado previamente empregado.[0058] Substitution with heavier isotopes, such as deuterium, i.e., 2H, may provide certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. Replacement with positron-emitting isotopes, such as 11C, 18F, 15O, and 13N, can be useful in Positron Emission Topography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of formula I can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically labeled reagent in place of the previously employed unlabeled reagent.
[0059] No uso terapêutico para tratar distúrbios em um mamífero, um composto da presente invenção ou as suas composições farmacêuticas podem ser administrados oralmente, parentericamente, topicamente, retalmente, transmucosalmente ou intestinalmente. As administrações parenterais incluem injeções indiretas para gerar um efeito sistêmico ou injeções diretas na área afetada. As administrações tópicas incluem o tratamento de pele ou órgãos facilmente acessíveis por aplicação local, por exemplo, olhos ou ouvidos. Também inclui liberação transdérmica para gerar um efeito sistêmico. A administração retal inclui a forma de supositórios. As rotinas preferidas de administração são orais e parenterais.[0059] In therapeutic use to treat disorders in a mammal, a compound of the present invention or its pharmaceutical compositions can be administered orally, parenterally, topically, rectally, transmucosally or intestinally. Parenteral administrations include indirect injections to generate a systemic effect or direct injections into the affected area. Topical administrations include treatment of skin or organs easily accessible by local application, for example, eyes or ears. It also includes transdermal release to generate a systemic effect. Rectal administration includes the form of suppositories. The preferred administration routines are oral and parenteral.
[0060] Os sais farmaceuticamente aceitáveis dos compostos de fórmula I e Ia-f incluem os seus sais de base e de adição de ácido. Os sais de adição de ácido adequados são formados a partir de ácidos que formam sais não tóxicos. Exemplos incluem os sais de acetato, adipato, aspartato, benzoato, besilato, bicarbonato/carbonato, bissulfato/sulfato, borato, cansilato, citrato, ciclamato, edisilato, esilato, formiato, fumarato, gluceptato, gliconato, glicuronato, hexafluorofosfato, hibenzato, cloridrato/cloreto, bromidrato/brometo, hidroiodeto/iodeto, isotionato, lactato, malato, maleato, malonato, mesilato, metilsulfato, naftilato, 2-napsilato, nicotinato, nitrato, orotato, oxalato, palmitato, pamoato, fosfato/hidrogenofosfato/di- hidrogenofosfato, piroglutamato, sacarato, estearato, succinato, tanato, tartarato, tosilato, trifluoroacetato e xinofoato.[0060] The pharmaceutically acceptable salts of the compounds of formula I and Ia-f include their base and acid addition salts. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include the salts of acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, cansylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride /chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsilate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogenphosphate/dihydrogenphosphate , pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate.
[0061] Os sais de base adequados são formados a partir de bases que formam sais não tóxicos. Exemplos incluem os sais de alumínio, arginina, benzatina, cálcio, colina, dietilamina, diolamina, glicina, lisina, magnésio, meglumina, olamina, potássio, sódio, trometamina e zinco.[0061] Suitable base salts are formed from bases that form non-toxic salts. Examples include the salts of aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc.
[0062] Hemissais de ácidos e bases podem também ser formados, por exemplo, sais de hemissulfato e hemicálico. Para uma revisão sobre sais adequados, consulte o Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).[0062] Hemissals of acids and bases can also be formed, for example, hemisulfate and hemicalic salts. For a review of suitable salts, see the Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).
[0063] Os sais farmaceuticamente aceitáveis dos compostos de fórmula I e Ia-f podem ser preparados, respectivamente, por um ou mais de três métodos: (i) fazendo reagir o composto de fórmula I e Ia-f com o ácido ou base desejado; (ii) removendo um grupo protetor lábil ao ácido ou base de um precursor adequado do composto de fórmula I e Ia-f ou por abertura de anel de um precursor cíclico adequado, por exemplo, uma lactona ou lactam, usando o ácido ou base desejado; ou (iii) convertendo um sal do composto de fórmula I ou Ia-f em outro por reação com um ácido ou base apropriado ou por meio de uma coluna de troca de íon adequada. Todas as três reações são tipicamente realizadas em solução. O sal resultante pode precipitar e ser coletado por filtração ou pode ser recuperado por evaporação do solvente. O grau de ionização no sal resultante pode variar de completamente ionizado a quase não ionizado.[0063] The pharmaceutically acceptable salts of the compounds of formula I and Ia-f can be prepared, respectively, by one or more of three methods: (i) by reacting the compound of formula I and Ia-f with the desired acid or base ; (ii) removing an acid- or base-labile protecting group from a suitable precursor of the compound of formula I and Ia-f or by ring opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base ; or (iii) converting one salt of the compound of formula I or Ia-f into another by reaction with an appropriate acid or base or by means of a suitable ion exchange column. All three reactions are typically carried out in solution. The resulting salt may precipitate and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the resulting salt can vary from completely ionized to almost non-ionized.
[0064] As composições farmacêuticas da presente invenção po dem ser fabricadas por métodos bem conhecidos na técnica, por exemplo, por meio de processos convencionais de mistura, dissolução, granulação, produção de drágeas, levigação, emulsificação, encapsu- lação, captura, liofilização ou secagem por pulverização.[0064] The pharmaceutical compositions of the present invention can be manufactured by methods well known in the art, for example, by means of conventional processes of mixing, dissolving, granulating, producing tablets, levigation, emulsification, encapsulation, capture, lyophilization or spray drying.
[0065] Composições farmacêuticas para uso de acordo com a pre sente invenção podem ser formuladas de modo convencional usando um ou mais veículos farmaceuticamente aceitáveis compreendendo excipientes e auxiliares, que facilitam o processamento do composto ativo em preparações, que podem ser usados farmaceuticamente. A formulação adequada é dependente da rotina de administração escolhida. Os excipientes e veículos farmaceuticamente aceitáveis são geralmente conhecidos por aqueles versados na técnica e estão assim incluídos na presente invenção. Tais excipientes e veículos são descritos, por exemplo, em Remington’s Pharmaceutical Sciences, Mack Pub. Co., New Jersey (1991). As formulações da invenção podem ser designadas para serem de ação curta, de liberação rápida, de ação prolongada e de liberação sustentada. Assim, as formulações farmacêuticas podem também ser formuladas para liberação controlada ou para liberação lenta.[0065] Pharmaceutical compositions for use in accordance with the present invention can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate the processing of the active compound into preparations, which can be used pharmaceutically. The appropriate formulation is dependent on the chosen administration routine. Pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus included in the present invention. Such excipients and vehicles are described, for example, in Remington's Pharmaceutical Sciences, Mack Pub. Co., New Jersey (1991). The formulations of the invention can be designed to be short-acting, rapid-release, long-acting and sustained-release. Thus, pharmaceutical formulations can also be formulated for controlled release or slow release.
[0066] Composições farmacêuticas adequadas para uso na pre sente invenção incluem composições em que os ingredientes activos estão contidos em uma quantidade suficiente para atingir o objetivo pretendido, isto é, controle ou tratamento de distúrbios ou doenças. Mais especificamente, uma quantidade terapeuticamente eficaz significa uma quantidade de composto eficaz para prevenir, aliviar ou melhorar sintomas/sinais de doença ou prolongar a sobrevivência do indivíduo a ser tratado.[0066] Pharmaceutical compositions suitable for use in the present invention include compositions in which the active ingredients are contained in an amount sufficient to achieve the intended objective, that is, control or treatment of disorders or diseases. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms/signs of disease or prolong the survival of the individual being treated.
[0067] A quantidade de componente ativo, que é o composto desta invenção, na composição farmacêutica e sua forma de dosagem unitária, pode ser variada ou ajustada amplamente dependendo do modo de administração, da potência do composto particular e da concentração desejada. A determinação de uma quantidade terapeuticamente eficaz está bem dentro da capacidade daqueles versados na técnica. Geralmente, a quantidade de componente ativo variará entre 0,01% a 99% em peso da composição.[0067] The amount of active component, which is the compound of this invention, in the pharmaceutical composition and its unit dosage form, can be varied or adjusted widely depending on the mode of administration, the potency of the particular compound and the desired concentration. Determination of a therapeutically effective amount is well within the ability of those skilled in the art. Generally, the amount of active component will vary between 0.01% to 99% by weight of the composition.
[0068] Geralmente, uma quantidade terapeuticamente eficaz de dosagem de componente ativo estará na faixa de cerca de 0,01 a cerca de 100 mg/kg de peso corporal/dia, preferivelmente cerca de 0,1 a cerca de 10 mg/kg de peso corporal/dia, mais preferivelmente cerca de 0,3 a 3 mg/kg de peso corporal/dia, ainda mais preferivelmente cerca de 0,3 a 1,5 mg/kg de peso corporal/dia. Deve ser entendido que as dosagens podem variar dependendo das necessidades de cada indivíduo e da gravidade dos distúrbios ou doenças a serem tratados.[0068] Generally, a therapeutically effective dosage amount of active component will be in the range of about 0.01 to about 100 mg/kg of body weight/day, preferably about 0.1 to about 10 mg/kg of body weight/day, more preferably about 0.3 to 3 mg/kg body weight/day, even more preferably about 0.3 to 1.5 mg/kg body weight/day. It should be understood that dosages may vary depending on the needs of each individual and the severity of the disorders or diseases being treated.
[0069] A dose desejada pode ser convenientemente apresentada em uma dose única ou como doses divididas administradas em intervalos apropriados, por exemplo, como duas, três, quatro ou mais subdoses por dia. A subdose propriamente dita pode ser também dividida, por exemplo, em um certo número de administrações ligeiramente espaçadas discretas; tais como múltiplas inalações de um insuflador ou pela aplicação de uma pluralidade de gotas no olho.[0069] The desired dose may be conveniently presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more subdoses per day. The subdose itself may also be divided, for example, into a number of discrete, slightly spaced administrations; such as multiple inhalations from an insufflator or by applying a plurality of drops to the eye.
[0070] Também, deve ser entendido que a dosagem inicial admi nistrada pode ser aumentada para além do nível superior acima, a fim de atingir rapidamente a concentração de plasma desejada. Por outro lado, a dosagem inicial pode ser menor do que a ideal e a dosagem diária pode ser progressivamente aumentada durante o curso do tratamento, dependendo da situação particular. Se desejado, a dose diária também pode ser dividida em múltiplas doses para administração, por exemplo, duas a quatro vezes por dia.[0070] Also, it should be understood that the initial dosage administered can be increased beyond the upper level above in order to quickly achieve the desired plasma concentration. On the other hand, the initial dosage may be lower than ideal and the daily dosage may be progressively increased during the course of treatment, depending on the particular situation. If desired, the daily dose can also be divided into multiple doses for administration, for example, two to four times per day.
[0071] A presente invenção também fornece quaisquer dos usos, métodos ou composições como definido acima em que o composto de fórmula I ou Ia-f, ou um sal farmaceuticamente aceitável do mesmo, ou solvato farmaceuticamente aceitável do referido composto ou sal, é usado em combinação com outro composto farmacologicamente ativo, particularmente uma das classes funcionalmente definidas ou compostos específicos listados abaixo. Estes agentes podem ser administra- dos como parte da mesma ou de formas de dosagem separadas, através das mesmas ou diferentes rotinas de administração, e dos mesmos ou diferentes programas de administração de acordo com a prática farmacêutica padrão conhecida por alguém versado na técnica.[0071] The present invention also provides any of the uses, methods or compositions as defined above in which the compound of formula I or Ia-f, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate of said compound or salt, is used in combination with another pharmacologically active compound, particularly one of the functionally defined classes or specific compounds listed below. These agents can be administered as part of the same or separate dosage forms, through the same or different administration routines, and the same or different administration schedules in accordance with standard pharmaceutical practice known to one skilled in the art.
[0072] Os agentes adequados para uso em terapia de combinação com um composto de fórmula I ou Ia-f, ou um sal farmaceuticamente aceitável do mesmo, ou solvato farmaceuticamente aceitável do referido composto ou sal, sulfassalazina, messalazina, prednisona, azatio- prina, infliximabe, adalimumabe, belimumabe, becertolizumabe, nata- lizumabe, vedolizumabe, hidrocortisona, budesonida, ciclosporina, tacrolimus, fexofenadina, 6-mercaptopurina, metotrexato, ácido ursode- soxicólico, ácido obeticólico, anti-histamínicos, rifampicina, prednisona, metotrexato, azatioprina, ciclofosfamida, hidroxicloroquina, mofetil, mi- cofenolato de sódio, tacrolimus, leflunomida, cloroquina e quinacrina, talidomida, rituxam, NSAIDs, solumedrol, depomedrol e dexametaso- na.[0072] Agents suitable for use in combination therapy with a compound of formula I or Ia-f, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate of said compound or salt, sulfasalazine, mesalazine, prednisone, azathioprine , infliximab, adalimumab, belimumab, becertolizumab, natalizumab, vedolizumab, hydrocortisone, budesonide, cyclosporine, tacrolimus, fexofenadine, 6-mercaptopurine, methotrexate, ursodeoxycholic acid, obeticholic acid, antihistamines, rifampicin, prednisone, methotrexate, oprina , cyclophosphamide, hydroxychloroquine, mofetil, mycophenolate sodium, tacrolimus, leflunomide, chloroquine and quinacrine, thalidomide, rituxam, NSAIDs, solumedrol, depomedrol and dexamethasone.
[0073] Outros agentes adequados para uso na terapia de combi nação com um composto de fórmula I ou Ia-f, ou um sal farmaceutica- mente aceitável do mesmo, ou solvato farmaceuticamente aceitável do referido composto ou sal, incluem: um antagonista de proteína ativado- ra da 5-lipoxigenase (FLAP); um antagonista de leucotrieno (LTRA) tal como um antagonista de LTB4, LTC4, LTD4, LTE4, CysLT1 ou CysLT2, por exemplo, montelucaste ou zafirlucaste; um antagonista do receptor de histamina, tal como um antagonista do receptor tipo 1 de histamina ou um antagonista do receptor tipo 2 de histamina, por exemplo, lorati- dina, fexofenadina, desloratidina, levocetirizina, metapirileno ou cetiri- zina; um agonista do α1-adrenoceptor ou um agonista α2- adrenoceptor, por exemplo, fenilefrina, metoxamina, oximetazolina ou metilnorefrina; um antagonista do receptor muscarínico M3, por exemplo, tiotrópio ou ipratrópio; um antagonista do receptor muscarínico M3 dual/β2 agonista; um inibidor de PDE, tal como um inibidor de PDE3, um inibidor de PDE4 ou um inibidor de PDE5, por exemplo, teofilina, sildenafila, vardenafila, tadalafila, ibudilaste, cilomilaste ou roflumilaste; cromoglicato de sódio ou nedocromil sódico; um inibidor da ciclo- oxigenase (COX), tal como um inibidor não seletivo (por exemplo, aspirina ou ibuprofeno) ou um inibidor seletivo (por exemplo, celecoxibe ou valdecoxibe); um glicocorticosteroide, por exemplo, fluticasona, mometasona, dexametasona, prednisolona, budesonida, ciclesonida ou beclametasona; um anticorpo monoclonal anti-inflamatório, por exemplo, infliximabe, adalimumabe, tanezumabe, ranibizumabe, be- vacizumabe ou mepolizumabe; um agonista β2, por exemplo, salmete- rol, albuterol, salbutamol, fenoterol ou formoterol, particularmente um agonista β2 de longa duração; um antagonista de intigrina, por exemplo, natalizumabe; um inibidor de molécula de adesão, tal como um antagonista de VLA-4; um antagonista do receptor de cinina B1 ou B2; um agente imunossupressor, tal como um inibidor da trilha de IgE (por exemplo, omalizumabe) ou ciclosporina; um inibidor de metaloprotease matriz (MMP), tal como um inibidor de MMP-9 ou MMP-12; um antagonista do receptor de taquicinina NK1, NK2 ou NK3; um inibidor de protease, tal como um inibidor de elastase, quimase ou cateopsina G; um agonista do receptor de adenosina A2a; um antagonista do receptor de adenosina A2b; um inibidor de urocinase; um agonista do receptor de dopamina (por exemplo, ropinirol), particularmente um agonista do receptor de dopamina D2 (por exemplo, bromocriptina); um modulador da trilha de NFkB, tal como um inibidor de IKK; um modulador adicional de uma trilha de sinalização de citoquina, tal como um inibidor de JAK cinase, syk cinase, p38 cinase, SPHK-1 cinase, Rho cinase, EGF- R ou MK-2; um agente mucolítico, mucocinético ou antitussígeno; um antibiótico; um agente antiviral; uma vacina; uma quimiocina; um blo- queador do canal de sódio epitelial (ENaC) ou inibidor do canal de só- dio Epitelial (ENaC); um agonista do receptor de nucleotídeo, tal como um agonista de P2Y2; um inibidor de tromboxano; niacina; um inibidor de 5-lipoxigenase (5-LO), por exemplo, Zileuton; um fator de adesão, tal como VLAM, ICAM ou ELAM; um antagonista do receptor de CRTH2 (DP2); um antagonista do receptor da prostaglandina D2 (DP1); um inibidor da prostaglandina D2 sintase hematopoética (HPGDS); interferon-β; um receptor de TNF humano solúvel, por exemplo, Etane- rcepte; um inibidor de HDAC; um inibidor de fosfoinositídeo 3-cinase gama (PI3Ky); um inibidor de fosfoinositídeo 3-cinase delta (PI3KG); um antagonista do receptor de CXCR-1 ou CXCR-2; um inibidor de IRAK-4; e, um inibidor de TLR-4 ou TLR-9, incluindo os sais farmaceu- ticamente aceitáveis dos compostos especificamente designados e os solvatos farmaceuticamente aceitáveis dos referidos compostos e sais especificamente designados.[0073] Other agents suitable for use in combination therapy with a compound of formula I or Ia-f, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate of said compound or salt, include: a protein antagonist 5-lipoxygenase activator (FLAP); a leukotriene antagonist (LTRA) such as an LTB4, LTC4, LTD4, LTE4, CysLT1 or CysLT2 antagonist, for example, montelukast or zafirlukast; a histamine receptor antagonist, such as a histamine type 1 receptor antagonist or a histamine type 2 receptor antagonist, for example, loratidine, fexofenadine, desloratidine, levocetirizine, methapyrilene or cetirizine; an α1-adrenoceptor agonist or an α2-adrenoceptor agonist, for example, phenylephrine, methoxamine, oxymetazoline or methylnorephrine; an M3 muscarinic receptor antagonist, for example, tiotropium or ipratropium; a dual M3 muscarinic receptor antagonist/β2 agonist; a PDE inhibitor, such as a PDE3 inhibitor, a PDE4 inhibitor or a PDE5 inhibitor, for example, theophylline, sildenafil, vardenafil, tadalafil, ibudilast, cilomilast or roflumilast; sodium cromoglycate or nedocromil sodium; a cyclooxygenase (COX) inhibitor, such as a non-selective inhibitor (e.g., aspirin or ibuprofen) or a selective inhibitor (e.g., celecoxib or valdecoxib); a glucocorticosteroid, for example fluticasone, mometasone, dexamethasone, prednisolone, budesonide, ciclesonide or beclamethasone; an anti-inflammatory monoclonal antibody, for example, infliximab, adalimumab, tanezumab, ranibizumab, bevacizumab or mepolizumab; a β2 agonist, for example salmeterol, albuterol, salbutamol, fenoterol or formoterol, particularly a long-acting β2 agonist; an intigrin antagonist, e.g., natalizumab; an adhesion molecule inhibitor, such as a VLA-4 antagonist; a kinin B1 or B2 receptor antagonist; an immunosuppressive agent, such as an IgE trail inhibitor (e.g., omalizumab) or cyclosporine; a matrix metalloprotease (MMP) inhibitor, such as an MMP-9 or MMP-12 inhibitor; an NK1, NK2 or NK3 tachykinin receptor antagonist; a protease inhibitor, such as an elastase, chymase or catheopsin G inhibitor; an adenosine A2a receptor agonist; an adenosine A2b receptor antagonist; a urokinase inhibitor; a dopamine receptor agonist (e.g. ropinirole), particularly a dopamine D2 receptor agonist (e.g. bromocriptine); a modulator of the NFkB pathway, such as an IKK inhibitor; an additional modulator of a cytokine signaling pathway, such as an inhibitor of JAK kinase, syk kinase, p38 kinase, SPHK-1 kinase, Rho kinase, EGF-R or MK-2; a mucolytic, mucokinetic or antitussive agent; an antibiotic; an antiviral agent; a vaccine; a chemokine; an epithelial sodium channel blocker (ENaC) or epithelial sodium channel inhibitor (ENaC); a nucleotide receptor agonist, such as a P2Y2 agonist; a thromboxane inhibitor; niacin; a 5-lipoxygenase (5-LO) inhibitor, for example, Zileuton; an adhesion factor, such as VLAM, ICAM or ELAM; a CRTH2 (DP2) receptor antagonist; a prostaglandin D2 (DP1) receptor antagonist; an inhibitor of hematopoietic prostaglandin D2 synthase (HPGDS); interferon-β; a soluble human TNF receptor, for example, Etanercept; an HDAC inhibitor; a phosphoinositide 3-kinase gamma (PI3Ky) inhibitor; a phosphoinositide 3-kinase delta (PI3KG) inhibitor; a CXCR-1 or CXCR-2 receptor antagonist; an IRAK-4 inhibitor; and, a TLR-4 or TLR-9 inhibitor, including pharmaceutically acceptable salts of specifically designated compounds and pharmaceutically acceptable solvates of said compounds and specifically designated salts.
[0074] Consequentemente, a invenção fornece métodos de trata mento ou prevenção de uma doença, condição ou distúrbio associado à JAK em um indivíduo, tal como um mamífero humano ou não humano, compreendendo administrar uma quantidade eficaz de um ou mais compostos aqui descritos ao indivíduo. Os indivíduos adequados que podem ser tratados incluem animais domésticos ou selvagens, animais de companhia, tais como cães, gatos, cavalos e similares; de criação incluindo, vacas e outros ruminantes, porcos, aves, coelhos e similares; primatas, por exemplo macacos, tais como macacos rhesus e macacos cinomolgos (também conhecidos como comedores de caranguejo ou de cauda longa), saguis, micos, chimpanzés, macacos e similares; e roedores, tais como ratos, camundongos, gerbos, porquinhos- da-índia e similares. Em uma modalidade, o composto é administrado em uma forma farmaceuticamente aceitável, opcionalmente em um veículo farmaceuticamente aceitável.[0074] Accordingly, the invention provides methods of treating or preventing a disease, condition or disorder associated with JAK in an individual, such as a human or non-human mammal, comprising administering an effective amount of one or more compounds described herein to the individual. Suitable individuals that can be treated include domestic or wild animals, companion animals such as dogs, cats, horses and the like; livestock including cows and other ruminants, pigs, poultry, rabbits and the like; primates, for example monkeys, such as rhesus monkeys and cynomolgus monkeys (also known as crab-eating or long-tailed monkeys), marmosets, tamarins, chimpanzees, monkeys and the like; and rodents, such as rats, mice, gerbils, guinea pigs and the like. In one embodiment, the compound is administered in a pharmaceutically acceptable form, optionally in a pharmaceutically acceptable carrier.
[0075] As condições em que o direcionamento selectivo da trilha de JAK ou modulação das JAK cinases, particularmenteTYK2, são contempladas como sendo terapeuticamente úteis incluem, inter alia, artrite, asma, doenças autoimunes, cânceres ou tumores, diabetes, certas doenças, distúrbios ou condições oculares, inflamação, inflamações intestinais, alergias ou condições, doenças neurodegenerativas, psoríase e rejeição de transplantes. As condições que podem beneficiar da inibição seletiva de TYK2 são discutidas em maiores detalhes abaixo.[0075] Conditions in which selective targeting of the JAK pathway or modulation of JAK kinases, particularly TYK2, are contemplated to be therapeutically useful include, inter alia, arthritis, asthma, autoimmune diseases, cancers or tumors, diabetes, certain diseases, disorders or eye conditions, inflammation, intestinal inflammations, allergies or conditions, neurodegenerative diseases, psoriasis and transplant rejection. Conditions that may benefit from selective TYK2 inhibition are discussed in greater detail below.
[0076] Consequentemente, o composto de fórmula I ou Ia-f ou os seus sais e solvatos farmaceuticamente aceitáveis, e suas composições farmacêuticas, podem ser usados para tratar uma variedade de condições ou doenças tais como as seguintes:[0076] Consequently, the compound of formula I or Ia-f or its pharmaceutically acceptable salts and solvates, and its pharmaceutical compositions, can be used to treat a variety of conditions or diseases such as the following:
[0077] Artrite, incluindo artrite reumatoide, artrite juvenil e artrite psoriática;[0077] Arthritis, including rheumatoid arthritis, juvenile arthritis and psoriatic arthritis;
[0078] Doenças ou distúrbios autoimunes ou inflamatórioas, por exemplo, tireoidite de Hashimoto, anemia hemolítica autoimune, gastrite atrófica autoimune de anemia perniciosa, encefalomielite autoimune, orquite autoimune, doença de Goodpasture, trombocitopenia autoimu- ne, oftalmia simpática, miastenia grave, doença de Grave, cirrose biliar primária, hepatite autoimune, colangite esclerosante primária, hepatite agressiva crônica, doença da esteatose hepática não alcoólica, este- atohepatite não alcoólica, colite ulcerativa e glomerulopatia membra- nosa, lúpus eritematoso sistêmico, artrite reumatoide, artrite psoriática, síndrome de Sjogren, síndrome de Reiter, polimiosite, dermatomiosite, interferonopatias tipo I incluindo síndrome de Aicardi-Goutières e outras doenças mendelianas de superexpressão de esclerose sistêmica de interferon tipo I, poliarterite nodosa, esclerose múltipla, esclerose múltipla remitente reincidente, esclerose múltipla progressiva primária, esclerose múltipla progressiva secundária e penfigoide bolhoso, e doenças autoimunes adicionais, que podem ser baseadas em células O (humorais) ou em células T, incluindo a síndrome de Cogan, espondili- te ancilosante, granulomatose de Wegener, alopecia autoimune, diabetes Tipo I ou juvenil ou tireoidite;[0078] Autoimmune or inflammatory diseases or disorders, for example, Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, disease Grave's disease, primary biliary cirrhosis, autoimmune hepatitis, primary sclerosing cholangitis, chronic aggressive hepatitis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, ulcerative colitis and membranous glomerulopathy, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, syndrome Sjogren's syndrome, Reiter's syndrome, polymyositis, dermatomyositis, type I interferonopathies including Aicardi-Goutières syndrome and other Mendelian diseases of type I interferon systemic sclerosis overexpression, polyarteritis nodosa, multiple sclerosis, relapsing-remitting multiple sclerosis, primary progressive multiple sclerosis, secondary progressive multiple sclerosis and bullous pemphigoid, and additional autoimmune diseases, which may be O-cell (humoral) or T-cell based, including Cogan syndrome, ankylosing spondylitis, Wegener's granulomatosis, autoimmune alopecia, Type I diabetes, or juvenile or thyroiditis;
[0079] Cânceres ou tumores, incluindo câncer do trato alimen- tar/gastrointestinal, câncer de cólon, câncer de fígado, câncer de pele, incluindo mastocitomas e carcinoma de células escamosas, câncer de mama e mamários, câncer de ovário, câncer de próstata, linfoma, leucemia, incluindo leucemia mielogenosa aguda e leucemia mielogenosa crônica, câncer de rim, câncer de pulmão, câncer muscular, câncer ósseo, câncer de bexiga, câncer cerebral, melanoma incluindo melanoma oral e metastático, sarcoma de Kaposi, mielomas incluindo mi- eloma múltiplo, distúrbios mieloproliferativos, retinopatia diabética pro- liferativa ou distúrbios associados angiogênicos incluindo tumores sólidos;[0079] Cancers or tumors, including cancer of the alimentary/gastrointestinal tract, colon cancer, liver cancer, skin cancer, including mast cell tumors and squamous cell carcinoma, breast and breast cancer, ovarian cancer, prostate cancer , lymphoma, leukemia, including acute myelogenous leukemia and chronic myelogenous leukemia, kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer, brain cancer, melanoma including oral and metastatic melanoma, Kaposi's sarcoma, myelomas including mi- multiple eloma, myeloproliferative disorders, proliferative diabetic retinopathy or associated angiogenic disorders including solid tumors;
[0080] Diabetes, incluindo diabetes Tipo I ou complicações do dia betes;[0080] Diabetes, including Type I diabetes or complications of diabetes;
[0081] Doenças, distúrbios ou condições oculares incluindo doen ças autoimunes do olho, ceratoconjuntivite, conjuntivite vernal, uveíte incluindo uveíte associada à doença de Behçet e uveíte induzida por lente, ceratite, ceratite herpética, ceratite cônica, distrofia epitelial da córnea, ceratoleucoma, pênfigo ocular, úlcera de Mooren, esclerite, oftalmopatia de Grave, síndrome de Koyanagi-Harada, ceratoconjunti- vite seca (olho seco), flictênulas, iridociclite, sarcoidose, oftalmopatia endócrina, oftalmite simpática, conjuntivite alérgica ou neovasculariza- ção ocular;[0081] Eye diseases, disorders or conditions including autoimmune diseases of the eye, keratoconjunctivitis, vernal conjunctivitis, uveitis including uveitis associated with Behçet's disease and lens-induced uveitis, keratitis, herpetic keratitis, conical keratitis, corneal epithelial dystrophy, keratoleucoma, ocular pemphigus, Mooren's ulcer, scleritis, Grave's ophthalmopathy, Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dry eye), phlyctenulae, iridocyclitis, sarcoidosis, endocrine ophthalmopathy, sympathetic ophthalmitis, allergic conjunctivitis or ocular neovascularization;
[0082] Inflamações intestinais, incluindo doença de Crohn, colite ulcerativa, doença intestinal inflamatória, doenças celíacas, proctite, gastroenterite eosinofílica ou mastocitose;[0082] Intestinal inflammations, including Crohn's disease, ulcerative colitis, inflammatory bowel disease, celiac disease, proctitis, eosinophilic gastroenteritis or mastocytosis;
[0083] Doenças neurodegenerativas incluindo doença do neurônio motor, doença de Alzheimer, doença de Parkinson, esclerose lateral amiotrófica, doença de Huntington, isquemia cerebral ou doença neu- rodegenerativa causada por lesão traumática, greve, neurotoxicidade do glutamato ou hipoxia; lesão isquêmica/reperfusão em acidente vascular cerebral, isquemia miocárdica, isquemia renal, ataques cardíacos, hipertrofia cardíaca, aterosclerose e arteriosclerose, hipóxia de órgão ou agregação plaquetária;[0083] Neurodegenerative diseases including motor neuron disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia or neurodegenerative disease caused by traumatic injury, strike, glutamate neurotoxicity or hypoxia; ischemic/reperfusion injury in stroke, myocardial ischemia, renal ischemia, heart attacks, cardiac hypertrophy, atherosclerosis and arteriosclerosis, organ hypoxia or platelet aggregation;
[0084] Doenças, condições ou distúrbios da pele, incluindo derma tite atópica, eczema, psoríase, esclerodermia, prurido ou outras condições pruriginosas, vitiligo, alopecia;[0084] Skin diseases, conditions or disorders, including atopic dermitis, eczema, psoriasis, scleroderma, pruritus or other pruritic conditions, vitiligo, alopecia;
[0085] Reações alérgicas incluindo dermatite alérgica em mamífe ros (incluindo doenças alérgicas do cavalo tal como ncluindo hipersen- sibilidade à mordida), eczema de verão, coceira doce em cavalos, vômitos, doença das vias aéreas inflamatórias, obstrução das vias aéreas recorrentes, hipersensibilidade das vias áereas, e doença pulmonar obstrutiva crônica;[0085] Allergic reactions including allergic dermatitis in mammals (including allergic diseases of the horse such as including bite hypersensitivity), summer eczema, sweet itch in horses, vomiting, inflammatory airway disease, recurrent airway obstruction, airway hypersensitivity, and chronic obstructive pulmonary disease;
[0086] Asma e outras doenças das vias aéreas obstrutivas, inclu indo asma crônica ou inveterada, asma tardia, bronquite, asma brôn- quica, asma alérgica, asma intrínseca, asma extrínseca ou asma por poeira;[0086] Asthma and other obstructive airway diseases, including chronic or inveterate asthma, late-onset asthma, bronchitis, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma or dust asthma;
[0087] Rejeição ao transplante, incluindo rejeição ao transplante de ilhotas pancreáticas, rejeição ao transplante de medula óssea, doença do enxerto-versus-hospedeiro, rejeição ao transplante de órgão e célula tal como medula óssea, cartilagem, córnea, coração, disco intervertebral, ilhota, rim, membro, fígado, pulmão, músculo, mioblastos, nervos, pâncreas, pele, intestino delgado ou traqueia, ou xeno transplante.[0087] Transplant rejection, including pancreatic islet transplant rejection, bone marrow transplant rejection, graft-versus-host disease, organ and cell transplant rejection such as bone marrow, cartilage, cornea, heart, intervertebral disc , islet, kidney, limb, liver, lung, muscle, myoblasts, nerves, pancreas, skin, small intestine or trachea, or xeno transplantation.
[0088] A pessoa versada apreciará que as condições experimen tais mencionadas nos esquemas que se seguem são ilustrativas das condições adequadas para realizar as transformações mostradas, e que pode ser necessário ou desejável variar as condições exatas empregadas para a preparação dos compostos de fórmula (I). Será também apreciado que pode ser necessário ou desejável realizar as transformações em uma ordem diferente da descrita nos esquemas, ou modificar uma ou mais das transformações, para fornecer o composto desejado da invenção.[0088] The skilled person will appreciate that the experimental conditions mentioned in the following schemes are illustrative of the conditions suitable for carrying out the transformations shown, and that it may be necessary or desirable to vary the exact conditions employed for the preparation of the compounds of formula (I ). It will also be appreciated that it may be necessary or desirable to carry out the transformations in an order different from that described in the schemes, or to modify one or more of the transformations, to provide the desired compound of the invention.
[0089] Todos os derivados de fórmula (I) podem ser preparados pelos procedimentos descritos nos métodos gerais apresentados abaixo ou por modificações de rotina dos mesmos. A presente invenção também abrange qualquer um ou mais destes processos para preparar os derivados de fórmula (I), além de quaisquer novos intermediários aqui usados. A pessoa versada na técnica apreciará que as seguintes reações podem ser aquecidas termicamente ou sob irradiação de micro-ondas.[0089] All derivatives of formula (I) can be prepared by the procedures described in the general methods presented below or by routine modifications thereof. The present invention also encompasses any one or more of these processes for preparing the derivatives of formula (I), in addition to any new intermediates used herein. The person skilled in the art will appreciate that the following reactions can be heated thermally or under microwave irradiation.
[0090] Será também apreciado que pode ser necessário ou dese jável realizar as transformações em uma ordem diferente da descrita nos esquemas, ou modificar uma ou mais das transformações, para proporcionar o composto desejado da invenção.[0090] It will also be appreciated that it may be necessary or desirable to carry out the transformations in an order different from that described in the schemes, or to modify one or more of the transformations, to provide the desired compound of the invention.
[0091] As rotinas abaixo, incluindo as mencionadas nos Exemplos e Preparações, ilustram métodos de sintetizar os compostos de fórmula (I). A pessoa versada apreciará que os compostos da invenção, e seus intermediários, podem ser feitos por métodos diferentes dos especificamente aqui descritos, por exemplo, por adaptação dos métodos aqui descritos, por exemplo, por métodos conhecidos na técnica. Guias adequadas para a síntese, interconversões de grupos funcionais, uso de grupos de proteção, etc., são por exemplo: "Comprehensive Organic Transformations" by RC Larock, VCH Publishers Inc. (1989); Advanced Organic Chemistry" by J. March, Wiley Interscience (1985); "Designing Organic Synthesis" by S Warren, Wiley Interscience (1978); "Organic Synthesis - The Disconnection Approach" by S War ren, Wiley Interscience (1982); "Guidebook to Organic Synthesis" by RK Mackie and DM Smith, Longman (1982); "Protective Groups in Organic Synthesis" by TW Greene and PGM Wuts, John Wiley and Sons, Inc. (1999); and "Protecting Groups" by PJ, Kocienski, Georg Thieme Verlag (1994); e quaisquer versões atualizadas dos referidos trabalhos padrão.[0091] The routines below, including those mentioned in the Examples and Preparations, illustrate methods of synthesizing the compounds of formula (I). The skilled person will appreciate that the compounds of the invention, and their intermediates, can be made by methods other than those specifically described herein, for example, by adapting the methods described herein, for example, by methods known in the art. Suitable guides for synthesis, interconversions of functional groups, use of protecting groups, etc., are for example: "Comprehensive Organic Transformations" by RC Larock, VCH Publishers Inc. (1989); Advanced Organic Chemistry" by J. March, Wiley Interscience (1985); "Designing Organic Synthesis" by S Warren, Wiley Interscience (1978); "Organic Synthesis - The Disconnection Approach" by S Warren, Wiley Interscience (1982); " Guidebook to Organic Synthesis" by RK Mackie and DM Smith, Longman (1982); "Protective Groups in Organic Synthesis" by TW Greene and PGM Wuts, John Wiley and Sons, Inc. (1999); and "Protecting Groups" by PJ, Kocienski, Georg Thieme Verlag (1994); and any updated versions of said standard works.
[0092] Além disso, a pessoa versada apreciará que pode ser ne cessário ou desejável em qualquer estágio na síntese dos compostos da invenção para proteger um ou mais grupos sensíveis, de modo a evitar reações secundárias indesejáveis. Em particular, pode ser necessário ou desejável proteger grupos amino ou ácido carboxílico. Os grupos protetores usados na preparação dos compostos da invenção podem ser usados de maneira convencional. Veja, por exemplo, aqueles descritos em "Greene's Protective Groups in Organic Synthesis" por Theodora W Greene and Peter GM Wuts, terceira edição, (John Wiley and Sons, 1999), em especial os capítulos 7 ("Protection for the Amino Group") e 5 ("Protection for the Carboxyl Group"), incorporados aqui por referência, que também descreve métodos para a remoção de tais grupos.[0092] Furthermore, the skilled person will appreciate that it may be necessary or desirable at any stage in the synthesis of the compounds of the invention to protect one or more sensitive groups, so as to avoid undesirable side reactions. In particular, it may be necessary or desirable to protect amino or carboxylic acid groups. The protecting groups used in preparing the compounds of the invention can be used in a conventional manner. See, for example, those described in "Greene's Protective Groups in Organic Synthesis" by Theodora W Greene and Peter GM Wuts, third edition, (John Wiley and Sons, 1999), especially chapters 7 ("Protection for the Amino Group" ) and 5 ("Protection for the Carboxyl Group"), incorporated herein by reference, which also describes methods for removing such groups.
[0093] Nos métodos sintéticos gerais abaixo, a menos que de ou tra maneira especificado, os substituintes são como definidos acima com referência aos compostos de fórmula (I) acima.[0093] In the general synthetic methods below, unless otherwise specified, the substituents are as defined above with reference to the compounds of formula (I) above.
[0094] Onde as relações de solventes são dadas, as relações são em volume.[0094] Where solvent ratios are given, the ratios are by volume.
[0095] Os compostos da invenção podem ser preparados por qualquer método conhecido na técnica para a preparação de compostos de estrutura análoga. Em particular, os compostos da invenção podem ser preparados pelos procedimentos descritos por referência aos Esquemas que seguem, ou pelos métodos específicos descritos nos Exemplos, ou por processos similares a ambos.[0095] The compounds of the invention can be prepared by any method known in the art for the preparation of compounds of analogous structure. In particular, the compounds of the invention may be prepared by the procedures described with reference to the Schemes that follow, or by the specific methods described in the Examples, or by processes similar to both.
[0096] A pessoa versada apreciará que as condições experimen tais mencionadas nos esquemas que seguem são ilustrativas de condições adequadas para efetuar as transformações mostradas, e que pode ser necessário ou desejável variar as condições exatas empregadas para a preparação dos compostos de fórmula (I).[0096] The skilled person will appreciate that the experimental conditions mentioned in the following schemes are illustrative of conditions suitable for carrying out the transformations shown, and that it may be necessary or desirable to vary the exact conditions employed for the preparation of the compounds of formula (I) .
[0097] Além disso, a pessoa versada apreciará que pode ser ne cessário ou desejável, em qualquer estágio na síntese dos compostos da invenção, proteger um ou mais grupos sensíveis, de modo a evitar reações secundárias indesejáveis. Em particular, pode ser necessário ou desejável proteger grupos amino ou ácido carboxílico. Os grupos protectores usados na preparação dos compostos da invenção podem ser usados de maneira convencional. Veja, por exemplo, aqueles descritos em "Greene's Protective Groups in Organic Synthesis" por Theodora W Greene and Peter GM Wuts, terceira edição, (John Wiley and Sons, 1999), em especial os capítulos 7 ("Protection for the Amino Group") e 5 ("Protection for the Carboxyl Group"), incorporados aqui por referência, que também descreve os métodos para a remoção de tais grupos.[0097] Furthermore, the skilled person will appreciate that it may be necessary or desirable, at any stage in the synthesis of the compounds of the invention, to protect one or more sensitive groups, so as to avoid undesirable side reactions. In particular, it may be necessary or desirable to protect amino or carboxylic acid groups. The protecting groups used in preparing the compounds of the invention may be used in conventional manner. See, for example, those described in "Greene's Protective Groups in Organic Synthesis" by Theodora W Greene and Peter GM Wuts, third edition, (John Wiley and Sons, 1999), especially chapters 7 ("Protection for the Amino Group" ) and 5 ("Protection for the Carboxyl Group"), incorporated herein by reference, which also describes methods for removing such groups.
[0098] Todos os derivados de fórmula (I) podem ser preparados pelos procedimentos descritos nos métodos gerais apresentados abaixo ou por modificações de rotina dos mesmos. A presente invenção também abrange qualquer um ou mais destes processos para preparar os derivados de fórmula (I), além dos quaisquer dos novos intermediários aqui usados. A pessoa versada na técnica apreciará que as seguintes reações podem ser aquecidas termicamente ou sob irradiação de micro-ondas.[0098] All derivatives of formula (I) can be prepared by the procedures described in the general methods presented below or by routine modifications thereof. The present invention also encompasses any one or more of these processes for preparing the derivatives of formula (I), in addition to any of the new intermediates used herein. The person skilled in the art will appreciate that the following reactions can be heated thermally or under microwave irradiation.
[0099] Será ainda apreciado que pode ser necessário ou desejável realizar as transformações em uma ordem diferente da descrita nos es-quemas, ou modificar uma ou mais das transformações, para fornecer o composto desejado da invenção. Os esquemas são representativos de métodos úteis na sintetização dos compostos da presente invenção. Eles não devem restringir o escopo da invenção de nenhuma maneira.[0099] It will further be appreciated that it may be necessary or desirable to carry out the transformations in an order different from that described in the schemes, or to modify one or more of the transformations, to provide the desired compound of the invention. The schemes are representative of methods useful in synthesizing the compounds of the present invention. They must not restrict the scope of the invention in any way.
[00100] De acordo com um primeiro processo, os compostos de fórmula I podem ser preparados a partir dos compostos de fórmulas (A), (B), (C) e (D), como ilustrado pelo Esquema 1. Esquema 1 [00100] According to a first process, compounds of formula I can be prepared from compounds of formulas (A), (B), (C) and (D), as illustrated by Scheme 1. Scheme 1
[00101] No esquema 1, composto da Fórmula Bi (onde Y=Hal) é convertido a um composto de Fórmula Bii (Y=B(OR*)2) por tratamento com um boronato adequado tal como B2(Pin)2, na presença de uma base adequada, tal como K2CO3, e um catalisador adequado, tal como Pd(dppf)Cl2 em um solvente adequado, tal como dioxano. Uma pessoa versada da mesma forma sabe que estratégias de acoplamento orga- nometálico alternativas podem ser usadas envolvendo pares de aco- polamento alternativos, metais e combinações de solvente. Um composto da Fórmula Bii é preparado e isolado como descrito anteriormente ou preparado in situ sem isolamento em uma estratégia de acoplamento cruzado sequencial que é bem entendido por uma pessoa versada. Desse modo, um composto de Fórmula Bii é acoplado cruzado com um composto de Fórmula A na presença de um catalisador ade-quado, tal como Pd(dppf)Cl2, com uma base adequada, tal como K2CO3 em um solvente adequado tal como dioxano em uma temperatura adequada a partir da temperatura ambiente até a temperatura de refluxo. O composto resultante de Fórmula C é acoplado cruzado com um composto da Fórmula D contendo um grupo de saída adequado, tal como Bu3Sn ou (Pin)2B, com um catalisador de metal adequado, tal como Pd(PPh3)4, em um solvente adequado, tal como MeCN em temperatura ambiente ou elevada.[00101] In scheme 1, compound of Formula Bi (where Y=Hal) is converted to a compound of Formula Bii (Y=B(OR*)2) by treatment with a suitable boronate such as B2(Pin)2, in presence of a suitable base, such as K2CO3, and a suitable catalyst, such as Pd(dppf)Cl2 in a suitable solvent, such as dioxane. A person skilled in the art also knows that alternative organometallic coupling strategies can be used involving alternative coupling pairs, metals and solvent combinations. A compound of Formula Bii is prepared and isolated as previously described or prepared in situ without isolation in a sequential cross-coupling strategy that is well understood by one of skill in the art. Thereby, a compound of Formula Bii is cross-coupled with a compound of Formula A in the presence of a suitable catalyst, such as Pd(dppf)Cl2, with a suitable base, such as K2CO3 in a suitable solvent such as dioxane in a suitable temperature from room temperature to reflux temperature. The resulting compound of Formula C is cross-coupled with a compound of Formula D containing a suitable leaving group, such as Bu3Sn or (Pin)2B, with a suitable metal catalyst, such as Pd(PPh3)4, in a suitable solvent. , such as MeCN at room or elevated temperature.
[00102] De acordo com um segundo processo, um composto da Fórmula I pode da mesma forma ser preparado pela reação de acoplamento cruzado organometálico de compostos da Fórmula F com compostos de Fórmula B, esquema 2. Esquema 2 [00102] According to a second process, a compound of Formula I can likewise be prepared by the organometallic cross-coupling reaction of compounds of Formula F with compounds of Formula B, scheme 2. Scheme 2
[00103] Composto da Fórmula Bi (onde Y=Hal) é convertido a um composto de Fórmula Bii (Y=B(OR*)2) por tratamento com um borona- to adequado tal como B(Pin)2, na presença de uma base adequada, tal como K2CO3, e um catalisador adequado, tal como Pd(dppf)Cl2 em um solvente adequado, tal como dioxano. Uma pessoa versada da mesma forma sabe que estratégias de acoplamento organometálico alternativas podem ser usadas envolvendo pares de acopolamento alternativos, metais e combinações de solvente. Um composto da Fórmula Bii é preparado e isolado como descrito anteriormente ou preparado in situ sem isolamento em uma estratégia de acoplamento cruzado sequencial que é bem entendido por uma pessoa versada. Desse modo, um composto de Fórmula Bii é acoplado cruzado com um composto de Fórmula F na presença de um catalisador adequado, tal como Pd(dppf)Cl2, com uma base adequada, tal como K2CO3 em um solvente adequado tal como dioxano em uma temperatura adequada a partir de temperatura ambiente até a temperatura de refluxo.[00103] Compound of Formula Bi (where Y=Hal) is converted to a compound of Formula Bii (Y=B(OR*)2) by treatment with a suitable boronate such as B(Pin)2, in the presence of a suitable base, such as K2CO3, and a suitable catalyst, such as Pd(dppf)Cl2 in a suitable solvent, such as dioxane. One of skill in the art knows that alternative organometallic coupling strategies can be used involving alternative coupling pairs, metals and solvent combinations. A compound of Formula Bii is prepared and isolated as previously described or prepared in situ without isolation in a sequential cross-coupling strategy that is well understood by one of skill in the art. Thereby, a compound of Formula Bii is cross-coupled with a compound of Formula F in the presence of a suitable catalyst, such as Pd(dppf)Cl2, with a suitable base, such as K2CO3 in a suitable solvent such as dioxane at a temperature suitable from room temperature to reflux temperature.
[00104] De acordo com um terceiro processo, o composto de Fórmula I é preparado pela alquilação, acilação, sulfonilação etc., de um composto de Fórmula G, Esquema 3. Alquilação e acilação de NH livre Esquema 3 [00104] According to a third process, the compound of Formula I is prepared by alkylation, acylation, sulfonylation, etc., of a compound of Formula G, Scheme 3. Alkylation and acylation of free NH Scheme 3
[00105] De acordo com um Quarto processo, o composto de Fórmula I é preparado pela adição de Michael de um composto de Fórmula H com um composto de Fórmula J na presença de uma base não nucleofílica adequada, tal como DBU em um solvente adequado, tal como MeCN em uma temperatura adequada, esquema 4. Esquema 4 [00105] According to a Fourth process, the compound of Formula I is prepared by the Michael addition of a compound of Formula H with a compound of Formula J in the presence of a suitable non-nucleophilic base, such as DBU in a suitable solvent, such as MeCN at a suitable temperature, Scheme 4. Scheme 4
[00106] Esquema 5 ilustra um método para a preparação de com postos de Fórmula F. Um diéster de Fórmula Ei é tratado com um agente de alquilação de Fórmula K e uma base tal como K2CO3 em um solvente adequado tal como MeCN. O diéster resultante de Fórmula Eii é em seguida ciclizado na presença de NH4OAc em um solvente adequado tal como EtOH em temperatura elevada durante produzir o composto heterocíclico bicíclico de Fórmula Eiii. O composto de Fórmula Eiii é hidrolisado a um composto de Fórmula Eiv com uma base adequada, tal como LiOH, em um solvente adequado tal como MeOH. O ácido carboxílico resultante de Fórmula Eiv é termicamente descar- boxilado em um solvente adequado, tal como sulfolano em temperatura elevada tal como 280oC. O composto resultante de Fórmula Ev é clorado por tratamento com um reagente adequado, tal como POCl3, em um solvente adequado, tal como MeCN, em uma temperatura adequada tal como refluxo para preparar os compostos da Fórmula F. Esquema 5 [00106] Scheme 5 illustrates a method for preparing compounds of Formula F. A diester of Formula Ei is treated with an alkylating agent of Formula K and a base such as K2CO3 in a suitable solvent such as MeCN. The resulting diester of Formula Eii is then cyclized in the presence of NH4OAc in a suitable solvent such as EtOH at elevated temperature to produce the bicyclic heterocyclic compound of Formula Eiii. The compound of Formula Eiii is hydrolyzed to a compound of Formula Eiv with a suitable base, such as LiOH, in a suitable solvent such as MeOH. The resulting carboxylic acid of Formula Eiv is thermally decarboxylated in a suitable solvent, such as sulfolane at elevated temperature such as 280°C. The resulting compound of Formula Ev is chlorinated by treatment with a suitable reagent, such as POCl3, in a suitable solvent, such as MeCN, at a suitable temperature such as reflux to prepare the compounds of Formula F. Scheme 5
[00107] Os seguintes esquemas e descrições escritas fornecem de- talhes gerais relativos à preparação dos compostos da invenção. Os compostos da invenção podem ser preparados por qualquer método conhecido na técnica para a preparação de compostos de estrutura análoga. Em particular, os compostos da invenção podem ser preparados pelos procedimentos descritos por referência aos esquemas que se seguem, ou pelos métodos específicos descritos nos exemplos, ou por processos semelhantes a ambos.[00107] The following schemes and written descriptions provide general details relating to the preparation of the compounds of the invention. The compounds of the invention can be prepared by any method known in the art for preparing compounds of analogous structure. In particular, the compounds of the invention may be prepared by the procedures described with reference to the following schemes, or by the specific methods described in the examples, or by processes similar to both.
[00108] A pessoa versada apreciará que as condições experimentais apresentadas nos esquemas que se seguem são ilustrativas de condições adequadas para efetuar as transformações apresentadas, e que pode ser necessário ou desejável variar as condições exatas em-pregadas para a preparação dos compostos de fórmula (I).[00108] The skilled person will appreciate that the experimental conditions presented in the following schemes are illustrative of conditions suitable for carrying out the transformations presented, and that it may be necessary or desirable to vary the exact conditions employed for the preparation of the compounds of formula ( I).
[00109] Além disso, a pessoa versada apreciará que pode ser necessário ou desejável, em qualquer estágio na síntese dos compostos da invenção, proteger um ou mais grupos sensíveis, de modo a evitar reacções secundárias indesejáveis. Em particular, pode ser necessário ou desejável proteger grupos amino ou ácido carboxílico. Os grupos protetores usados na preparação dos compostos da invenção podem ser usados de maneira convencional. Veja, por exemplo, aqueles descritos em Protective Groups in Organic Synthesis por Theodora W. Greene and Peter GM Wuts, 3a edição, (John Wiley and Sons, 1999), em especial os capítulos 7 ("Protection for the Amino Group") e 5 ("Protection for the Carboxyl Group"), incorporados aqui por referência, que também descreve métodos para a remoção de tais grupos.[00109] Furthermore, the skilled person will appreciate that it may be necessary or desirable, at any stage in the synthesis of the compounds of the invention, to protect one or more sensitive groups, so as to avoid undesirable side reactions. In particular, it may be necessary or desirable to protect amino or carboxylic acid groups. The protecting groups used in preparing the compounds of the invention can be used in a conventional manner. See, for example, those described in Protective Groups in Organic Synthesis by Theodora W. Greene and Peter GM Wuts, 3rd edition, (John Wiley and Sons, 1999), especially chapters 7 ("Protection for the Amino Group") and 5 ("Protection for the Carboxyl Group"), incorporated herein by reference, which also describes methods for removing such groups.
[00110] Todos os derivados de fórmula I e Ia-f podem ser preparados pelos procedimentos descritos nos métodos gerais apresentados abaixo ou por modificações de rotina dos mesmos. A presente invenção também abrange qualquer um ou mais destes processos para preparar os derivados de fórmula (I), além de quaisquer novos intermediários aqui usados. A pessoa versada na técnica apreciará que as seguintes reações podem ser aquecidas termicamente ou sob irradiação de micro-ondas.[00110] All derivatives of formula I and Ia-f can be prepared by the procedures described in the general methods presented below or by routine modifications thereof. The present invention also encompasses any one or more of these processes for preparing the derivatives of formula (I), in addition to any new intermediates used herein. The person skilled in the art will appreciate that the following reactions can be heated thermally or under microwave irradiation.
[00111] Na execução da síntese dos compostos da invenção, alguém versado na técnica reconhecerá a necessidade de amostrar e ensaiar misturas de reação antes do trabalho para monitorar o progresso das reações e decidir se a reação deve ser continuada ou se pronta para ser trabalhado para obter o produto desejado. Métodos comuns para ensaiar misturas reacionais incluem cromatografia de camada fina (TLC), cromatografia líquida/espectroscopia de massa (LCMS) e ressonância magnética nuclear (RMN).[00111] In carrying out the synthesis of the compounds of the invention, one skilled in the art will recognize the need to sample and assay reaction mixtures prior to work to monitor the progress of the reactions and decide whether the reaction should be continued or ready to be worked on for obtain the desired product. Common methods for assaying reaction mixtures include thin-layer chromatography (TLC), liquid chromatography/mass spectroscopy (LCMS), and nuclear magnetic resonance (NMR).
[00112] Alguém versado na técnica também reconhecerá que os compostos da invenção podem ser preparados como misturas de dias- tereômeros ou isômeros geométricos (por exemplo, substituição cis e trans em um anel de cicloalcano). Estes isômeros podem ser separados por técnicas cromatográficas padrão, tais como cromatografia de fase normal em sílica gel, cromatografia líquida de alta pressão preparativa de fase reversa ou cromatografia de fluido supercrítico. Alguém versado na técnica também reconhecerá que alguns compostos da invenção são quirais e assim podem ser preparados como misturas racêmicas ou escalêmicas de enantiômeros. Vários métodos estão disponíveis e são bem conhecidos dos versados na técnica para a separação de enantiômeros. Um método preferido para os enantiômeros de separação de rotina é a cromatografia de fluido supercrítica empregando uma fase estacionária quiral.[00112] One skilled in the art will also recognize that the compounds of the invention can be prepared as mixtures of diastereomers or geometric isomers (e.g., cis and trans substitution on a cycloalkane ring). These isomers can be separated by standard chromatographic techniques, such as normal-phase chromatography on silica gel, preparative reversed-phase high-pressure liquid chromatography, or supercritical fluid chromatography. One skilled in the art will also recognize that some compounds of the invention are chiral and thus can be prepared as racemic or scalemic mixtures of enantiomers. Various methods are available and well known to those skilled in the art for separating enantiomers. A preferred method for routine separation of enantiomers is supercritical fluid chromatography employing a chiral stationary phase.
[00113] Exceto onde indicado de outra maneira, as reações foram executadas sob uma atmosfera de nitrogênio. A cromatografia em sílica gel foi realizada usando sílica gel de malha 250-400 usando nitrogênio pressurizado (~ 0,70-1,05 kg/cm2 (10-15 psi)) para conduzir o solvente através da coluna ("cromatografia flash"). Onde indicado, as soluções e misturas de reação foram concentradas por evaporação rotativa sob vácuo.[00113] Except where otherwise indicated, the reactions were carried out under a nitrogen atmosphere. Silica gel chromatography was performed using 250-400 mesh silica gel using pressurized nitrogen (~0.70-1.05 kg/cm2 (10-15 psi)) to drive the solvent through the column ("flash chromatography") . Where indicated, solutions and reaction mixtures were concentrated by rotary evaporation under vacuum.
[00114] A nomenclatura nesta patente é escrita como descrito pela IUPAC (União Internacional de Química Pura e Aplicada e usando ChemBioDraw Ultra 13.0, Perkin Elmer para gerar nomes.[00114] The nomenclature in this patent is written as described by IUPAC (International Union of Pure and Applied Chemistry and using ChemBioDraw Ultra 13.0, Perkin Elmer to generate names.
[00115] As seguintes Preparações e Exemplos não limitativos ilustram a preparação de compostos e sais da presente invenção. Nos Exemplos e Preparações que são apresentados abaixo, e nos Esquemas acima mencionados, as seguintes abreviaturas, definições e procedimentos analíticos podem ser referidos. Outras abreviaturas comuns na técnica podem também ser usadas. A nomenclatura da IUPAC padrão foi usada. AcOH é ácido acético; aq. é aquosa; Boc é terc-butoxicarbonila; br é amplo; salmoura é uma solução saturada de cloreto de sódio em água; t-Bu é terc-butila; n-BuLi é n-butillítio; °C é graus celcius; Cbz é carbobenzilóxi; CDCl3 é deutero-clorofórmio; CDI é 1,1’-carbonoildiimidazol; conc. é concentrado (em referência aos reagentes); Cs2CO3 é carbonoato de césio; δ é desvio químico; d é dubleto; DBU é 1,8-diazabiciclo[5.4.0]undec-7-eno; DCM é diclorometano; DHP é 3,4-di-hidro-2H-pirano; DIPEA é N,N-diisopropiletilamina; DMAP é 4-dimetilaminopiridina; DMF é N,N-dimetilformamida; DMSO é dimetil sulfóxido; Et2O é dietil éter; EtOAc é acetato de etila; EtOH é etanol; (EtO)2P(O)CH2CN é dietil (cianometil)fosfonato; g é grama; GCMS é espectroscopia de massa por cromatografia gaso- HCl é ácido clorídrico; HCO2H é ácido fórmico; HPLC é cromatografia líquida de alto desempenho; hrs é horas; H2SO4 é ácido sulfúrico; K2CO3 é carbonato de potássio; KH2PO4 é di-hidrogenofosfato de potássio K2HPO4 é mono-hidrogenofosfato de potássio; K3PO4 é fosfato de potássio (tribásico); KOAc é acetato de potássio L é litro; LCMS é cromatografia líquida - espectrometria de massa; LiBr é brometo de lítio; LiOH é hidróxido de lítio; m é multipleto; M é molar; MeCN é acetonitrila; MeOH é metanol; mg é miligrama; MgSO4 é sulfato de magnésio; MHz é megaHertz; min é minutos; mL é mililitro; mmol é milimol; mol é mol; MS m/z é pico de íon de espectro de massa; MTBE é metil t-butil éter NaBH(OAc)3 é triacetoxiboro-hidreto de sódio; Na2CO3 é carbonoato de sódio; NaHCO3 é hidrogenocarbonato de sódio; NaH2PO4 é di-hidrogenofosfato de sódio; Na2HPO4 é mono-hidrogenofosfato de sódio; NaI é iodeto de sódio; NaIO4 é periodato de sódio; NaOAc é acetato de sódio; NaOCl é hipoclorito de sódio; NaOH é hidróxido de sódio; NH3 é amônia; NH4Cl é cloreto de amônio; NH4OH é hidróxido de amônio; NH4OAc é acetato de amônio; RMN é ressonância magnética nuclear; OsO4 é tetróxido ósmio; Pd/C é paládio sobre carbonoo; Pd(dppf)Cl2 é dicloreto de 1,1-bis(difenilfosfino)ferroceno paládio (II) (CAS: 72287-26-4); Pd(dppf)Cl2.DCM é dicloreto de 1,1- bis(difenilfosfino)ferroceno paládio (II); complexo com diclorometano (CAS: 95464-05-4); Pd(OAc)2 é acetato de paládio; Pd(PPh3)4 é tetracis(trifenilfosfina)paládio; PMB-Cl é cloreto de (4-metóxi)benzila; POCl3 é oxicloreto de fósforo(V); ppm é partes por milhão; psi é libras por polegada quadrada; PTSUma é ácido para-toluenossulfônico PyHBr3 é perbrometo de hidrobrometo de piridina PyHCl é cloridrato de piridina q é quarteto; Rt é tempo de retenção; Rh2(OAc)4 é dímero de acetato de ródio (II); RuCl3 hidrato é hidrato de cloreto de rutênio(II); s é singleto; SOCl2 é cloreto de tionila; t é tripleto; TBAB é brometo de tetrabutilamônio TEA é trietilamina; TFA é ácido trifluoroacético; THF é tetra-hidrofurano; TMSCl é clorotrimetilsilano; μL é microlitro; μmol é micromol XPhos Pd G2 é cloro(2-diciclo-hexilfosfino-2',4',6'-triisopropil- 1,r-bifenil)[2-(2-amino-1,r-bifenil)]paládio (II); CAS 1310584 - 14-5.[00115] The following non-limiting Preparations and Examples illustrate the preparation of compounds and salts of the present invention. In the Examples and Preparations that are presented below, and in the Schemes mentioned above, the following abbreviations, definitions and analytical procedures may be referred to. Other abbreviations common in the art may also be used. Standard IUPAC nomenclature was used. AcOH is acetic acid; aq. it is watery; Boc is tert-butoxycarbonyl; br is broad; brine is a saturated solution of sodium chloride in water; t-Bu is tert-butyl; n-BuLi is n-butyllithium; °C is degrees Celsius; Cbz is carbobenzyloxy; CDCl3 is deutero-chloroform; CDI is 1,1'-carbonoyldiimidazole; conc. is concentrated (in reference to the reagents); Cs2CO3 is cesium carbonate; δ is chemical shift; d is doublet; DBU is 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM is dichloromethane; DHP is 3,4-dihydro-2H-pyran; DIPEA is N,N-diisopropylethylamine; DMAP is 4-dimethylaminopyridine; DMF is N,N-dimethylformamide; DMSO is dimethyl sulfoxide; Et2O is diethyl ether; EtOAc is ethyl acetate; EtOH is ethanol; (EtO)2P(O)CH2CN is diethyl (cyanomethyl)phosphonate; g is grass; GCMS is gas chromatography mass spectroscopy- HCl is hydrochloric acid; HCO2H is formic acid; HPLC is high-performance liquid chromatography; hrs is hours; H2SO4 is sulfuric acid; K2CO3 is potassium carbonate; KH2PO4 is potassium dihydrogen phosphate K2HPO4 is potassium monohydrogen phosphate; K3PO4 is potassium phosphate (tribasic); KOAc is potassium acetate L is liter; LCMS is liquid chromatography - mass spectrometry; LiBr is lithium bromide; LiOH is lithium hydroxide; m is multiplet; M is molar; MeCN is acetonitrile; MeOH is methanol; mg is milligram; MgSO4 is magnesium sulfate; MHz is megaHertz; min is minutes; mL is milliliter; mmol is millimol; mole is mole; MS m/z is mass spectrum ion peak; MTBE is methyl t-butyl ether NaBH(OAc)3 is sodium triacetoxyborohydride; Na2CO3 is sodium carbonate; NaHCO3 is sodium hydrogen carbonate; NaH2PO4 is sodium dihydrogen phosphate; Na2HPO4 is sodium monohydrogen phosphate; NaI is sodium iodide; NaIO4 is sodium periodate; NaOAc is sodium acetate; NaOCl is sodium hypochlorite; NaOH is sodium hydroxide; NH3 is ammonia; NH4Cl is ammonium chloride; NH4OH is ammonium hydroxide; NH4OAc is ammonium acetate; NMR is nuclear magnetic resonance; OsO4 is osmium tetroxide; Pd/C is palladium on carbon; Pd(dppf)Cl2 is 1,1-bis(diphenylphosphine)ferrocene palladium(II) dichloride (CAS: 72287-26-4); Pd(dppf)Cl2.DCM is 1,1-bis(diphenylphosphine)ferrocene palladium (II) dichloride; complex with dichloromethane (CAS: 95464-05-4); Pd(OAc)2 is palladium acetate; Pd(PPh3)4 is tetracys(triphenylphosphine)palladium; PMB-Cl is (4-methoxy)benzyl chloride; POCl3 is phosphorus(V) oxychloride; ppm is parts per million; psi is pounds per square inch; PTSUma is para-toluenesulfonic acid PyHBr3 is pyridine hydrobromide perbromide PyHCl is pyridine hydrochloride which is quartet; Rt is retention time; Rh2(OAc)4 is rhodium (II) acetate dimer; RuCl3 hydrate is ruthenium(II) chloride hydrate; s is singlet; SOCl2 is thionyl chloride; t is triplet; TBAB is tetrabutylammonium bromide TEA is triethylamine; TFA is trifluoroacetic acid; THF is tetrahydrofuran; TMSCl is chlorotrimethylsilane; μL is microliter; μmol is micromol ); CAS 1310584 - 14-5.
[00116] Os espectros de ressonância magnética nuclear de 1H (RMN) foram em todos os casos consistentes com as estruturas propostas. Os desvios químicos característicos (δ) são dados em partes por milhão a jusante ao tetrametilsilano usando abreviaturas convenci- onais para designação dos picos maiores: por exemplo, s, singleto; d, dupleto; t, tripleto; q quarteto; m, multipleto; br, amplo. As seguintes abreviaturas foram usadas para solventes de RMN comuns: CD3CN, deuteroacetonitrila; CDCl3, deuteroclorofórmio; DMSO-d6, deuterodi- metilsulfóxido; e CD3OD, deuterometanol. Onde apropriado, os tautô- meros podem ser registrados dentro dos dados de RMN; e alguns pró-tons trocáveis podem não estar visíveis.[00116] The 1H nuclear magnetic resonance (NMR) spectra were in all cases consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts per million downstream of tetramethylsilane using conventional abbreviations for designation of major peaks: for example, s, singlet; d, doublet; t, triplet; q quartet; m, multiplet; br, broad. The following abbreviations have been used for common NMR solvents: CD3CN, deuteroacetonitrile; CDCl3, deuterochloroform; DMSO-d6, deuterodimethyl sulfoxide; and CD3OD, deuteromethanol. Where appropriate, tautomers can be recorded within the NMR data; and some exchangeable protons may not be visible.
[00117] Os espectros de massa foram registados usando ionização por impacto de elétron (EI), ionização por eletropulverização (ESI) ou ionização química por pressão atmosférica (APCI). Os íons observados são referidos como MS m/z e podem ser íons positivos do composto [M]+, composto mais um próton [MH]+ ou composto mais um íon de sódio [MNa]+. Em alguns casos, os únicos íons observados podem ser fragmentos iônicos relatados como [MH- (fragmento perdido)]+. Quando relevante, os íons relatados são atribuídos a isótopos de cloro (35Cl e/ou 37Cl), bromo (79Br e/ou 81Br) e estanho (120Sn).[00117] Mass spectra were recorded using electron impact ionization (EI), electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI). The observed ions are referred to as MS m/z and can be positive ions of the compound [M]+, compound plus a proton [MH]+, or compound plus a sodium ion [MNa]+. In some cases, the only ions observed may be fragment ions reported as [MH- (lost fragment)]+. When relevant, reported ions are assigned to isotopes of chlorine (35Cl and/or 37Cl), bromine (79Br and/or 81Br) and tin (120Sn).
[00118] Em que a TLC, cromatografia, ou HPLC foi usada para purificar os compostos, alguém versado na técnica pode escolher qualquer solvente apropriado ou combinação de solventes para purificar o com-posto desejado. As separações cromatográficas (excluindo HPLC) foram realizadas usando adsorvente de sílica gel, a menos que de outra maneira indicado.[00118] Where TLC, chromatography, or HPLC has been used to purify the compounds, one skilled in the art can choose any appropriate solvent or combination of solvents to purify the desired compound. Chromatographic separations (excluding HPLC) were performed using silica gel adsorbent unless otherwise indicated.
[00119] Todas as reacções foram realizadas usando agitação contínua sob uma atmosfera de gás nitrogênio ou argônio, a menos que de outra maneira indicado. Em alguns casos, as reações foram purgadas com nitrogênio ou argônio antes do início da reação. Nestes casos, o gás nitrogênio ou argônio foi borbulhado através da fase líquida da mistura durante o tempo especificado aproximado. Os solventes usados foram os graus comerciais anidrosos. Todos os materiais de partida foram produtos comercialmente disponíveis. Em alguns casos, o número de identificação do Chemical Abstracts Service (CAS) é for-necido para ajudar com clareza. Em alguns casos, os materiais de par-tida foram preparados de acordo com os procedimentos descritos na literatura, conforme indicado por um asterisco (*). Será evidente para alguém versado na técnica que a palavra "concentrado", quando aqui usada, refere-se geralmente à prática de evaporação do solvente sob pressão reduzida, tipicamente realizada pelo uso de um evaporador rotativo. CONDIÇÕES DE GCMS Coluna: 12m x 0,2mm, HP - 1 Metil Siloxane, película de 0,33μm, 1,0 ml/min de fluxo da coluna. Métodos: 7,6 min: Temperatura Inicial do Forno 105°C; 0,1 min de manutenção; rampa de 30 °C/min até o ponto final de 300 °C em 7,6 min; ou 7,6 min: Temperatura Inicial do Forno 60° C; 0,1 min de manutenção; rampa de 40 °C/min até o ponto final de 320 °C em 7,6 min; ou 5,1 min: Temperatura Inicial do Forno 40 °C; 0,1 min de manutenção; tampa de 30 °C/minuto até o ponto final de 150 °C em 5,1 minutos. Parâmetros de Entrada de GC: Entrada Frontal, Divisão 30:1, He, Pressão de 0,56 kg/cm2 (8 psi), Injetor de 250 °C, fluxo total de 33,9 ml/min. Modulação de MSD: Temperatura da Fonte de 230 °C, Temperatura de Quad de 150 °C, Temperatura de Aux2 de 280 °C Volume de Injeção: 1,0 μL Componentes do Sistema: Forno GC Agilent 5890 com De-tector de Massa Seletivo Agilent 5973 CONDIÇÕES DE LCMS Ácido: Waters Acquity HSS T3, 2,1mm x 50 mm, C18, 1,7μm; Temperatura da Coluna 60°C Base: Waters Acquity UPLC BEH, 2,1mm x 50 mm, C18, 1,8μm; Temperatura da Coluna 60°C Fase Móvel: A: 0,1 % de ácido fórmico em água (v/v); Fase móvel B: 0,1 % de ácido fórmico em acetonitrila (v/v). Fase Móvel A: 0,1 % de amônia em água (v/v); Fase móvel B: 0,1 % de amônia em acetonitrila (v/v) Perfis de Gradiente: Execução de 1,5 min: Condições iniciais: A-95 %:B-5 %; manutenção no início a partir de 0,0-0,1min; Rampa Linear para A-5 %:B-95 % durante 0,1 - 1,0 min; manutenção em A- 5 %:B-95 % de 1,0 - 1,1min; returno às condições iniciais 1,1 - 1,5min[00119] All reactions were carried out using continuous stirring under an atmosphere of nitrogen or argon gas, unless otherwise indicated. In some cases, reactions were purged with nitrogen or argon before starting the reaction. In these cases, nitrogen or argon gas was bubbled through the liquid phase of the mixture for the approximate specified time. The solvents used were anhydrous commercial grades. All starting materials were commercially available products. In some cases, the Chemical Abstracts Service (CAS) identification number is provided to help with clarity. In some cases, the starting materials were prepared according to procedures described in the literature, as indicated by an asterisk (*). It will be apparent to one skilled in the art that the word "concentrate", when used herein, generally refers to the practice of evaporating the solvent under reduced pressure, typically accomplished by the use of a rotary evaporator. GCMS CONDITIONS Column: 12m x 0.2mm, HP - 1 Methyl Siloxane, 0.33μm film, 1.0 ml/min column flow. Methods: 7.6 min: Initial Oven Temperature 105°C; 0.1 min maintenance; ramp from 30 °C/min to the end point of 300 °C in 7.6 min; or 7.6 min: Initial Oven Temperature 60° C; 0.1 min maintenance; ramp from 40 °C/min to the end point of 320 °C in 7.6 min; or 5.1 min: Initial Oven Temperature 40 °C; 0.1 min maintenance; cap at 30°C/minute to the endpoint of 150°C in 5.1 minutes. GC Inlet Parameters: Front Inlet, 30:1 Split, He, 0.56 kg/cm2 (8 psi) Pressure, 250 °C Injector, 33.9 ml/min total flow. MSD Modulation: 230°C Source Temperature, 150°C Quad Temperature, 280°C Aux2 Temperature Injection Volume: 1.0 μL System Components: Agilent 5890 GC Oven with Selective Mass Detector Agilent 5973 LCMS CONDITIONS Acid: Waters Acquity HSS T3, 2.1mm x 50mm, C18, 1.7μm; Column Temperature 60°C Base: Waters Acquity UPLC BEH, 2.1mm x 50 mm, C18, 1.8μm; Column Temperature 60°C Mobile Phase: A: 0.1% formic acid in water (v/v); Mobile phase B: 0.1% formic acid in acetonitrile (v/v). Mobile Phase A: 0.1% ammonia in water (v/v); Mobile phase B: 0.1% ammonia in acetonitrile (v/v) Gradient Profiles: 1.5 min run: Initial conditions: A-95 %:B-5 %; maintenance at start from 0.0-0.1min; Linear ramp for A-5 %:B-95 % for 0.1 - 1.0 min; maintenance at A- 5%:B-95% of 1.0 - 1.1min; return to initial conditions 1.1 - 1.5min
[00120] Os compostos dos Exemplos foram purificados de acordo com um dos Métodos de Purificação (PM) referidos abaixo a menos que de outra maneira descrito: Método de Purificação A: HPLC preparativa usando [Agel- la venusil ASB C18 150 x 21,2mm x 5 μm, de 16 % de MeCN em água (0,225 % de ácido fórmico) a 36 % de MeCN em água (0,225 % de ácido fórmico)] Método de Purificação B: HPLC preparativa usando [Phe- nomenex Gemini C18 250 x 21,2mm x 8um ou 150 mm x 25mm x 5 μm; de 16-55 % de MeCN em água (0,1 % de amônia) a 36-60 % de MeCN em água (0,1 % de amônia)] Método de Purificação C: [YMC -Actus Triart C18 150 x 30 μm, de 24 % de MeCN em água (0,1 % de amônia) a 44 % de MeCN em água (0,1 % de amônia)] Método de Purificação D: HPLC preparativa usando [Phe- nomenex Gemini C18 250 x 21,2mm x 8μm, de 25 % de MeCN em água (amônia pH=10) a 45 % de MeCN em água (amônia pH=10)] seguido por cromatografia quiral usando coluna AS 250 x 25mm I.D. 20 μM, com CO2 supercrítico: EtOH ou IPA (0,05 % de amônia aquosa) 70:30 de 50-80 mL/min Método de Purificação E: HPLC preparativa usando [Phe- nomenex Gemini C18 250 x 21,2mm x 8μm, de 25 % de MeCN em água (0,225 % de amônia) a 45 % de MeCN em água (0,225 % de amônia) seguido por cromatografia quiral usando AD 250 mm x 30 mm x 20 μm coluna com fase móvel A: supercrítica CO2 e fase móvel B MeOH com 0,1 % de amônia A:B 50:50 a 180 mL / min Método de Purificação F: Cromatografia de coluna em sílica gel eluindo com 100 % de DCM a 12 % de MeOH com 1 % de NH4OH. Método de Purificação G: Cromatografia de coluna em sílica gel eluindo com 97:2:1 DCM:MeOH:NH3 seguido por HPLC preparativa. Método de Purificação H: HPLC preparativa usando Coluna: Waters XBridge C18 19 mm x 100 mm, 5 μ; Fase móvel A: 0,03 % de hidróxido de amônio em água (v / v); Fase móvel B: 0,03 % de hidróxido de amônio em acetonitrila (v / v); de 5-20 % de B a 40 - 100 % de B à razão de fluxo de 25 mL / min. Método de Purificação I: HPLC preparativa usando Coluna: Waters Sunfire C18 19 mm x 100 mm, 5 μ; Fase móvel A: 0,05 % de TFA em água (v / v); Fase móvel B: 0,05 % de TFA em acetonitrila (v / v); de 20 % de B a 40 % de B a 6,75 minutos, em seguida a 100 % de B a 7 minutos à razão de fluxo de 30 mL / min.[00120] The compounds of the Examples were purified according to one of the Purification Methods (PM) referred to below unless otherwise described: Purification Method A: Preparative HPLC using [Agel-la venusil ASB C18 150 x 21.2mm x 5 μm, from 16% MeCN in water (0.225% formic acid) to 36% MeCN in water (0.225% formic acid)] Purification Method B: Preparative HPLC using [Phenomenex Gemini C18 250 x 21 .2mm x 8um or 150mm x 25mm x 5μm; from 16-55% MeCN in water (0.1% ammonia) to 36-60% MeCN in water (0.1% ammonia)] Purification Method C: [YMC -Actus Triart C18 150 x 30 μm , from 24% MeCN in water (0.1% ammonia) to 44% MeCN in water (0.1% ammonia)] Purification Method D: Preparative HPLC using [Phenomenex Gemini C18 250 x 21, 2mm x 8μm, from 25% MeCN in water (ammonia pH=10) to 45% MeCN in water (ammonia pH=10)] followed by chiral chromatography using AS column 250 x 25mm I.D. 20 μM, with supercritical CO2: EtOH or IPA (0.05% aqueous ammonia) 70:30 at 50-80 mL/min Purification Method E: Preparative HPLC using [Phenomenex Gemini C18 250 x 21.2mm x 8μm , from 25% MeCN in water (0.225% ammonia) to 45% MeCN in water (0.225% ammonia) followed by chiral chromatography using AD 250 mm x 30 mm x 20 μm column with mobile phase A: supercritical CO2 and mobile phase B MeOH with 0.1% ammonia A:B 50:50 at 180 mL / min Purification Method F: Column chromatography on silica gel eluting with 100% DCM to 12% MeOH with 1% NH4OH. Purification Method G: Column chromatography on silica gel eluting with 97:2:1 DCM:MeOH:NH3 followed by preparative HPLC. Purification Method H: Preparative HPLC using Column: Waters XBridge C18 19 mm x 100 mm, 5 μ; Mobile phase A: 0.03% ammonium hydroxide in water (v / v); Mobile phase B: 0.03% ammonium hydroxide in acetonitrile (v / v); from 5-20% B to 40 - 100% B at a flow rate of 25 mL/min. Purification Method I: Preparative HPLC using Column: Waters Sunfire C18 19 mm x 100 mm, 5 μ; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in acetonitrile (v/v); from 20% B to 40% B at 6.75 minutes, then to 100% B at 7 minutes at a flow rate of 30 mL/min.
[00121] Rotações específica com base na equação [α] = (100-α) / (i-c) e são relatados como números sem unidade onde a concentração c está em g / l00 mL e o comprimento do percurso l está em decíme- tros. As unidades da rotação específica, (deg-mL) / (g-dm), estão implícitos e não estão incluídos com o valor relatado. Preparação 1 Etil 1-(cianometil)-1H-pirazol-3-carboxilato e Etil 1-(cianometil)-1H-pirazol-5-carboxilato [00121] Specific rotations based on the equation [α] = (100-α) / (ic) and are reported as unitless numbers where the concentration c is in g / l00 mL and the path length l is in decimeters . The units of the specific rotation, (deg-mL) / (g-dm), are implicit and are not included with the reported value. Preparation 1 Ethyl 1-(cyanomethyl)-1H-pyrazol-3-carboxylate and Ethyl 1-(cyanomethyl)-1H-pyrazol-5-carboxylate
[00122] A uma suspensão de Cs2CO3 (2100 g, 6,44 mol) em DMF (12 L) foi adicionado etil 1H-pirazol-3-carboxilato (750 g, 5,36 mol), seguido por 2-cloroacetonitrila (450 g, 5,96 mol), e a mistura foi agitada a cerca de 25 °C durante cerca de 16 hrs. A reação foi vertida em água (12 L) e extraída com EtOAc (5 x 5 L). Os extratos de EtOAc combinados foram lavados com salmoura (2 x 5 L), secados (Na2SO4) e concentrados para proporcionar um resíduo o qual foi purificado por cro- matografia para proporcionar etil 1-(cianometil)-1H-pirazol-3- carboxilato (398 g, 39 %) como um óleo amarelo e etil 1-(cianometil)- 1H-pirazol-5-carboxilato (680 g). O etil 1-(cianometil)-1H-pirazol-5- carboxilato foi dissolvido em MTBE (15 L) e lavado com salmoura (3 x 5 L), secado (Na2SO4) e concentrado para proporcionar o composto como um óleo amarelo (489 g, 51 %).[00122] To a suspension of Cs2CO3 (2100 g, 6.44 mol) in DMF (12 L) was added ethyl 1H-pyrazol-3-carboxylate (750 g, 5.36 mol), followed by 2-chloroacetonitrile (450 g, 5.96 mol), and the mixture was stirred at about 25°C for about 16 hrs. The reaction was poured into water (12 L) and extracted with EtOAc (5 x 5 L). The combined EtOAc extracts were washed with brine (2 x 5 L), dried (Na2SO4) and concentrated to provide a residue which was purified by chromatography to provide ethyl 1-(cyanomethyl)-1H-pyrazol-3-carboxylate (398 g, 39%) as a yellow oil and ethyl 1-(cyanomethyl)-1H-pyrazol-5-carboxylate (680 g). Ethyl 1-(cyanomethyl)-1H-pyrazol-5-carboxylate was dissolved in MTBE (15 L) and washed with brine (3 x 5 L), dried (Na2SO4) and concentrated to provide the compound as a yellow oil (489 g, 51%).
[00123] 1H RMN (400 MHz, CDCl3) δ: 7,49 (s, 1 H), 6,82 (s, 1 H), 5,45 (s, 2 H), 4,29 (q, 2 H), 1,29 (t, 3H).[00123] 1H NMR (400 MHz, CDCl3) δ: 7.49 (s, 1 H), 6.82 (s, 1 H), 5.45 (s, 2 H), 4.29 (q, 2 H), 1.29 (t, 3H).
[00124] LCMS m/z = 180,1 [MH]+ Preparação 2 Etil 1-(2-amino-2-oxoetil)-1H-pirazol-5-carboxilato [00124] LCMS m/z = 180.1 [MH]+ Preparation 2 Ethyl 1-(2-amino-2-oxoethyl)-1H-pyrazol-5-carboxylate
[00123] Duas reações idênticas foram realizadas em paralelo.[00123] Two identical reactions were carried out in parallel.
[00124] A uma solução de etil 1-(cianometil)-1H-pirazol-5-carboxilato (Preparação 1, 235,5 g, 1,32 mol) em TFA (1,2 L) foi adicionado H2SO4 conc. (377 mL, 7,04 mol) a cerca de 25 °C. A mistura de reação foi agita-da a cerca de 25 °C durante cerca de 16 hrs antes de ser combinada com a reação paralela e concentrada para remover a maior parte do TFA. O resíduo foi vertido em água gelada (5 L) e extraída com EtOAc (5 L). A fase aquosa também foi extraída com EtOAc (10 x 5 L) e os extratos de EtOAc combinados foram lavados com NaHCO3 aq. saturado (2 x 10 L), secados (Na2SO4) e concentrados para proporcionar o composto título como um sólido amarelo (477 g, 92 %).[00124] To a solution of ethyl 1-(cyanomethyl)-1H-pyrazol-5-carboxylate (Preparation 1, 235.5 g, 1.32 mol) in TFA (1.2 L) was added conc. H2SO4. (377 mL, 7.04 mol) at about 25 °C. The reaction mixture was stirred at about 25 ° C for about 16 hrs before being combined with the parallel reaction and concentrated to remove most of the TFA. The residue was poured into ice water (5 L) and extracted with EtOAc (5 L). The aqueous phase was also extracted with EtOAc (10 x 5 L) and the combined EtOAc extracts were washed with aq. saturated (2 x 10 L), dried (Na2SO4) and concentrated to provide the title compound as a yellow solid (477 g, 92%).
[00125] 1H RMN (400 MHz, CDCl3) δ: 7,60 (s, 1 H), 6,93 (s, 1 H), 5,90 (br. s, 1 H), 5,71 (br. s, 1 H), 5,27 (s, 2 H), 4,35 (q, 2 H), 1,37 (t, 3H).[00125] 1H NMR (400 MHz, CDCl3) δ: 7.60 (s, 1 H), 6.93 (s, 1 H), 5.90 (br. s, 1 H), 5.71 (br. s, 1H), 5.27 (s, 2H), 4.35 (q, 2H), 1.37 (t, 3H).
[00126] LCMS m/z = 198,2 [MH]+ Preparação 3 Pirazolo[1,5-a]pirazina-4,6(5H,7H)-diona [00126] LCMS m/z = 198.2 [MH]+ Preparation 3 Pyrazolo[1,5-a]pyrazine-4,6(5H,7H)-dione
[00127] A uma solução de etil 1-(2-amino-2-oxoetil)-1H-pirazol-5- carboxilato (Preparação 2, 466 g, 2,17 mol) em EtOH (56 L) foi adicio-nado NaOtBu (498 g, 5,20 mol) em THF (4 L) a cerca de 25 °C. Uma suspensão branca desenvolveu-se durante a adição, e a mistura foi em seguida aquecida a cerca de 70 °C durante cerca de 16 hrs. A mistura de reação foi resfriada a cerca de 25 °C e acidificada a cerca de pH 6 com HCl aq. a 12 M (500 mL), resultando na formação de uma suspensão branca. A mistura foi concentrada para proporcionar o composto título (misturado com cloreto de sódio) como sólido amarelo (783 g). Este foi usado sem outra purificação.[00127] To a solution of ethyl 1-(2-amino-2-oxoethyl)-1H-pyrazol-5-carboxylate (Preparation 2, 466 g, 2.17 mol) in EtOH (56 L) was added NaOtBu (498 g, 5.20 mol) in THF (4 L) at about 25 °C. A white suspension developed during the addition, and the mixture was then heated to about 70°C for about 16 hrs. The reaction mixture was cooled to about 25°C and acidified to about pH 6 with aq. at 12 M (500 mL), resulting in the formation of a white suspension. The mixture was concentrated to provide the title compound (mixed with sodium chloride) as a yellow solid (783 g). This was used without further purification.
[00128] 1H RMN (400 MHz, DMSO-d6) δ: 11,82 (s, 1 H), 7,74 (s, 1 H), 6,97 (s, 1 H), 5,19 (s, 2H).[00128] 1H NMR (400 MHz, DMSO-d6) δ: 11.82 (s, 1 H), 7.74 (s, 1 H), 6.97 (s, 1 H), 5.19 (s , 2H).
[00129] LCMS m/z = 152,1 [MH]+ Preparação 4 4,6-Dicloropirazolo[1,5-a]pirazina [00129] LCMS m/z = 152.1 [MH]+ Preparation 4 4,6-Dichloropyrazolo[1,5-a]pyrazine
[00130] Três reações idênticas foram realizadas em paralelo.[00130] Three identical reactions were carried out in parallel.
[00131] Pirazolo[1,5-a]pirazina-4,6(5H,7H)-diona (Preparação 3, 278 g, 1,14 mol) foi adicionado a POCl3 (1,84 kg, 12 mol) a cerca de 25 °C, seguido por PyHCl (131 g, 1,14 mol). A mistura de reação foi aquecida a cerca de 120 °C durante cerca de 16 hrs. A reações foram resfriadas a cerca de 25 °C e concentradas para remover a maior parte do POCl3. Cada resíduo foi diluído com EtOAc (2 L) e os três extratos de EtOAc foram combinados e vertidos em NaH2PO4 aq. a 1 M (7,5 L) a cerca de 25 °C e filtrados através de uma almofada de Celite®. A massa filtrante foi lavada com EtOAc (3 x 2 L) e todos os filtrados foram combinados e separados a partir da fase aquosa. A fase aquosa foi extraída com MTBE (10 L). Os extratos de EtOAc e MTBE combinados foram lavados com salmoura (2 x 5 L), secados (Na2SO4) e concentrados. O resíduo foi purificado por cromatografia e o produto foi triturado com éter de petróleo (300 mL) e filtrado. A massa filtrante foi secada para proporcionar o composto título como um sólido branco (110 g, 22 %).[00131] Pyrazolo[1,5-a]pyrazine-4,6(5H,7H)-dione (Preparation 3, 278 g, 1.14 mol) was added to POCl3 (1.84 kg, 12 mol) at ca. 25 °C, followed by PyHCl (131 g, 1.14 mol). The reaction mixture was heated to about 120°C for about 16 hrs. The reactions were cooled to about 25 °C and concentrated to remove most of the POCl3. Each residue was diluted with EtOAc (2 L) and the three EtOAc extracts were combined and poured into aq. to 1 M (7.5 L) at about 25 °C and filtered through a pad of Celite®. The filter cake was washed with EtOAc (3 x 2 L) and all filtrates were combined and separated from the aqueous phase. The aqueous phase was extracted with MTBE (10 L). The combined EtOAc and MTBE extracts were washed with brine (2 x 5 L), dried (Na2SO4) and concentrated. The residue was purified by chromatography and the product was triturated with petroleum ether (300 ml) and filtered. The filter cake was dried to provide the title compound as a white solid (110 g, 22%).
[00132] 1H RMN (400 MHz, CDCl3) δ: 8,42 (s, 1 H), 8,06 (s, 1 H), 6,93 (s, 1 H).[00132] 1H NMR (400 MHz, CDCl3) δ: 8.42 (s, 1 H), 8.06 (s, 1 H), 6.93 (s, 1 H).
[00133] LCMS m/z = 189,8 [MH]+ (isótopo 37Cl) Preparação 5 1-(1-Metil-1H-pirazol-4-il)etan-1-ona [00133] LCMS m/z = 189.8 [MH]+ (isotope 37Cl) Preparation 5 1-(1-Methyl-1H-pyrazol-4-yl)ethan-1-one
[00134] Duas reações idênticas foram realizadas em paralelo.[00134] Two identical reactions were carried out in parallel.
[00135] A uma mistura de 1-metilpirazol (750 g, 9,16 mol) e anidrido acético (1,7 kg, 16,67 mol) foi adicionado H2SO4 concentrado (75 g, 0,75 mol) a cerca de 20 °C. A mistura de reação foi aquecida a cerca de 150 °C durante cerca de 3 hrs. Depois de resfriar, as duas misturas foram combinadas, vertidas em água gelada (15 L), ajustadas a cerca de pH 10 com 20 % de NaOH aq. e extraídas com DCM (4 x 10 L). Os extratos de DCM combinados foram secados (Na2SO4) e concentrados para proporcionar o composto título como um óleo marrom (1240 g, 72 %).[00135] To a mixture of 1-methylpyrazole (750 g, 9.16 mol) and acetic anhydride (1.7 kg, 16.67 mol) was added concentrated H2SO4 (75 g, 0.75 mol) at about 20 °C. The reaction mixture was heated to about 150°C for about 3 hrs. After cooling, the two mixtures were combined, poured into ice water (15 L), adjusted to about pH 10 with 20% aq. and extracted with DCM (4 x 10 L). The combined DCM extracts were dried (Na2SO4) and concentrated to provide the title compound as a brown oil (1240 g, 72%).
[00136] 1H RMN (400 MHz, CDCl3) δ: 7,86 (s, 1 H), 7,84 (s, 1 H), 3,92 (s, 3 H), 2,40 (s, 3H).[00136] 1H NMR (400 MHz, CDCl3) δ: 7.86 (s, 1 H), 7.84 (s, 1 H), 3.92 (s, 3 H), 2.40 (s, 3H ).
[00137] GCMS m/z = 109,0 [M-CH3]+ Preparação 6 2-Bromo-1-(1-metil-1H-pirazol-4-il)etan-1-ona [00137] GCMS m/z = 109.0 [M-CH3]+ Preparation 6 2-Bromo-1-(1-methyl-1H-pyrazol-4-yl)ethan-1-one
[00138] Duas reações idênticas foram realizadas em paralelo.[00138] Two identical reactions were carried out in parallel.
[00139] A uma solução de 1-(1-metil-1H-pirazol-4-il)etan-1-ona (Preparação 5, 620 g, 5 mol) em DCM (12 L) e etanol (3 L) foi adicionado PiHBr3 (1,6 kg, 5 mol) a cerca de 15 °C. A mistura foi agitada a cerca de 15 °C durante cerca de 18 hrs. As duas misturas de reação foram combinadas, extinguidas com água (10 L), separadas, e a fase aquosa foi extraída com DCM (4 x 10 L). Os extratos de DCM combinados foram secados (Na2SO4) e concentrados para remover cerca de 69 L de solvente. O resíduo foi diluído com éter de petróleo (5 L), agitado a cerca de 15 °C durante cerca de 30 min, e a mistura foi filtrada. O precipitado foi secado para proporcionar o composto título como um sólido amarelo (1,73 kg, 85 %).[00139] A solution of 1-(1-methyl-1H-pyrazol-4-yl)ethan-1-one (Preparation 5, 620 g, 5 mol) in DCM (12 L) and ethanol (3 L) was PiHBr3 (1.6 kg, 5 mol) was added at about 15 °C. The mixture was stirred at about 15°C for about 18 hrs. The two reaction mixtures were combined, quenched with water (10 L), separated, and the aqueous phase was extracted with DCM (4 x 10 L). The combined DCM extracts were dried (Na2SO4) and concentrated to remove about 69 L of solvent. The residue was diluted with petroleum ether (5 L), stirred at about 15 °C for about 30 min, and the mixture was filtered. The precipitate was dried to provide the title compound as a yellow solid (1.73 kg, 85%).
[00140] 1H RMN (400 MHz, CDCl3) δ: 7,97 (s, 1 H), 7,91 (s, 1 H), 4,17 (s, 2 H), 3,93 (s, 3H).[00140] 1H NMR (400 MHz, CDCl3) δ: 7.97 (s, 1 H), 7.91 (s, 1 H), 4.17 (s, 2 H), 3.93 (s, 3H ).
[00141] LCMS m/z = 203,1 [MH]+ (isótopo 79Br) Preparação 7 Dietil 1-(2-(1-metil-1H-pirazol-4-il)-2-oxoetil)-1H-pirazol-3,5- Dicarboxilato [00141] LCMS m/z = 203.1 [MH]+ (isotope 79Br) Preparation 7 Diethyl 1-(2-(1-methyl-1H-pyrazol-4-yl)-2-oxoethyl)-1H-pyrazol- 3,5- Dicarboxylate
[00142] Duas reações foram realizadas em paralelo.[00142] Two reactions were carried out in parallel.
[00143] A uma mistura de 2-bromo-1-(1-metil-1H-pirazol-4-il)etan-1- ona (Preparação 6; 500 g, 2,46 mol) e dietil-1H-pirazol-3,5- dicarboxilato (580 g, 2,73 mol) em DMF (8 L) foi adicionado Cs2CO3 (1050 g, 3,23 mol) a cerca de 20 °C. Depois de cerca de 18 hrs, as duas misturas de reação foram combinadas, diluídas com água (10 L) e extraídas com DCM (3 x 10 L). Os extratos de DCM combinados foram secados (Na2SO4) e concentrados. O resíduo foi purificado por cromatografia para proporcionar o composto título como um sólido amarelo (1,53 kg, 93 %).[00143] To a mixture of 2-bromo-1-(1-methyl-1H-pyrazol-4-yl)ethan-1-one (Preparation 6; 500 g, 2.46 mol) and diethyl-1H-pyrazol- 3,5-dicarboxylate (580 g, 2.73 mol) in DMF (8 L) was added to Cs2CO3 (1050 g, 3.23 mol) at about 20 °C. After about 18 hrs, the two reaction mixtures were combined, diluted with water (10 L) and extracted with DCM (3 x 10 L). The combined DCM extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography to provide the title compound as a yellow solid (1.53 kg, 93%).
[00144] 1H RMN (400 MHz, CDCl3) δ: 7,96 (s, 2 H), 7,46 (s, 1 H), 5,86 (s, 2 H), 4,45 (q, 2 H), 4,32 (q, 2 H), 3,99 (s, 3 H), 1,44 (t, 3 H), 1,36 (t, 3H).[00144] 1H NMR (400 MHz, CDCl3) δ: 7.96 (s, 2 H), 7.46 (s, 1 H), 5.86 (s, 2 H), 4.45 (q, 2 H), 4.32 (q, 2H), 3.99 (s, 3H), 1.44 (t, 3H), 1.36 (t, 3H).
[00145] LCMS m/z = 335,0 [MH]+ Preparação 8 Etil 4-hidróxi-6-(1-metil-1H-pirazol-4-il)pirazolo[1,5-a]pirazina-2- Carboxilato [00145] LCMS m/z = 335.0 [MH]+ Preparation 8 Ethyl 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-Carboxylate
[00146] Três reações idênticas foram realizadas em paralelo.[00146] Three identical reactions were carried out in parallel.
[00147] A uma solução de dietil 1-(2-(1-metil-1H-pirazol-4-il)-2- oxoetil)-1H-pirazol-3,5-dicarboxilato (Preparação 7; 510 g, 1,52 mol) em etanol (6 L) foi adicionado NH4OAc (352 g, 4,57 mol) a cerca de 20 °C. A mistura foi aquecida em uma autoclave a cerca de 130 °C durante cerca de 24 hrs. A misturas de reação foram resfriadas a cerca de 50 °C e foram combinadas e filtradas. O precipitado foi secado para proporcionar o composto título (1090 g, 83 %) como um sólido esbranquiçado.[00147] To a solution of diethyl 1-(2-(1-methyl-1H-pyrazol-4-yl)-2-oxoethyl)-1H-pyrazol-3,5-dicarboxylate (Preparation 7; 510 g, 1. 52 mol) in ethanol (6 L) was added NH4OAc (352 g, 4.57 mol) at about 20°C. The mixture was heated in an autoclave at about 130 °C for about 24 hrs. The reaction mixtures were cooled to about 50 °C and combined and filtered. The precipitate was dried to provide the title compound (1090 g, 83%) as an off-white solid.
[00148] 1H RMN (400 MHz, DMSO-d6) δ: 11,35 (br. s, 1 H), 8,31 (s, 1 H), 8,20 (s, 1 H), 8,05 (s, 1 H), 7,38 (s, 1 H), 4,34 (q, 2 H), 3,89 (s, 3 H), 1,33 (t, 3H).[00148] 1H NMR (400 MHz, DMSO-d6) δ: 11.35 (br. s, 1 H), 8.31 (s, 1 H), 8.20 (s, 1 H), 8.05 (s, 1H), 7.38 (s, 1H), 4.34 (q, 2H), 3.89 (s, 3H), 1.33 (t, 3H).
[00149] LCMS m/z = 288,0 [MH]+ Preparação 9 Ácido 4-hidróxi-6-(1-metil-1H-pirazol-4-il)pirazolo[1,5-a]pirazina-2- carboxílico [00149] LCMS m/z = 288.0 [MH]+ Preparation 9 4-Hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylic acid
[00150] Duas reações idênticas foram realizadas em paralelo.[00150] Two identical reactions were carried out in parallel.
[00151] A uma suspensão de etil 4-hidróxi-6-(1-metil-1H-pirazol-4- il)pirazolo[1,5-a]pirazina-2-carboxilato (Preparação 8, 545 g, 1,9 mol) em MeOH (10 L) foi adicionado NaOH aq. a 1 M (5,75 L) a cerca de 20 °C. Depois de cerca de 30 min, a suspensão tornou-se uma solução clara, e a agitação foi continuada a cerca de 20 °C durante cerca de 18 hrs. As misturas de reação foram ajustadas a cerca de pH 2 com HCl aq. a 12 M (650 mL), combinadas e concentradas para remover a maior parte do MeOH. O resíduo foi filtrado e o precipitado foi secado para proporcionar o composto título como um sólido esbranquiçado (1040 g, 100 %).[00151] To a suspension of ethyl 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate (Preparation 8, 545 g, 1.9 mol) in MeOH (10 L) aq. NaOH was added. to 1 M (5.75 L) at about 20 °C. After about 30 min, the suspension became a clear solution, and stirring was continued at about 20 °C for about 18 hrs. The reaction mixtures were adjusted to about pH 2 with aq. at 12 M (650 mL), combined and concentrated to remove most of the MeOH. The residue was filtered and the precipitate was dried to provide the title compound as an off-white solid (1040 g, 100%).
[00152] 1H RMN (400 MHz, DMSO-d6) δ: 13,25 (br. s, 1 H), 11,67 (s, 1 H), 8,34 (s, 1 H), 8,16 (s, 1 H), 8,06 (s, 1 H), 7,32 (s, 1 H), 3,88 (s, 3H).[00152] 1H NMR (400 MHz, DMSO-d6) δ: 13.25 (br. s, 1 H), 11.67 (s, 1 H), 8.34 (s, 1 H), 8.16 (s, 1H), 8.06 (s, 1H), 7.32 (s, 1H), 3.88 (s, 3H).
[00153] LCMS m/z = 260,0 [MH]+ Preparação 10 6-(1-Metil-1H-pirazol-4-il)pirazolo[1,5-a]pirazin-4-ol [00153] LCMS m/z = 260.0 [MH]+ Preparation 10 6-(1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-ol
[00154] Cinco reações idênticas foram realizadas em paralelo.[00154] Five identical reactions were carried out in parallel.
[00155] Ácido 4-hidróxi-6-(1-metil-1H-pirazol-4-il)pirazolo[1,5- a]pirazina-2-carboxílico (Preparação 9, 85 g, 0,328 mol) foi adicionado em porções em sulfolano pré-aquecido (800 mL) a cerca de 280 °C. As cinco misturas de reação foram agitadas a cerca de 280 °C durante cerca de 2 hrs, resfriadas a cerca de 25 °C e agitadas durante cerca de 18 hrs. As misturas de reação foram combinadas, e a mistura foi purificada por cromatografia eluindo com éter de petróleo-EtOAc (10:1 a 0:1), seguido por DCM-MeOH (10:1) para proporcionar o composto título como um sólido amarelo (490 g, 75 %).[00155] 4-Hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylic acid (Preparation 9, 85 g, 0.328 mol) was added in portions in preheated sulfolane (800 mL) at about 280 °C. The five reaction mixtures were stirred at about 280°C for about 2 hrs, cooled to about 25°C and stirred for about 18 hrs. The reaction mixtures were combined, and the mixture was purified by chromatography eluting with petroleum ether-EtOAc (10:1 to 0:1), followed by DCM-MeOH (10:1) to provide the title compound as a yellow solid. (490 g, 75%).
[00156] 1H RMN (400 MHz, DMSO-d6) δ: 11,45 (s, 1 H), 8,28 (s, 1 H), 8,10 (s, 1 H), 8,04 (s, 1 H), 7,88 (s, 1 H), 6,99 (s, 1 H), 3,88 (s, 3 H).[00156] 1H NMR (400 MHz, DMSO-d6) δ: 11.45 (s, 1 H), 8.28 (s, 1 H), 8.10 (s, 1 H), 8.04 (s , 1 H), 7.88 (s, 1 H), 6.99 (s, 1 H), 3.88 (s, 3 H).
[00157] LCMS m/z = 216,0 [MH]+ Preparação 11 4-Cloro-6-(1-metil-1H-pirazol-4-il)pirazolo[1,5-a]pirazina [00157] LCMS m/z = 216.0 [MH]+ Preparation 11 4-Chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine
[00158] Duas reações idênticas foram realizadas em paralelo.[00158] Two identical reactions were carried out in parallel.
[00159] A uma suspensão de 6-(1-metil-1H-pirazol-4-il)pirazolo[1,5- a]pirazin-4-ol (Preparação 10, 307 g, 1,43 mol) em MeCN (7,5 L) foi adicionado POCl3 (2006 g, 13 mol) a cerca de 25 °C. A mistura foi aquecida a cerca de 85 °C durante cerca de 48 hrs. As misturas de reação foram combinadas e filtradas. O precipitado foi lavado com EtOAc e secado sob vácuo. O precipitado secado foi purificado por cromatografia para proporcionar um sólido amarelo o qual foi dissolvido em DCM (15 L) e lavado com NaHCO3 aq. a 1 M (5 L). O DCM foi concentrado para remover cerca de 13 L de solvente e o resíduo foi diluído com MTBE (2 L) e éter de petróleo (2 L). A mistura foi filtrada e o precipitado foi secado para proporcionar o composto título como um sólido amarelo (385 g, 58 %).[00159] To a suspension of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-ol (Preparation 10, 307 g, 1.43 mol) in MeCN ( 7.5 L) POCl3 (2006 g, 13 mol) was added at about 25 °C. The mixture was heated to about 85°C for about 48 hrs. The reaction mixtures were combined and filtered. The precipitate was washed with EtOAc and dried under vacuum. The dried precipitate was purified by chromatography to provide a yellow solid which was dissolved in DCM (15 L) and washed with aq. at 1 M (5 L). The DCM was concentrated to remove about 13 L of solvent and the residue was diluted with MTBE (2 L) and petroleum ether (2 L). The mixture was filtered and the precipitate was dried to provide the title compound as a yellow solid (385 g, 58%).
[00160] 1H RMN (400 MHz, DMSO-d6) δ: 9,22 (s, 1 H), 8,27 (s, 1 H), 8,21 (s, 1 H), 8,04 (s, 1 H), 7,02 (s, 1 H), 3,88 (s, 3 H).[00160] 1H NMR (400 MHz, DMSO-d6) δ: 9.22 (s, 1 H), 8.27 (s, 1 H), 8.21 (s, 1 H), 8.04 (s , 1 H), 7.02 (s, 1 H), 3.88 (s, 3 H).
[00161] LCMS m/z = 233,8 [MH]+(isótopo 35Cl) Preparação 12 Ácido 1-(4-metoxibenzil)-1H-pirazol-4-carboxílico [00161] LCMS m/z = 233.8 [MH]+(isotope 35Cl) Preparation 12 1-(4-methoxybenzyl)-1H-pyrazol-4-carboxylic acid
[00162] Parte 1: Três reações idênticas foram realizadas em paralelo.[00162] Part 1: Three identical reactions were carried out in parallel.
[00163] A uma solução agitada de etil 1H-pirazol-4-carboxilato (16 g, 110 mmol) em MeCN (160 mL) foram adicionados PMB-Cl (85,8 g, 548 mmol) e K2CO3 (23,7 g, 171 mmol), e a mistura foi aquecida sob refluxo durante cerca de 18 hrs. As três bateladas foram resfriadas, combinadas e filtradas. O filtrado foi concentrado para proporcionar etil 1-(4-metoxibenzil)-1H-pirazol-4-carboxilato como um óleo amarelo que foi usado sem outra purificação.[00163] To a stirred solution of ethyl 1H-pyrazol-4-carboxylate (16 g, 110 mmol) in MeCN (160 mL) were added PMB-Cl (85.8 g, 548 mmol) and K2CO3 (23.7 g , 171 mmol), and the mixture was heated under reflux for about 18 hrs. The three batches were cooled, combined and filtered. The filtrate was concentrated to provide ethyl 1-(4-methoxybenzyl)-1H-pyrazol-4-carboxylate as a yellow oil which was used without further purification.
[00164] Parte 2: Três reações idênticas foram realizadas em paralelo.[00164] Part 2: Three identical reactions were carried out in parallel.
[00165] A uma solução agitada de etil 1-(4-metoxibenzil)-1H-pirazol- 4-carboxilato cru (Parte 1, 50,0 g, 96 mmol) em THF (150 mL) e MeOH (150 mL) foi adicionado uma solução de LiOH (10 g, 238 mmol) em água (75 mL). A mistura foi aquecida a cerca de 60 °C durante cerca de 18 hrs. As três bateladas foram combinadas e evaporadas até a secura. O resíduo foi diluído com água (800 mL) e MeOH (150 mL) e lavado com EtOAc (2 x 500 mL). Os extratos de EtOAc foram descartados, e a solução aquosa foi acidificada a cerca de pH 2 com HCl aq. a 6 M e extraída com EtOAc (2 x 800 mL). Os extratos de EtOAc combinados foram lavados com salmoura (500 mL), secados (Na2SO4) e concentrados para proporcionar o composto título como um sólido branco (33,0 g, 83 % para as duas etapas).[00165] A stirred solution of crude ethyl 1-(4-methoxybenzyl)-1H-pyrazol-4-carboxylate (Part 1, 50.0 g, 96 mmol) in THF (150 mL) and MeOH (150 mL) was A solution of LiOH (10 g, 238 mmol) in water (75 mL) was added. The mixture was heated to about 60°C for about 18 hrs. The three batches were combined and evaporated to dryness. The residue was diluted with water (800 mL) and MeOH (150 mL) and washed with EtOAc (2 x 500 mL). The EtOAc extracts were discarded, and the aqueous solution was acidified to about pH 2 with aq. at 6 M and extracted with EtOAc (2 x 800 mL). The combined EtOAc extracts were washed with brine (500 mL), dried (Na2SO4) and concentrated to provide the title compound as a white solid (33.0 g, 83% for both steps).
[00166] 1H RMN (400 MHz, DMSO-d6) δ: 12,34 (br. s, 1 H), 8,32 (s, 1 H), 7,79 (s, 1 H), 7,23 (m, 2 H), 6,89 (m, 2 H), 5,26 (s, 2 H), 3,72 (s, 3H). Preparação 13 Cloreto de 1-(4-metoxibenzil)-1H-pirazol-4-carbonila [00166] 1H NMR (400 MHz, DMSO-d6) δ: 12.34 (br. s, 1 H), 8.32 (s, 1 H), 7.79 (s, 1 H), 7.23 (m, 2H), 6.89 (m, 2H), 5.26 (s, 2H), 3.72 (s, 3H). Preparation 13 1-(4-methoxybenzyl)-1H-pyrazol-4-carbonyl chloride
[00167] Uma solução de ácido 1-(4-metoxibenzil)-1H-pirazol-4- carboxílico (Preparação 12, 25,0 g, 110 mmol) em SOCl2 (40 mL) foi agitada a cerca de 60 °C durante cerca de 5 hrs. A solução foi concen-trada para proporcionar o composto título como um óleo marrom (27,0 g, 100 %) o qual foi usado sem outra purificação ou caracterização. Preparação 14 N-Metóxi-1-(4-metoxibenzil)-N-metil-1H-pirazol-4-carboxamida [00167] A solution of 1-(4-methoxybenzyl)-1H-pyrazol-4-carboxylic acid (Preparation 12, 25.0 g, 110 mmol) in SOCl2 (40 mL) was stirred at about 60 °C for about 5 hrs. The solution was concentrated to provide the title compound as a brown oil (27.0 g, 100%) which was used without further purification or characterization. Preparation 14 N-Methoxy-1-(4-methoxybenzyl)-N-methyl-1H-pyrazol-4-carboxamide
[00168] A uma solução de cloridrato de N,O-dimetil-hidroxilamina (26,3 g, 269 mmol) e TEA (131,0 g, 1,29 mol) em DCM (200 mL) foi lentamente adicionado uma solução de cloreto de 1-(4-metoxibenzil)- 1H-pirazol-4-carbonila (Preparação 13, 27,0 g, 108 mmol) em DCM (50 mL). Depois que a adição foi concluída, a mistura de reação foi agitada a cerca de 20 °C durante cerca de 5 hrs. A mistura foi diluída com DCM (150 mL) e água (300 mL). Os extratos de DCM combinados foram lavados com salmoura, secados (Na2SO4) e concentrados para proporcionar o composto título (20,0 g, 67 %) como um óleo marrom o qual foi usado sem outra purificação.[00168] To a solution of N,O-dimethylhydroxylamine hydrochloride (26.3 g, 269 mmol) and TEA (131.0 g, 1.29 mol) in DCM (200 mL) was slowly added a solution of 1-(4-methoxybenzyl)-1H-pyrazol-4-carbonyl chloride (Preparation 13, 27.0 g, 108 mmol) in DCM (50 mL). After the addition was complete, the reaction mixture was stirred at about 20 °C for about 5 hrs. The mixture was diluted with DCM (150 mL) and water (300 mL). The combined DCM extracts were washed with brine, dried (Na2SO4) and concentrated to provide the title compound (20.0 g, 67%) as a brown oil which was used without further purification.
[00169] 1H RMN (400MHz, CDCl3) δ: 7,99 (s, 1 H), 7,90 (s, 1 H), 7,22 (d, 2 H), 6,89 (d, 2 H), 5,25 (s, 2 H), 3,81 (s, 3 H), 3,69 (s, 3 H), 3,31 (s, 3H).[00169] 1H NMR (400MHz, CDCl3) δ: 7.99 (s, 1 H), 7.90 (s, 1 H), 7.22 (d, 2 H), 6.89 (d, 2 H ), 5.25 (s, 2H), 3.81 (s, 3H), 3.69 (s, 3H), 3.31 (s, 3H).
[00170] LCMS m/z = 275,0 [MH]+ Preparação 15 1-(1-(4-Metoxibenzil)-1H-pirazol-4-il)etan-1-ona [00170] LCMS m/z = 275.0 [MH]+ Preparation 15 1-(1-(4-Methoxybenzyl)-1H-pyrazol-4-yl)ethan-1-one
[00171] Duas reações idênticas foram realizadas em paralelo.[00171] Two identical reactions were carried out in parallel.
[00172] A uma solução de N-metóxi-1-(4-metoxibenzil)-N-metil-1H- pirazol-4-carboxamida (Preparação 14, 10,0 g, 36,3 mmol) em THF (120 mL) foi adicionado gota a gota brometo de metilmagnésio em éter a 3 M (24,2 mL) a cerca de 0 °C. A mistura de reação foi aquecida a cerca de 25 °C e agitada durante cerca de 5 hrs. A reação foi extinguida pela adição de NH4Cl aq. saturado (100 mL) e extraída com EtOAc (2 x 200 mL). Os extratos de EtOAc combinados foram secados (Na2SO4) e concentrados. Os resíduos concentrados de ambas experiências foram combinados e purificados por cromatografia para proporcionar o composto título (10,0 g, 60 %) como um sólido marrom.[00172] To a solution of N-methoxy-1-(4-methoxybenzyl)-N-methyl-1H-pyrazol-4-carboxamide (Preparation 14, 10.0 g, 36.3 mmol) in THF (120 mL) methylmagnesium bromide in 3M ether (24.2 mL) was added dropwise at about 0°C. The reaction mixture was heated to about 25°C and stirred for about 5 hrs. The reaction was quenched by the addition of aq. NH4Cl. saturated (100 mL) and extracted with EtOAc (2 x 200 mL). The combined EtOAc extracts were dried (Na2SO4) and concentrated. The concentrated residues from both experiments were combined and purified by chromatography to provide the title compound (10.0 g, 60%) as a brown solid.
[00173] 1H RMN (400 MHz, DMSO-d6) δ: 8,47 (s, 1 H), 7,91 (s, 1 H), 7,25 (m, 2 H), 6,90 (m, 2 H), 5,27 (s, 2 H), 3,72 (s, 3 H), 2,34 (s, 3H). LCMS m/z = 231,7 [MH]+ Preparação 16 2-Bromo-1-(1-(4-metoxibenzil)-1H-pirazol-4-il)etan-1-ona [00173] 1H NMR (400 MHz, DMSO-d6) δ: 8.47 (s, 1 H), 7.91 (s, 1 H), 7.25 (m, 2 H), 6.90 (m , 2H), 5.27 (s, 2H), 3.72 (s, 3H), 2.34 (s, 3H). LCMS m/z = 231.7 [MH]+ Preparation 16 2-Bromo-1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)ethan-1-one
[00174] Duas reações idênticas foram realizadas em paralelo.[00174] Two identical reactions were carried out in parallel.
[00175] A uma solução de 1-(1-(4-metoxibenzil)-1H-pirazol-4-il)etan- 1-ona (Preparação 15, 8,0 g, 34,7 mmol) em DCM (96 mL) e EtOH (24 mL) foi adicionado PiHBr3 (13,3 g, 41,7 mmol) a cerca de 20 °C. As misturas de reação foram mantidas a cerca de 25 °C durante cerca de 18 hrs e extinguidas com água (100 mL) antes de ser combinadas e extraídas com EtOAc (2 x 300 mL). Os extratos de EtOAc combinados foram lavados com salmoura, secados (Na2SO4) e concentrados. O resíduo foi purificado por cromatografia para proporcionar um sólido amarelo. Este foi triturado com MTBE (100 mL) para proporcionar o composto título (15,0 g, 70 %) como um sólido amarelo. Uma amostra adicional (5,0 g, 23 %) de produto levemente impuro foi obtida como um sólido amarelo por concentração dos licores de trituração.[00175] To a solution of 1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)ethan-1-one (Preparation 15, 8.0 g, 34.7 mmol) in DCM (96 mL ) and EtOH (24 mL) PiHBr3 (13.3 g, 41.7 mmol) was added at about 20 °C. The reaction mixtures were maintained at about 25°C for about 18 hrs and quenched with water (100 mL) before being combined and extracted with EtOAc (2 x 300 mL). The combined EtOAc extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by chromatography to provide a yellow solid. This was triturated with MTBE (100 mL) to provide the title compound (15.0 g, 70%) as a yellow solid. An additional sample (5.0 g, 23%) of slightly impure product was obtained as a yellow solid by concentration of the trituration liquors.
[00176] 1H RMN (400 MHz, CDCl3) δ: 7,99 (s, 1 H), 7,89 (s, 1 H), 7,23 (m, 2 H), 6,92 (m, 2 H), 6,92 (m, 2 H), 5,25 (s, 2 H), 4,15 (s, 2 H), 3,81 (s, 3H).[00176] 1H NMR (400 MHz, CDCl3) δ: 7.99 (s, 1 H), 7.89 (s, 1 H), 7.23 (m, 2 H), 6.92 (m, 2 H), 6.92 (m, 2H), 5.25 (s, 2H), 4.15 (s, 2H), 3.81 (s, 3H).
[00177] LCMS m/z = 333,0 [MNa]+(isótopo 81Br) Preparação 17 Dimetil 1-(2-(1-(4-metoxibenzil)-1H-pirazol-4-il)-2-oxoetil)-1H- pirazol-3,5-dicarboxilato [00177] LCMS m/z = 333.0 [MNa]+(isotope 81Br) Preparation 17 Dimethyl 1-(2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2-oxoethyl)- 1H- pyrazole-3,5-dicarboxylate
[00178] A uma mistura de dimetil 1H-pirazol-3,5-dicarboxilato (1 g, 5 mmol) e 2-bromo-1-(1-(4-metoxibenzil)-1H-pirazol-4-il)etan-1-ona (Preparação 16, 2,18 g, 7,06 mmol) em DMF (20 mL) foi adicionado Cs2CO3 (2,3 g, 7,06 mmol) a cerca de 20 °C. Depois de cerca de 2 dias, a mistura foi concentrada até a secura. O resíduo foi dissolvido em DCM e lavado uma vez com NH4Cl aq. saturado. O DCM foi concentrado, e o resíduo foi purificado por cromatografia. O produto foi agitado em EtOAc (20 mL) a cerca de 20 °C durante cerca de 18 hrs. O sólido formado foi filtrado e secado para proporcionar o composto título (1,38 g, 60 %).[00178] A mixture of dimethyl 1H-pyrazol-3,5-dicarboxylate (1 g, 5 mmol) and 2-bromo-1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)ethane 1-one (Preparation 16, 2.18 g, 7.06 mmol) in DMF (20 mL) was added Cs2CO3 (2.3 g, 7.06 mmol) at about 20 °C. After about 2 days, the mixture was concentrated to dryness. The residue was dissolved in DCM and washed once with aq. saturated. The DCM was concentrated, and the residue was purified by chromatography. The product was stirred in EtOAc (20 mL) at about 20°C for about 18 hrs. The solid formed was filtered and dried to provide the title compound (1.38 g, 60%).
[00179] 1H RMN (400MHz, CDCl3) δ: 7,96 (s, 1 H), 7,82 (s, 1 H), 7,42 (s, 1 H), 7,24 (d, 2 H), 6,93 (d, 2 H), 5,80 (s, 2 H), 5,27 (s, 2 H), 3,95 (s, 3 H), 3,84 (s, 3 H), 3,83 (s, 3H).[00179] 1H NMR (400MHz, CDCl3) δ: 7.96 (s, 1 H), 7.82 (s, 1 H), 7.42 (s, 1 H), 7.24 (d, 2 H ), 6.93 (d, 2 H), 5.80 (s, 2 H), 5.27 (s, 2 H), 3.95 (s, 3 H), 3.84 (s, 3 H ), 3.83 (s, 3H).
[00180] LCMS m/z = 413,1 [MH]+ Preparação 18 Metil 4-hidróxi-6-(1-(4-metoxibenzil)-1H-pirazol-4-il)pirazolo[1,5- a]pirazina-2-carboxilato e Etil 4-hidróxi-6-(1-(4-metoxibenzil)-1H-pirazol-4-il)pirazolo[1,5- a]pirazina-2-carboxilato [00180] LCMS m/z = 413.1 [MH]+ Preparation 18 Methyl 4-hydroxy-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine -2-carboxylate and Ethyl 4-hydroxy-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazine-2-carboxylate
[00181] Seis reações idênticas foram realizadas em paralelo.[00181] Six identical reactions were carried out in parallel.
[00182] Em cada de seis frasconetes foi adicionado dimetil 1-(2-(1- (4-metoxibenzil)-1H-pirazol-4-il)-2-oxoetil)-1H-pirazol-3,5-dicarboxilato (Preparação 17, 300 mg, 0,73 mmol), NH4OAc (336 mg, 4,37 mmol) e EtOH (6 mL). As misturas foram aquecidas sob irradiação de microondas a cerca de 150 °C durante cerca de 2 hrs, em seguida resfriada a cerca de 20 °C, agitada durante cerca de 1 hr e filtrada. Os sólidos combinados foram secados para proporcionar uma mistura de ambos os compostos título os quais foram usados sem outra purificação na próxima etapa (1,61 g).[00182] In each of six bottles, dimethyl 1-(2-(1- (4-methoxybenzyl)-1H-pyrazol-4-yl)-2-oxoethyl)-1H-pyrazol-3,5-dicarboxylate was added (Preparation 17, 300 mg, 0.73 mmol), NH4OAc (336 mg, 4.37 mmol) and EtOH (6 mL). The mixtures were heated under microwave irradiation at about 150°C for about 2 hrs, then cooled to about 20°C, stirred for about 1 hr and filtered. The combined solids were dried to provide a mixture of both title compounds which were used without further purification in the next step (1.61 g).
[00183] 1H RMN (400 MHz, DMSO-d6) δ: 11,65 (br. s., 1 H), 8,38 (s, 1 H), 8,17 (s, 1 H), 8,07 (s, 1 H), 7,36 (s, 1 H), 7,26 (d, 2 H), 6,93 (d, 2 H), 5,75 (s, 1 H), 5,28 (s, 2 H), 3,86 (s, 3 H), 3,74 (s, 3 H). Este é o me- til éster, o qual foi o principal componente.[00183] 1H NMR (400 MHz, DMSO-d6) δ: 11.65 (br. s., 1 H), 8.38 (s, 1 H), 8.17 (s, 1 H), 8, 07 (s, 1 H), 7.36 (s, 1 H), 7.26 (d, 2 H), 6.93 (d, 2 H), 5.75 (s, 1 H), 5, 28 (s, 2 H), 3.86 (s, 3 H), 3.74 (s, 3 H). This is the methyl ester, which was the main component.
[00184] LCMS m/z = 380,1 [MH]+, 394,1 [MH]+ Preparação 19 Ácido 4-hidróxi-6-(1-(4-metoxibenzil)-1H-pirazol-4-il)pirazolo[1,5- a]pirazina-2-carboxílico [00184] LCMS m/z = 380.1 [MH]+, 394.1 [MH]+ Preparation 19 4-Hydroxy-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazole acid [1,5- a]pyrazine-2-carboxylic acid
[00185] A uma solução da mistura de metil 4-hidróxi-6-(1-(4- metoxibenzil)-1H-pirazol-4-il)pirazolo[1,5-a]pirazina-2-carboxilato e etil 4-hidróxi-6-(1-(4-metoxibenzil)-1H-pirazol-4-il)pirazolo[1,5-a]pirazina-2- carboxilato (Preparação 18, 524 mg, cerca de 1,38 mmol) em MeOH (10 mL) foi adicionado NaOH aq. a 1 M (4,83 mL). A mistura foi mantida a cerca de 20 °C durante cerca de 18 hrs antes de NaOH aq. a 1 M adicional (1,38 mL) ter sido adicionado. A mistura foi mantida a cerca de 20 °C durante cerca de 24 horas adicionais. O MeOH foi evaporado, e o resíduo foi diluído com água (2 mL) e agitado a cerca de 40 °C até que todos os sólidos tenham dissolvido. A solução foi acidificada com HCl aq. a 12 M e agitada a cerca de 0 °C durante cerca de 10 min. O precipitado resultante foi filtrado e o precipitado foi lavado com água. O sólido foi secado sob vácuo para proporcionar o composto título (487 mg, 96 %).[00185] A solution of a mixture of methyl 4-hydroxy-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate and ethyl 4- hydroxy-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate (Preparation 18, 524 mg, about 1.38 mmol) in MeOH (10 mL) aq. NaOH was added. at 1 M (4.83 mL). The mixture was maintained at about 20°C for about 18 hrs before aq. an additional 1 M (1.38 mL) was added. The mixture was maintained at about 20°C for about an additional 24 hours. The MeOH was evaporated, and the residue was diluted with water (2 mL) and stirred at about 40 °C until all solids had dissolved. The solution was acidified with aq. HCl. at 12 M and stirred at about 0°C for about 10 min. The resulting precipitate was filtered and the precipitate was washed with water. The solid was dried under vacuum to provide the title compound (487 mg, 96%).
[00186] 1H RMN (400 MHz, DMSO-d6) δ: 11,65 (s, 1 H), 8,38 (s, 1 H), 8,18 (m, 1 H), 8,10 (s, 1 H), 7,25 - 7,32 (m, 4 H), 6,95 (m, 2 H), 5,28 (s, 2 H), 3,78 (s, 3 H).[00186] 1H NMR (400 MHz, DMSO-d6) δ: 11.65 (s, 1 H), 8.38 (s, 1 H), 8.18 (m, 1 H), 8.10 (s , 1 H), 7.25 - 7.32 (m, 4 H), 6.95 (m, 2 H), 5.28 (s, 2 H), 3.78 (s, 3 H).
[00187] LCMS m/z = 366,0 [MH]+ Preparação 20 6-(1-(4-Metoxibenzil)-1H-pirazol-4-il)38irazol[1,5-a]38irazol-4-ol [00187] LCMS m/z = 366.0 [MH]+ Preparation 20 6-(1-(4-Methoxybenzyl)-1H-pyrazol-4-yl)38irazol[1,5-a]38irazol-4-ol
[00188] Três reações foram realizadas em paralelo.[00188] Three reactions were carried out in parallel.
[00189] Ácido 4-hidróxi-6-(1-(4-metoxibenzil)-1H-pirazol-4-il)39irazol [1,5-a]piazina-2-carboxílico (Preparação 19, 40 mg, 0,11 mmol) foi aquecido a cerca de 350 °C durante cerca de 10 segundos até que o sólido esbranquiçado fundiu e mudou para um líquido marrom escuro.[00189] 4-Hydroxy-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)39irazol [1,5-a]piazine-2-carboxylic acid (Preparation 19, 40 mg, 0.11 mmol) was heated to about 350 °C for about 10 seconds until the off-white solid melted and changed to a dark brown liquid.
[00190] Ácido 4-hidróxi-6-(1-(4-metoxibenzil)-1H-pirazol-4-il)39irazol [1,5-a]pirazina-2-carboxílico (Preparação 19, 120 mg, 0,33 mmol) foi aquecido a cerca de 350 °C durante cerca de 15 segundos até que o sólido esbranquiçado fundiu e mudou para um líquido marrom escuro.[00190] 4-Hydroxy-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)39irazol [1,5-a]pyrazine-2-carboxylic acid (Preparation 19, 120 mg, 0.33 mmol) was heated to about 350 °C for about 15 seconds until the off-white solid melted and changed to a dark brown liquid.
[00191] Ácido 4-hidróxi-6-(1-(4-metoxibenzil)-1H-pirazol-4-il)39irazol [1,5-a]pirazina-2-carboxílico (Preparação 19, 310 mg, 0,85 mmol) foi aquecido a cerca de 350 °C durante cerca de 15 segundos até que o sólido esbranquiçado todos os fundiu e mudou para um líquido marrom escuro.[00191] 4-Hydroxy-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)39irazol [1,5-a]pyrazine-2-carboxylic acid (Preparation 19, 310 mg, 0.85 mmol) was heated to about 350 °C for about 15 seconds until the whitish solid all melted and changed to a dark brown liquid.
[00192] Todas as três bateladas foram resfriadas, combinadas e concentradas duas vezes com tolueno para proporcionar o composto título, o qual foi usado sem purificação adicional na próxima etapa.[00192] All three batches were cooled, combined and concentrated twice with toluene to provide the title compound, which was used without further purification in the next step.
[00193] 1H RMN (400 MHz, DMSO-d6) δ: 11,43 (s, 1 H), 8,37 (s, 1 H), 8,11 (s, 1 H), 8,08 (s, 1 H), 7,88 (d, 1 H), 7,28 (d, 2 H), 6,99 (d, 1 H), 6,94 (d, 2 H), 5,28 (s, 2 H), 3,76 (s, 3 H).[00193] 1H NMR (400 MHz, DMSO-d6) δ: 11.43 (s, 1 H), 8.37 (s, 1 H), 8.11 (s, 1 H), 8.08 (s , 1 H), 7.88 (d, 1 H), 7.28 (d, 2 H), 6.99 (d, 1 H), 6.94 (d, 2 H), 5.28 (s , 2 H), 3.76 (s, 3 H).
[00194] LCMS m/z = 322,1 [MH]+ Preparação 21 4-Cloro-6-(1-(4-metoxibenzil)-1H-pirazol-4-il)pirazolo[1,5-a]pirazina [00194] LCMS m/z = 322.1 [MH]+ Preparation 21 4-Chloro-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine
[00195] 6-(1-(4-Metoxibenzil)-1H-pirazol-4-il)pirazolo[1,5-a]pirazin-4- ol (Preparação 20, 390 mg, 1,21 mmol), PyHCl (143 mg, 1,21 mmol) e POCl3 (10 mL) foram aquecidos a cerca de 120 °C durante cerca de 18 hrs. A mistura foi concentrada, e o resíduo foi tratado com solução de NaH2PO4 aq. para manter cerca de pH 4. A solução resultante foi agitada a cerca de 20 °C durante cerca de 10 min e extraída três vezes com DCM. Os extratos de DCM combinados foram secados e concentrados para proporcionar o composto título como um sólido marrom (300 mg, 72 %).[00195] 6-(1-(4-Methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-ol (Preparation 20, 390 mg, 1.21 mmol), PyHCl ( 143 mg, 1.21 mmol) and POCl3 (10 mL) were heated to about 120 °C for about 18 hrs. The mixture was concentrated, and the residue was treated with aq. to maintain about pH 4. The resulting solution was stirred at about 20°C for about 10 min and extracted three times with DCM. The combined DCM extracts were dried and concentrated to provide the title compound as a brown solid (300 mg, 72%).
[00196] 1H RMN (400 MHz, CDCl3) δ: 8,74 (s, 1 H), 8,50 (s, 1 H), 8,22 (m, 2 H), 7,45 (m, 2 H), 6,92 - 7,02 (m, 3 H), 3,88 (s, 2 H), 2,15 (s, 3 H).[00196] 1H NMR (400 MHz, CDCl3) δ: 8.74 (s, 1 H), 8.50 (s, 1 H), 8.22 (m, 2 H), 7.45 (m, 2 H), 6.92 - 7.02 (m, 3 H), 3.88 (s, 2 H), 2.15 (s, 3 H).
[00197] LCMS m/z = 340,0 [MH]+ Preparação 22[00197] LCMS m/z = 340.0 [MH]+ Preparation 22
[00198] terc-Butil 4-(6-cloropirazolo[1,5-a]pirazin-4-il)-1H-pirazol -1-carboxilato [00198] tert-Butyl 4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazole-1-carboxylate
[00199] Uma solução de 4,6-dicloropirazolo[1,5-a]pirazina (Preparação 4, 700 mg, 3,72 mmol), terc-butil 4-(4,4,5,5-tetrametil-1,3,2- dioxaborolan-2-il)-1H-pirazol-1-carboxilato (1100 mg, 3,72 mmol), K3PO4 aq. a 2 M (3 mL, 6 mmol) em 1,4-dioxano (10,0 mL) foi purgada com argônio durante cerca de 5 min. A isto foi adicionado bis(tri-t- butilfosfina)paládio (0) (96,1 mg, 0,19 mmol), e a reação foi mantida a cerca de 20 °C durante cerca de 18 hrs. O solvente foi concentrado para proporcionar um resíduo ambarino o qual foi apreendido em DCM e purificado por cromatografia para proporcionar o composto título (710 mg, 60 %).[00199] A solution of 4,6-dichloropyrazolo[1,5-a]pyrazine (Preparation 4, 700 mg, 3.72 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-1H-pyrazol-1-carboxylate (1100 mg, 3.72 mmol), K3PO4 aq. 2 M (3 mL, 6 mmol) in 1,4-dioxane (10.0 mL) was purged with argon for about 5 min. To this was added bis(tri-t-butylphosphine)palladium (0) (96.1 mg, 0.19 mmol), and the reaction was maintained at about 20 °C for about 18 hrs. The solvent was concentrated to give an amber residue which was taken up in DCM and purified by chromatography to give the title compound (710 mg, 60%).
[00200] 1H RMN (400 MHz, CDCl3) δ: 8,82 (m, 1 H), 8,44 (m, 3 H), 8,14 (s, 1 H), 1,60 (s, 9H).[00200] 1H NMR (400 MHz, CDCl3) δ: 8.82 (m, 1 H), 8.44 (m, 3 H), 8.14 (s, 1 H), 1.60 (s, 9H ).
[00201] LCMS m/z = 220,1 [MH-BOC]+ Preparação 23 terc-Butil 4-(6-vinilpirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-carboxi lato [00201] LCMS m/z = 220.1 [MH-BOC]+ Preparation 23 tert-Butyl 4-(6-vinylpyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-carboxylate
[00202] Uma solução de terc-butil 4-(6-cloropirazolo[1,5-a]pirazin-4- il)-1H-pirazol-1-carboxilato (Preparação 22, 700 mg, 2,19 mmol) e tri- butil (vinil)estanano (694 mg, 2,19 mmol) em 1,4-dioxano (30 mL) foi purgada com argônio durante cerca de 5 min, seguido pela adição de XPhos Pd G2 (344 mg, 0,44 mmol). A mistura foi aquecida a cerca de 55 °C durante cerca de 18 hrs. A mistura foi concentrada e o resíduo foi purificado por cromatografia para proporcionar o composto título (449 mg, 66 %).[00202] A solution of tert-butyl 4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-carboxylate (Preparation 22, 700 mg, 2.19 mmol) and tri - butyl(vinyl)stannan (694 mg, 2.19 mmol) in 1,4-dioxane (30 mL) was purged with argon for about 5 min, followed by the addition of XPhos Pd G2 (344 mg, 0.44 mmol ). The mixture was heated to about 55°C for about 18 hrs. The mixture was concentrated and the residue was purified by chromatography to provide the title compound (449 mg, 66%).
[00203] 1H RMN (400 MHz, CDCl3) δ: 8,79 (s, 1 H), 8,46 (s, 1 H), 8,26 (s, 1 H), 8,07 (d, 1 H), 6,95 (dd, 1 H), 6,77 (dd, 1 H), 6,43 (dd, 1 H), 5,52 (dd, 1 H), 1,74 (s, 9 H).[00203] 1H NMR (400 MHz, CDCl3) δ: 8.79 (s, 1 H), 8.46 (s, 1 H), 8.26 (s, 1 H), 8.07 (d, 1 H), 6.95 (dd, 1 H), 6.77 (dd, 1 H), 6.43 (dd, 1 H), 5.52 (dd, 1 H), 1.74 (s, 9 H).
[00204] LCMS m/z = 312,3 [MH]+ Preparação 24 terc-Butil 4-(6-formilpirazolo[1,5-a]pirazina-4-il)-1H-pirazol-1- carboxilato [00204] LCMS m/z = 312.3 [MH]+ Preparation 24 tert-Butyl 4-(6-formylpyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-carboxylate
[00205] Uma solução de terc-butil 4-(6-vinilpirazolo[1,5-a]pirazina-4- il)-1H-pirazol-1-carboxilato (Preparação 23; 446 mg, 1,43 mmol) e 2,6- lutidina (767 mg, 7,16 mmol) em 1,4-dioxano (9 mL) e água (3 mL) foi resfriada a cerca de 0 °C, e NaIO4 (1530 mg, 7,16 mmol) e solução de OsO4 aq. A 4 % (0,54 mL) foram adicionados. A mistura foi permitida aquecer a cerca de 20 °C durante cerca de 3 hrs. Os sólidos foram removidos por filtração e lavados com éter. Os 1,4-dioxano e éter combinados foram concentrados, e o resíduo foi purificado por croma- tografia para proporcionar o composto título como um sólido esbran-quiçado (289 mg, 65 %).[00205] A solution of tert-butyl 4-(6-vinylpyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-carboxylate (Preparation 23; 446 mg, 1.43 mmol) and 2 ,6-lutidine (767 mg, 7.16 mmol) in 1,4-dioxane (9 mL) and water (3 mL) was cooled to about 0 °C, and NaIO4 (1530 mg, 7.16 mmol) and aq. OsO4 solution. A 4% (0.54 mL) was added. The mixture was allowed to heat to about 20°C for about 3 hrs. The solids were removed by filtration and washed with ether. The combined 1,4-dioxane and ether were concentrated, and the residue was purified by chromatography to provide the title compound as an off-white solid (289 mg, 65%).
[00206] 1H RMN (400 MHz, CDCl3) δ: 10,20 (s, 1 H), 9,01 (s, 1 H), 8,85 (s, 1 H), 8,50 (s, 1 H), 8,30 (d, 1 H), 7,08 - 7,12 (m, 1 H), 1,73 (s, 9 H).[00206] 1H NMR (400 MHz, CDCl3) δ: 10.20 (s, 1 H), 9.01 (s, 1 H), 8.85 (s, 1 H), 8.50 (s, 1 H), 8.30 (d, 1 H), 7.08 - 7.12 (m, 1 H), 1.73 (s, 9 H).
[00207] LCMS m/z = 314,2 [MH]+ Preparação 25 terc-Butil €-4-(6-((hidroxiimino)metil)pirazina[1,5-a]41pirazina-4-il)- 1H-pirazol-1-carboxilato [00207] LCMS m/z = 314.2 [MH]+ Preparation 25 tert-Butyl €-4-(6-((hydroxyimino)methyl)pyrazine[1,5-a]41pyrazine-4-yl)- 1H- pyrazole-1-carboxylate
[00208] Hidroxilamina HCl (112 mg, 1,58 mmol) foi adicionada a uma mistura de terc-butil 4-(6-formilpirazolo[1,5-a]41irazina-4-il)-1H- pirazol-1-carboxilato (Preparação 24, 450 mg, 1,44 mmol), e Na2CO3 (196 mg, 1,58 mmol) em MeOH (20 mL). A mistura foi mantida a cerca de 20 °C durante cerca de 1,5 hrs. A mistura foi concentrada, água (30 mL) foi adicionada, e a mistura foi agitada durante cerca de 5 min antes do sólido ter sido filtrado e secado para produzir o composto título como um sólido esbranquiçado (325 mg, 69 %).[00208] Hydroxylamine HCl (112 mg, 1.58 mmol) was added to a mixture of tert-butyl 4-(6-formylpyrazolo[1,5-a]41yrazin-4-yl)-1H-pyrazol-1-carboxylate (Preparation 24, 450 mg, 1.44 mmol), and Na2CO3 (196 mg, 1.58 mmol) in MeOH (20 mL). The mixture was maintained at about 20°C for about 1.5 hrs. The mixture was concentrated, water (30 mL) was added, and the mixture was stirred for about 5 min before the solid was filtered and dried to give the title compound as an off-white solid (325 mg, 69%).
[00209] 1H RMN (400 MHz, CDCl3) δ: 10,46 (br. s., 1 H), 9,53 (s, 1 H), 8,81 (s, 1 H), 8,46 (s, 1 H), 8,41 (s, 1 H), 8,19 (d, 1 H), 7,03 (d, 1 H), 1,73 (s, 9 H).[00209] 1H NMR (400 MHz, CDCl3) δ: 10.46 (br. s., 1 H), 9.53 (s, 1 H), 8.81 (s, 1 H), 8.46 ( s, 1 H), 8.41 (s, 1 H), 8.19 (d, 1 H), 7.03 (d, 1 H), 1.73 (s, 9 H).
[00210] LCMS m/z = 329,2 [MH]+ Preparação 26 (3-(4-(1H-Pirazol-4-il)pirazolo[1,5-a]pirazin-6-il)isoxazol-5- il)metanol [00210] LCMS m/z = 329.2 [MH]+ Preparation 26 (3-(4-(1H-Pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)isoxazol-5- il)methanol
[00211] Solução de hipoclorito de sódio (cerca de 12 % a 15 %, 0,19 mL cerca de 3,0 mmol) foi adicionada gota a gota a uma solução de terc-butil (E)-4-(6-((hidroxiimino)metil)pirazolo[1,5-a]pirazin-4-il)-1H- pirazol-1-carboxilato (Preparação 25, 200 mg, 0,61 mmol) e álcool propargílico (171 mg, 3,05 mmol) em DCM (5 mL) a cerca de 0 °C. A mistura foi permitida aquecer a cerca de 20 °C durante cerca de 18 hrs. O sólido resultante foi filtrado para proporcionar o composto título (115 mg, 67 %).[00211] Sodium hypochlorite solution (about 12% to 15%, 0.19 mL about 3.0 mmol) was added dropwise to a solution of tert-butyl (E)-4-(6-( (hydroxyimino)methyl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-carboxylate (Preparation 25, 200 mg, 0.61 mmol) and propargyl alcohol (171 mg, 3.05 mmol ) in DCM (5 mL) at about 0 °C. The mixture was allowed to heat to about 20°C for about 18 hrs. The resulting solid was filtered to provide the title compound (115 mg, 67%).
[00212] 1H RMN (400 MHz, DMSO-d6) δ: 9,14 (s, 1 H), 8,56 (s, 2 H), 8,31 (d, 1 H), 7,50 (d, 1 H), 7,09 (s, 1 H), 4,57 - 4,75 (m, 2 H).[00212] 1H NMR (400 MHz, DMSO-d6) δ: 9.14 (s, 1 H), 8.56 (s, 2 H), 8.31 (d, 1 H), 7.50 (d , 1 H), 7.09 (s, 1 H), 4.57 - 4.75 (m, 2 H).
[00213] LCMS m/z = 283,1 [MH]+ Preparação 27 3-(Cianometileno)ciclobutano-1-carbonitrila [00213] LCMS m/z = 283.1 [MH]+ Preparation 27 3-(Cyanomethylene)cyclobutane-1-carbonitrile
[00214] Uma solução de 3-oxociclobutano-1-carbonitrila* (CAS: 20249 - 16-5, 14,5 g, 152 mmol) em THF (250 mL) foi adicionada a uma mistura de (EtO)2P(O)CH2CN (31,1 g, 175 mmol), LiBr (19,9 g, 229 mmol) e TEA (30,9 g, 305 mmol) em THF (300 mL) a cerca de 25 °C. Depois de cerca de 16 hrs, a mistura foi filtrada e o filtrado foi concentrada. O resíduo foi purificado por cromatografia para proporcionar o composto título como um óleo amarelo leve (16,01 g, 89 %).[00214] A solution of 3-oxocyclobutane-1-carbonitrile* (CAS: 20249 - 16-5, 14.5 g, 152 mmol) in THF (250 mL) was added to a mixture of (EtO)2P(O) CH2CN (31.1 g, 175 mmol), LiBr (19.9 g, 229 mmol) and TEA (30.9 g, 305 mmol) in THF (300 mL) at about 25 °C. After about 16 hrs, the mixture was filtered and the filtrate was concentrated. The residue was purified by chromatography to provide the title compound as a light yellow oil (16.01 g, 89%).
[00215] *Veja Synthetic Communications 2005, 35, 657 - 662.[00215] *See Synthetic Communications 2005, 35, 657 - 662.
[00216] 1H RMN (400 MHz, CD3CN) δ: 5,38 (s, 1 H), 3,30 - 3,43 (m, 2 H), 3,16 - 3,30 (m, 3 H).[00216] 1H NMR (400 MHz, CD3CN) δ: 5.38 (s, 1 H), 3.30 - 3.43 (m, 2 H), 3.16 - 3.30 (m, 3 H) .
[00217] LCMS m/z = 119,1 [MH]+ Exemplo 1 (1s,3s)-3-(Cianometil)-3-(4-(6-(5-(hidroximetil)isoxazol-3-il)pirazolo [1,5-a]pirazin-4-il)-1H-pirazol-1-il)ciclobutano-1-carbonitrila (cis isômero) [00217] LCMS m/z = 119.1 [MH]+ Example 1 (1s,3s)-3-(Cyanomethyl)-3-(4-(6-(5-(hydroxymethyl)isoxazol-3-yl)pyrazole [1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile (cis isomer)
[00218] DBU (89,0 mg, 0,58 mmol) foi adicionado a uma solução de (3-(4-(1H-pirazol-4-il)pirazolo[1,5-a]pirazin-6-il)isoxazol-5-il)metanol (Preparação 26; 55,0 mg, 0,19 mmol) e 3-(cianometileno)ciclobutano- 1-carbonitrila (Preparação 27; 23,0 mg, 0,19 mmol) em MeCN (4 mL). A reação foi purgada com nitrogênio e agitada a cerca de 20 °C durante cerca de 20 hrs. A mistura foi dividida entre EtOAc (5 mL) e NaH2PO4 aq. a 1 M (5 mL). O EtOAc foi separado, secado (Na2SO4) e concentrado. O resíduo foi purificado cromatografia para proporcionar o composto título (5 mg, 6 %).[00218] DBU (89.0 mg, 0.58 mmol) was added to a solution of (3-(4-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl) isoxazol-5-yl)methanol (Preparation 26; 55.0 mg, 0.19 mmol) and 3-(cyanomethylene)cyclobutane-1-carbonitrile (Preparation 27; 23.0 mg, 0.19 mmol) in MeCN (4 mL). The reaction was purged with nitrogen and stirred at about 20 °C for about 20 hrs. The mixture was partitioned between EtOAc (5 mL) and aq. at 1 M (5 mL). The EtOAc was separated, dried (Na2SO4) and concentrated. The residue was purified by chromatography to provide the title compound (5 mg, 6%).
[00219] 1H RMN (400 MHz, DMSO-d6) δ: 9,26 (m, 1 H), 8,92 (m, 1 H), 8,54 (m, 1 H), 8,40 (m, 1 H), 7,52 (m, 1 H), 7,14 (m, 1 H), 5,55 (br s, 1 H), 4,70 (s, 2 H), 3,60 (m, 3 H), 3,42 - 3,45 (m, 2 H), 2,78 - 2,83 (m, 2 H).[00219] 1H NMR (400 MHz, DMSO-d6) δ: 9.26 (m, 1 H), 8.92 (m, 1 H), 8.54 (m, 1 H), 8.40 (m , 1 H), 7.52 (m, 1 H), 7.14 (m, 1 H), 5.55 (br s, 1 H), 4.70 (s, 2 H), 3.60 ( m, 3 H), 3.42 - 3.45 (m, 2 H), 2.78 - 2.83 (m, 2 H).
[00220] LCMS m/z = 401,4 [MH]+ Preparação 28 terc-Butil 3-(cianometil)-3-(4-(4,4,5,5-tetrametil-1,3,2-dioxaborolan- 2-il)-1H-pirazol-1-il)azetidina-1-carboxilato [00220] LCMS m/z = 401.4 [MH]+ Preparation 28 tert-Butyl 3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate
[00221] A uma solução de terc-butil 3-(cianometileno)azetidina-1- carboxilato (CAS 1153949 - 11 - 1, 7,00 g, 36,1 mmol) em MeCN (100 mL) foi adicionado éster de pinacol de ácido 4-pirazolborônico (7,71 g, 39,7 mmol) e DBU (2,75 g, 18,0 mmol) a cerca de 25 °C. Depois de cerca de 18 hrs, a mistura foi concentrada e o resíduo foi purificado cromatografia de coluna para proporcionar o composto título como um sólido branco (11 g, 78 %).[00221] To a solution of tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (CAS 1153949 - 11 - 1, 7.00 g, 36.1 mmol) in MeCN (100 mL) was added pinacol ester of 4-pyrazolboronic acid (7.71 g, 39.7 mmol) and DBU (2.75 g, 18.0 mmol) at about 25 °C. After about 18 hrs, the mixture was concentrated and the residue was purified by column chromatography to provide the title compound as a white solid (11 g, 78%).
[00222] 1H RMN (400 MHz, CDCl3) δ: 7,92 (s, 1 H), 7,86 (s, 1 H), 4,40 (m, 2 H), 4,21 (m, 2 H), 3,52 (s, 2 H), 1,44 (s, 9 H), 1,32 (s, 12 H).[00222] 1H NMR (400 MHz, CDCl3) δ: 7.92 (s, 1 H), 7.86 (s, 1 H), 4.40 (m, 2 H), 4.21 (m, 2 H), 3.52 (s, 2 H), 1.44 (s, 9 H), 1.32 (s, 12 H).
[00223] LC-MS m/z = 333,0 [MH-C4H8]+ Preparação 29 terc-Butil 3-(4-(6-cloropirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)-3- (cianometil)azetidina-1-carboxilato [00223] LC-MS m/z = 333.0 [MH-C4H8]+ Preparation 29 tert-Butyl 3-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazole -1-yl)-3- (cyanomethyl)azetidine-1-carboxylate
[00224] A uma solução de terc-butil 3-(cianometil)-3-(4-(4,4,5,5- tetrametil-1,3,2-dioxaborolan-2-il)-1H-pirazol-1-il)azetidina-1- carboxilato (Preparação 28, 362 mg, 0,93 mmol) e 4,6- dicloropirazolo[1,5-a]pirazina (Preparação 4; 167 mg, 0,89 mmol) em 1,4-dioxano (5 mL) foi adicionado K3PO4 aq. a 2 M (1,40 mL) a cerca de 25 °C. A mistura foi purgada com argônio durante cerca de 2 min e bis(tri-t-butilfosfina)paládio (0) (94,3 mg, 0,184 mmol) foi adicionado. A mistura foi agitada a cerca de 20 °C durante cerca de 2 hrs. A mistura foi diluída com DCM, separada, e a fase aquosa foi extraída duas vezes com DCM. Os extratos de DCM combinados foram secados (Na2SO4) e concentrados. O resíduo foi purificado por cromatografia para proporcionar o composto título como um sólido branco (295 mg, 75 %).[00224] To a solution of tert-butyl 3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1 -yl)azetidine-1-carboxylate (Preparation 28, 362 mg, 0.93 mmol) and 4,6-dichloropyrazolo[1,5-a]pyrazine (Preparation 4; 167 mg, 0.89 mmol) in 1.4 -dioxane (5 mL) was added aq. at 2 M (1.40 mL) at about 25 °C. The mixture was purged with argon for about 2 min and bis(tri-t-butylphosphine)palladium (0) (94.3 mg, 0.184 mmol) was added. The mixture was stirred at about 20°C for about 2 hrs. The mixture was diluted with DCM, separated, and the aqueous phase was extracted twice with DCM. The combined DCM extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography to provide the title compound as a white solid (295 mg, 75%).
[00225] 1H RMN (400 MHz, CDCl3) δ: 8,42 (s, 1 H), 8,41 (s, 1 H), 8,31 (s, 1 H), 8,10 (d, 1 H), 7,02 (d, 1 H), 4,54 (d, 2 H), 4,31 (d, 3 H), 3,33 (s, 2 H), 1,49 (s, 9 H).[00225] 1H NMR (400 MHz, CDCl3) δ: 8.42 (s, 1 H), 8.41 (s, 1 H), 8.31 (s, 1 H), 8.10 (d, 1 H), 7.02 (d, 1 H), 4.54 (d, 2 H), 4.31 (d, 3 H), 3.33 (s, 2 H), 1.49 (s, 9 H).
[00226] LCMS m/z = 358,1 [MH-C4H8]+ Preparação 30 2-(3-(4-(6-Cloropirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)-1- (ciclopropilmetil)azetidin-3-il)acetonitrila [00226] LCMS m/z = 358.1 [MH-C4H8]+ Preparation 30 2-(3-(4-(6-Chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazole-1 -yl)-1- (cyclopropylmethyl)azetidin-3-yl)acetonitrile
[00227] A uma solução de terc-butil 3-(4-(6-cloropirazolo[1,5- a]pirazin-4-il)-1H-pirazol-1-il)-3-(cianometil)azetidina-1-carboxilato (Preparação 29, 0,56 g, 1,35 mmol) em DCM (13,5 mL) foi adicionado TFA (7 mL) a cerca de 25 °C. Depois de cerca de 4 hrs, a mistura foi concentrada até a secura para proporcionar 2-(3-(4-(6- cloropirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)azetidin-3-il)acetonitrila como um sólido amarelo (578 mg, cerca de 100 %) o qual foi usado sem outra purificação.[00227] To a solution of tert-butyl 3-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)azetidine-1 -carboxylate (Preparation 29, 0.56 g, 1.35 mmol) in DCM (13.5 mL) was added TFA (7 mL) at about 25 °C. After about 4 hrs, the mixture was concentrated to dryness to provide 2-(3-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl) azetidin-3-yl)acetonitrile as a yellow solid (578 mg, about 100%) which was used without further purification.
[00228] A uma solução de 2-(3-(4-(6-cloropirazolo[1,5-a]pirazin-4-il)- 1H-pirazol-1-il)azetidin-3-il)acetonitrila (Parte 1, 1,35 mmol) e bromo- metilciclopropano (365 mg, 2,71 mmol) em DMF (13,5 mL) foi adicionado TEA (548 mg, 5,41 mmol) a cerca de 25 °C. A mistura foi aquecida a cerca de 50 °C durante cerca de 14 hrs. A solução resfriada foi diluída com água (20 mL) e extraída com EtOAc (3 x 20 mL). Os extratos de EtOAc combinados foram lavados com salmoura (30 mL), secados (Na2SO4) e concentrados. O resíduo foi purificado por cromato- grafia para proporcionar o composto título como um sólido amarelo (314 mg, 63 %).[00228] To a solution of 2-(3-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)- 1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (Part 1, 1.35 mmol) and bromomethylcyclopropane (365 mg, 2.71 mmol) in DMF (13.5 mL) TEA (548 mg, 5.41 mmol) was added at about 25 °C. The mixture was heated to about 50°C for about 14 hrs. The cooled solution was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined EtOAc extracts were washed with brine (30 mL), dried (Na2SO4) and concentrated. The residue was purified by chromatography to provide the title compound as a yellow solid (314 mg, 63%).
[00229] 1H RMN (400 MHz, CDCl3) δ: 8,39 (s, 1 H), 8,37 (s, 1 H), 8,27 (s, 1 H), 8,08 (d, 1 H), 7,02 (d, 1 H), 3,78 - 3,84 (m, 2 H), 3,59 (d, 2 H), 3,42 (s, 2 H), 2,45 (d, 2 H), 0,77 - 0,87 (m, 1 H), 0,48 - 0,55 (m, 2 H), 0,14 (q, 2 H).[00229] 1H NMR (400 MHz, CDCl3) δ: 8.39 (s, 1 H), 8.37 (s, 1 H), 8.27 (s, 1 H), 8.08 (d, 1 H), 7.02 (d, 1 H), 3.78 - 3.84 (m, 2 H), 3.59 (d, 2 H), 3.42 (s, 2 H), 2.45 (d, 2 H), 0.77 - 0.87 (m, 1 H), 0.48 - 0.55 (m, 2 H), 0.14 (q, 2 H).
[00230] LCMS m/z = 367,9 [MH]+(isótopo 35Cl) Preparação 31 Etil 3-(tributilestanil)-1H-pirazol-5-carboxilato [00230] LCMS m/z = 367.9 [MH]+(isotope 35Cl) Preparation 31 Ethyl 3-(tributylstanyl)-1H-pyrazole-5-carboxylate
[00231] Etiniltributilestanano (50 g, 158 mmol) foi adicionado a uma solução de etildiazoacetato (19,9 g, 175 mmol) em tolueno (500 mL) a cerca de 25 °C. A solução foi aquecida durante cerca de 16 hrs a cerca de 100 °C, em seguida foi concentrada para proporcionar o produto cru como um óleo amarelo (110 g). Este foi combinado com o produto cru de uma reação equivalente realizada com etiniltributilestanano (22 g, 70 mmol) e etildiazoacetato (8,76 g, 77 mmol), e os resíduos combinados foram purificados por cromatografia de coluna em alumina para proporcionar o composto título como um óleo amarelo (42 g, 61 %).[00231] Ethynyltributylstannan (50 g, 158 mmol) was added to a solution of ethyldiazoacetate (19.9 g, 175 mmol) in toluene (500 mL) at about 25 °C. The solution was heated for about 16 hrs at about 100°C, then concentrated to provide the crude product as a yellow oil (110 g). This was combined with the crude product of an equivalent reaction carried out with ethinyltributylstannan (22 g, 70 mmol) and ethyldiazoacetate (8.76 g, 77 mmol), and the combined residues were purified by column chromatography on alumina to provide the title compound. as a yellow oil (42 g, 61 %).
[00232] 1H RMN (400 MHz, CDCl3) δ: 10,28 (br. s., 1 H), 6,84 - 6,99 (m, 1 H), 4,41 (q, 2 H), 1,47 - 1,67 (m, 6 H), 1,41 (t, 3 H), 1,28 - 1,39 (m, 6 H), 1,04 - 1,24 (m, 6 H), 0,90 (t, 9 H).[00232] 1H NMR (400 MHz, CDCl3) δ: 10.28 (br. s., 1 H), 6.84 - 6.99 (m, 1 H), 4.41 (q, 2 H), 1.47 - 1.67 (m, 6 H), 1.41 (t, 3 H), 1.28 - 1.39 (m, 6 H), 1.04 - 1.24 (m, 6 H ), 0.90 (t, 9H).
[00233] LCMS m/z 431,2 [MH]+ (isótopo 120Sn). Preparação 32 (3-(Tributilestanil)-1H-pirazol-5-il)metanol [00233] LCMS m/z 431.2 [MH]+ (isotope 120Sn). Preparation 32 (3-(Tributylstanyl)-1H-pyrazol-5-yl)methanol
[00234] Etil 3-(tributilestanil)-1H-pirazol-5-carboxilato (Preparação 31, 6000 mg, 13,98 mmol) em THF (200 mL) foi adicionado a uma suspensão agitada de hidreto de alumínio de lítio (3108 mg, 83,9 mmol) em THF (200 mL) a cerca de - 10 °C. Depois de cerca de 4 hrs, a mistura foi extinguida com deca-hidrato de Na2SO4 a cerca de - 10 °C até que a efervescência tenha cessado. A mistura foi filtrada, e a massa filtrante foi lavada com THF (500 mL) e DCM (5 x 500 mL). Os filtrados combinados foram concentrados para proporcionar o composto título como um sólido branco (4460 mg, 82 %).[00234] Ethyl 3-(tributylstanyl)-1H-pyrazol-5-carboxylate (Preparation 31, 6000 mg, 13.98 mmol) in THF (200 mL) was added to a stirred suspension of lithium aluminum hydride (3108 mg , 83.9 mmol) in THF (200 mL) at about -10°C. After about 4 hrs, the mixture was quenched with Na2SO4 decahydrate at about -10°C until the effervescence had ceased. The mixture was filtered, and the filter cake was washed with THF (500 mL) and DCM (5 x 500 mL). The combined filtrates were concentrated to provide the title compound as a white solid (4460 mg, 82%).
[00235] 1H RMN (400 MHz, CDCl3) δ: 10,35 (br. s., 1 H), 6,28 - 6,43 (m, 1 H), 4,75 (s, 2 H), 1,49 - 1,60 (m, 6 H), 1,29 - 1,39 (m, 6 H), 1,08 - 1,15 (m, 6 H), 0,87 - 0,93 (m, 9 H).[00235] 1H NMR (400 MHz, CDCl3) δ: 10.35 (br. s., 1 H), 6.28 - 6.43 (m, 1 H), 4.75 (s, 2 H), 1.49 - 1.60 (m, 6 H), 1.29 - 1.39 (m, 6 H), 1.08 - 1.15 (m, 6 H), 0.87 - 0.93 ( m, 9 H).
[00236] LCMS m/z = 388,9 [MH]+(isótopo 120Sn) Exemplo 2 2-(1-(Ciclopropilmetil)-3-(4-(6-(5-(hidroximetil)-1H-pirazol-3- il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)azetidin-3-il)acetonitrila [00236] LCMS m/z = 388.9 [MH]+(isotope 120Sn) Example 2 2-(1-(Cyclopropylmethyl)-3-(4-(6-(5-(hydroxymethyl)-1H-pyrazol-3 - il)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile
[00237] A uma solução de 2-(3-(4-(6-cloropirazolo[1,5-a]pirazin-4-il)- 1H-pirazol-1-il)-1-(ciclopropilmetil)azetidin-3-il)acetonitrila (Preparação 30, 204 mg, 0,55 mmol) e 3-(tributilestanil)-1H-pirazol-5-il)metanol (Preparação 32, 215 mg, 0,55 mmol) foi adicionado XPhos Pd G2 (43,6 mg, 0,055 mmol) em 1,4-dioxano (5,5 mL). A mistura foi aquecida a cerca de 110 °C durante cerca de 4 hrs. A mistura foi evaporada até a secura e o resíduo foi combinado com o resíduo de uma reação equivalente usando 2-(3-(4-(6-cloropirazolo[1,5-a]pirazin-4-il)-1H- pirazol-1-il)-1-(ciclopropilmetil)azetidin-3-il)acetonitrila (Preparação 30, 110 mg, 0,27 mmol) e 3-(tributilestanil)-1H-pirazol-5-il)metanol (Prepa-ração 32, 105 mg, 0,27 mmol). Os resíduos combinados foram purifi-cados por HPLC para proporcionar o composto título (112 mg, 31 %).[00237] To a solution of 2-(3-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)- 1H-pyrazol-1-yl)-1-(cyclopropylmethyl)azetidin-3 -yl)acetonitrile (Preparation 30, 204 mg, 0.55 mmol) and 3-(tributylstanyl)-1H-pyrazol-5-yl)methanol (Preparation 32, 215 mg, 0.55 mmol) were added to XPhos Pd G2 ( 43.6 mg, 0.055 mmol) in 1,4-dioxane (5.5 mL). The mixture was heated to about 110°C for about 4 hrs. The mixture was evaporated to dryness and the residue was combined with the residue from an equivalent reaction using 2-(3-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol- 1-yl)-1-(cyclopropylmethyl)azetidin-3-yl)acetonitrile (Preparation 30, 110 mg, 0.27 mmol) and 3-(tributylstanyl)-1H-pyrazol-5-yl)methanol (Preparation 32 , 105 mg, 0.27 mmol). The combined residues were purified by HPLC to provide the title compound (112 mg, 31%).
[00238] 1H RMN (400 MHz, CDCl3) δ: 8,66 (s, 1 H), 8,64 - 8,69 (m, 1 H), 8,38 (s, 1 H), 8,23 (s, 1 H), 8,06 (d, 1 H), 6,94 (d, 1 H), 6,67 (s, 1 H), 4,80 (s, 2 H), 3,80 (d, 2 H), 3,62 (d, 2 H), 3,41 (s, 2 H), 2,44 (d, 2 H), 0,76 - 0,86 (m, 1 H), 0,46 - 0,53 (m, 2 H), 0,10 - 0,16 (m, 2 H).[00238] 1H NMR (400 MHz, CDCl3) δ: 8.66 (s, 1 H), 8.64 - 8.69 (m, 1 H), 8.38 (s, 1 H), 8.23 (s, 1 H), 8.06 (d, 1 H), 6.94 (d, 1 H), 6.67 (s, 1 H), 4.80 (s, 2 H), 3.80 (d, 2 H), 3.62 (d, 2 H), 3.41 (s, 2 H), 2.44 (d, 2 H), 0.76 - 0.86 (m, 1 H) , 0.46 - 0.53 (m, 2 H), 0.10 - 0.16 (m, 2 H).
[00239] LCMS m/z 430,1 [MH]+ Preparação 33 2-(3-(4-(6-Cloropirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)azetidin-3- il)acetonitrila [00239] LCMS m/z 430.1 [MH]+ Preparation 33 2-(3-(4-(6-Chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl) azetidin-3-yl)acetonitrile
[00240] A uma solução de terc-butil 3-(4-(6-cloropirazolo[1,5- a]pirazin-4-il)-1H-pirazol-1-il)-3-(cianometil)azetidina-1-carboxilato (Preparação 29, 485 mg, 1,17 mmol) em DCM (20 mL) foi adicionado TFA (6 mL) a cerca de 0 °C. A mistura foi agitada a cerca de 25 °C du-rante cerca de 4 hrs. A solução foi concentrada. O resíduo foi ajustado em cerca de pH 9 com NH4OH conc. (cerca de 0,5 mL) e dividido en- tre água (10 mL) e DCM (30 mL). A solução aquosa foi extraída com DCM (3 x 30 mL). Os extratos de DCM combinados foram secados (Na2SO4) e concentrados para proporcionar o composto título como um sólido amarelo (300 mg, 81 %).[00240] To a solution of tert-butyl 3-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)azetidine-1 -carboxylate (Preparation 29, 485 mg, 1.17 mmol) in DCM (20 mL) was added TFA (6 mL) at about 0 °C. The mixture was stirred at about 25°C for about 4 hrs. The solution was concentrated. The residue was adjusted to about pH 9 with conc. NH4OH. (about 0.5 mL) and divided between water (10 mL) and DCM (30 mL). The aqueous solution was extracted with DCM (3 x 30 mL). The combined DCM extracts were dried (Na2SO4) and concentrated to provide the title compound as a yellow solid (300 mg, 81%).
[00241] 1H RMN (400 MHz, CD3OD) δ: 8,91 (s, 1 H), 8,72 (s, 1 H), 8,53 (s, 1 H), 8,20 (d, 1 H), 7,40 (d, 1 H), 4,90 (d, 2 H), 4,66 (d, 2 H), 3,72 (s, 2 H).[00241] 1H NMR (400 MHz, CD3OD) δ: 8.91 (s, 1 H), 8.72 (s, 1 H), 8.53 (s, 1 H), 8.20 (d, 1 H), 7.40 (d, 1 H), 4.90 (d, 2 H), 4.66 (d, 2 H), 3.72 (s, 2 H).
[00242] LCMS m/z 313,9 [MH]+ (isótopo 35Cl) Preparação 34 2-(3-(4-(6-Cloropirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)-1- etilazetidin-3-il)acetonitrila [00242] LCMS m/z 313.9 [MH]+ (35Cl isotope) Preparation 34 2-(3-(4-(6-Chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol- 1-yl)-1-ethilazetidin-3-yl)acetonitrile
[00243] Acetato de sódio (314 mg, 3,82 mmol) e acetaldeído (842 mg, 19,1 mmol) foram adicionados a uma solução de 2-(3-(4-(6- cloropirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)azetidin-3-il)acetonitrila (Preparação 33, 120 mg, 0,38 mmol) em MeOH (6 mL), e a mistura foi agitada durante cerca de 4 hrs. Em seguida, NaBH(OAc)3 (243 mg, 1,15 mmol) foi adicionado, e a mistura foi agitada durante cerca de 16 hrs a mais a cerca de 25 °C. A mistura foi concentrada e o resíduo foi purificado por cromatografia para proporcionar o composto título como um sólido amarelo (115 mg, 88 %).[00243] Sodium acetate (314 mg, 3.82 mmol) and acetaldehyde (842 mg, 19.1 mmol) were added to a solution of 2-(3-(4-(6-chloropyrazolo[1.5-a ]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (Preparation 33, 120 mg, 0.38 mmol) in MeOH (6 mL), and the mixture was stirred for ca. 4 hrs. Then, NaBH(OAc)3 (243 mg, 1.15 mmol) was added, and the mixture was stirred for about 16 hrs more at about 25°C. The mixture was concentrated and the residue was purified by chromatography to provide the title compound as a yellow solid (115 mg, 88%).
[00244] 1H RMN (400 MHz, CDCl3) δ: 8,41 (s, 1 H), 8,39 (s, 1 H), 8,29 (s, 1 H), 8,10 (d, 1 H), 7,04 (d, 1 H), 3,79 (d, 2 H), 3,59 (d, 2 H), 3,43 (s, 2 H), 2,65 (q, 2 H), 1,06 (t, 3 H).[00244] 1H NMR (400 MHz, CDCl3) δ: 8.41 (s, 1 H), 8.39 (s, 1 H), 8.29 (s, 1 H), 8.10 (d, 1 H), 7.04 (d, 1 H), 3.79 (d, 2 H), 3.59 (d, 2 H), 3.43 (s, 2 H), 2.65 (q, 2 H), 1.06 (t, 3 H).
[00245] LCMS m/z = 342,1 [MH]+(isótopo35Cl) Exemplo 3 2-(1-Etil-3-(4-(6-(5-(hidroximetil)-1H-pirazol-3-il)pirazolo[1,5- a]pirazin-4-il)-1H-pirazol-1-il)azetidin-3-il)acetonitrila [00245] LCMS m/z = 342.1 [MH]+(isotope35Cl) Example 3 2-(1-Ethyl-3-(4-(6-(5-(hydroxymethyl)-1H-pyrazol-3-yl) pyrazolo[1,5- a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile
[00246] A uma solução de 2-(3-(4-(6-cloropirazolo[1,5-a]pirazin-4-il)- 1H-pirazol-1-il)-1-etilazetidin-3-il)acetonitrila (Preparação 34, 100 mg, 0,29 mmol) em 1,4-dioxano (5 mL) foi adicionado 3-(tributilestanil)-1H- pirazol-5-il)metanol (Preparação 32, 136 mg, 0,35 mmol) e XPhos Pd G2 (23,0 mg, 0,029 mmol). A mistura foi aquecida a cerca de 110 °C durante cerca de 16 hrs. A mistura foi concentrada e o resíduo foi purificado por cromatografia. O produto também foi purificado por HPLC para proporcionar o composto título como um sólido amarelo (59 mg, 46 %).[00246] To a solution of 2-(3-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)- 1H-pyrazol-1-yl)-1-ethylazetidin-3-yl) Acetonitrile (Preparation 34, 100 mg, 0.29 mmol) in 1,4-dioxane (5 mL) was added 3-(tributylstanyl)-1H-pyrazol-5-yl)methanol (Preparation 32, 136 mg, 0.35 mmol) and XPhos Pd G2 (23.0 mg, 0.029 mmol). The mixture was heated to about 110°C for about 16 hrs. The mixture was concentrated and the residue was purified by chromatography. The product was also purified by HPLC to provide the title compound as a yellow solid (59 mg, 46%).
[00247] 1H RMN (400 MHz, DMSO-d6) δ: 13,21 (s, 0,5 H), 12,93 (s, 0,5 H), 9,23 (s, 0,5 H), 9,07 (s, 1 H), 8,6 - 8,89 (m, 1 H), 8,69 (s, 0,5 H), 8,47 (s, 0,5 H), 8,26 (s, 1 H), 7,47 - 7,53 (m, 1 H), 6. - 9-6,94 (m, 1 H), 5,35 (s, 0,5 H), 5,35 (s, 0,5 H), 4,50 - 4,57 (m, 2 H), 3,68 - 3,71 (m, 2 H), 3,57 - 3,54 (m, 4 H), 3,17 - 3,16 (m, 0,5 H), 2,57 - 2,54 (m, 2 H), 0,96 - 0,93 (m, 3 H). Este espectro foi consistente com a presença de tautômeros distinguíveis.[00247] 1H NMR (400 MHz, DMSO-d6) δ: 13.21 (s, 0.5 H), 12.93 (s, 0.5 H), 9.23 (s, 0.5 H) , 9.07 (s, 1 H), 8.6 - 8.89 (m, 1 H), 8.69 (s, 0.5 H), 8.47 (s, 0.5 H), 8 .26 (s, 1 H), 7.47 - 7.53 (m, 1 H), 6. - 9-6.94 (m, 1 H), 5.35 (s, 0.5 H), 5.35 (s, 0.5 H), 4.50 - 4.57 (m, 2 H), 3.68 - 3.71 (m, 2 H), 3.57 - 3.54 (m, 4 H), 3.17 - 3.16 (m, 0.5 H), 2.57 - 2.54 (m, 2 H), 0.96 - 0.93 (m, 3 H). This spectrum was consistent with the presence of distinguishable tautomers.
[00248] LCMS m/z = 404,3 [MH]+ Preparação 35 2-Ciclobutilidenoacetonitrila [00248] LCMS m/z = 404.3 [MH]+ Preparation 35 2-Cyclobutylideneacetonitrile
[00249] Uma mistura de (EtO)2P(O)CH2CN (4,48 g, 25,2 mmol), LiBr (1,96 g, 22,6 mmol) e TEA (2,28 g, 22,6 mmol) em THF seco (40 mL) foi agitada a cerca de 25 °C durante cerca de 2 hrs. A isto foi adi-cionado uma solução de ciclobutanona (1,58 g, 22,6 mmol) em THF (5 mL) a cerca de 25 °C. Depois de cerca de 16 hrs, a mistura foi concen-trada e o resíduo foi purificado por cromatografia para proporcionar o composto título como um óleo incolor (1,2 g, 57 %).[00249] A mixture of (EtO)2P(O)CH2CN (4.48 g, 25.2 mmol), LiBr (1.96 g, 22.6 mmol) and TEA (2.28 g, 22.6 mmol ) in dry THF (40 mL) was stirred at about 25°C for about 2 hrs. To this was added a solution of cyclobutanone (1.58 g, 22.6 mmol) in THF (5 mL) at about 25 °C. After about 16 hrs, the mixture was concentrated and the residue was purified by chromatography to provide the title compound as a colorless oil (1.2 g, 57%).
[00250] 1H RMN (400 MHz, CDCl3) δ: 5,11 (quin), 2,93 - 3,05 (m), 2,82 - 2,92 (m), 2,04 - 2,17 (m). Preparação 36 2-(1-(4-(4,4,5,5-Tetrametil-1,3,2-dioxaborolan-2-il)-1H-pirazol-1- il)ciclobutil)acetonitrila [00250] 1H NMR (400 MHz, CDCl3) δ: 5.11 (quin), 2.93 - 3.05 (m), 2.82 - 2.92 (m), 2.04 - 2.17 ( m). Preparation 36 2-(1-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrile
[00251] A uma mistura de 2-ciclobutilidenoacetonitrila (Preparação 35, 200 mg, 2,15 mmol) e éster de pinacol de ácido 4-pirazolborônico (458 mg, 2,36 mmol) em MeCN (15 mL) foi adicionado DBU (981 mg, 6,44 mmol). A reação foi agitada a cerca de 25 °C durante cerca de 16 hrs e em seguida aquecida a cerca de 50 °C durante cerca de 24 hrs. A mistura foi concentrada e o resíduo foi purificado por cromatografia para proporcionar o composto título como um óleo incolor (150 mg, 24 %).[00251] To a mixture of 2-cyclobutylideneacetonitrile (Preparation 35, 200 mg, 2.15 mmol) and 4-pyrazolboronic acid pinacol ester (458 mg, 2.36 mmol) in MeCN (15 mL) was added DBU ( 981 mg, 6.44 mmol). The reaction was stirred at about 25°C for about 16 hrs and then heated to about 50°C for about 24 hrs. The mixture was concentrated and the residue was purified by chromatography to provide the title compound as a colorless oil (150 mg, 24%).
[00252] 1H RMN (400 MHz, CDCl3) δ: m 7,89 (s, 1 H), 7,86 (s, 1 H), 3,09 (s, 2 H), 2,68 - 2,80 (m, 2 H), 2,45 - 2,55 (m, 2 H), 2,01 - 2,10 (m, 2 H), 1,33 (s, 12 H).[00252] 1H NMR (400 MHz, CDCl3) δ: m 7.89 (s, 1 H), 7.86 (s, 1 H), 3.09 (s, 2 H), 2.68 - 2, 80 (m, 2 H), 2.45 - 2.55 (m, 2 H), 2.01 - 2.10 (m, 2 H), 1.33 (s, 12 H).
[00253] LCMS m/z = 287,9 [MH]+ Exemplo 4 2-(1-(4-(6-(1-Metil-1H-pirazol-4-il)pirazolo[1,5-a]pirazin-4-il)-1H- pirazol-1-il)ciclobutil)acetonitrila [00253] LCMS m/z = 287.9 [MH]+ Example 4 2-(1-(4-(6-(1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine -4-yl)-1H- pyrazol-1-yl)cyclobutyl)acetonitrile
[00254] A uma mistura de 2-(1-(4-(4,4,5,5-tetrametil-1,3,2- dioxaborolan-2-il)-1H-pirazol-1-il)ciclobutil)acetonitrila (Preparação 36, 129 mg, 0,45 mmol) e 4-cloro-6-(1-metil-1H-pirazol-4-il)pirazolo[1,5- a]pirazina (Preparação 11, 100 mg, 0,43 mmol) em 1,4-dioxano (4,3 mL) foi adicionado K3PO4 aq. a 2 M (0,85 mL) e PdCl2(dppf) (15,7 mg, 0,021 mmol). A mistura foi purgada com nitrogênio durante cerca de 1 min e agitada a cerca de 80 °C durante cerca de 16 hrs. A mistura de reação foi combinada com uma reação equivalente conduzida usando 2-(1-(4-(4,4,5,5-tetrametil-1,3,2-dioxaborolan-2-il)-1H-pirazol-1- il)ciclobutil)acetonitrila (Preparação 36, 20 mg, 0,07 mmol) e 4-cloro-6- (1-metil-1H-pirazol-4-il)pirazolo[1,5-a]pirazina (Preparação 11, 19. mg, 0,083 mmol), K3PO4 aq. a 2 M (0,14 mL) e PdCl2(dppf) (2,5 mg, 0,0035 mmol) em 1,4-dioxano (2 mL). As misturas de reação combinadas foram concentradas e o resíduo foi purificado por cromatografia. O composto também foi purificado por HPLC para proporcionar o composto título como um sólido branco (22 mg, 12 %).[00254] A mixture of 2-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrile (Preparation 36, 129 mg, 0.45 mmol) and 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazine (Preparation 11, 100 mg, 0. 43 mmol) in 1,4-dioxane (4.3 mL) aq. K3PO4 was added. at 2 M (0.85 mL) and PdCl2(dppf) (15.7 mg, 0.021 mmol). The mixture was purged with nitrogen for about 1 min and stirred at about 80 °C for about 16 hrs. The reaction mixture was combined with an equivalent reaction conducted using 2-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1- yl)cyclobutyl)acetonitrile (Preparation 36, 20 mg, 0.07 mmol) and 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (Preparation 11, 19. mg, 0.083 mmol), K3PO4 aq. at 2 M (0.14 mL) and PdCl2(dppf) (2.5 mg, 0.0035 mmol) in 1,4-dioxane (2 mL). The combined reaction mixtures were concentrated and the residue was purified by chromatography. The compound was also purified by HPLC to provide the title compound as a white solid (22 mg, 12%).
[00255] 1H RMN (400 MHz, CD3OD) δ: 8,68 (s, 1 H), 8,63 (s, 1 H), 8,39 (s, 1 H), 8,22 (s, 1 H), 8,07 (d, 1 H), 8,06 (s, 1 H), 7,21 (d, 1 H), 3,97 (s, 3 H), 3,94 - 3,99 (m, 1 H), 3,37 (s, 2 H), 3,35 - 3,39 (m, 1 H), 2,84 - 2,95 (m, 2 H), 2,54 (ddd, 2 H), 2,05 - 2,21 (m, 2 H).[00255] 1H NMR (400 MHz, CD3OD) δ: 8.68 (s, 1 H), 8.63 (s, 1 H), 8.39 (s, 1 H), 8.22 (s, 1 H), 8.07 (d, 1 H), 8.06 (s, 1 H), 7.21 (d, 1 H), 3.97 (s, 3 H), 3.94 - 3.99 (m, 1 H), 3.37 (s, 2 H), 3.35 - 3.39 (m, 1 H), 2.84 - 2.95 (m, 2 H), 2.54 (ddd , 2 H), 2.05 - 2.21 (m, 2 H).
[00256] LCMS m/z = 358,9 [MH]+ Preparação 37 2-((1r,3s)-1-(4-Bromo-1H-pirazol-1-il)-3-metoxiciclobutil) acetonitri- la (trans isômero) 2-((1s,3r)-1-(4-Bromo-1H-pirazol-1-il)-3-metoxiciclobutil) acetonitri- la (cis isômero). [00256] LCMS m/z = 358.9 [MH]+ Preparation 37 2-((1r,3s)-1-(4-Bromo-1H-pyrazol-1-yl)-3-methoxycyclobutyl) acetonitrile ( trans isomer) 2-((1s,3r)-1-(4-Bromo-1H-pyrazol-1-yl)-3-methoxycyclobutyl) acetonitrile (cis isomer).
[00257] DBU (4,25 mL, 28,4 mmol) foi adicionado a uma solução de 2-(3-metoxiciclobutilideno)acetonitrila (Preparação90, 3,50 g, 28,4 mmol) e 4-bromopirazol (4,18 g, 28,4 mmol) em MeCN (80 mL) a cerca de 25 °C. Depois de cerca de 18 hrs, a mistura foi vertida em NaH2PO4 (17,04 g, 142 mmol) em água e as fases foram separadas. A camada aquosa foi extraída duas vezes com EtOAc e os extratos de EtOAc combinados fo-ram concentrados. O 4-bromopirazol em excesso foi removido por cro- matografia eluindo com DCM:THF (100:0 a 95:5). O material também foi purificado por cromatografia eluindo com éter:heptano para proporcionar 2-((1r,3s)-1-(4-bromo-1H-pirazol-1-il)-3-metoxiciclobutil)acetonitrila como um sólido branco (trans isômero, 2,19 g, 28 %)[00257] DBU (4.25 mL, 28.4 mmol) was added to a solution of 2-(3-methoxycyclobutylidene)acetonitrile (Preparation 90, 3.50 g, 28.4 mmol) and 4-bromopyrazole (4.18 g, 28.4 mmol) in MeCN (80 mL) at about 25 °C. After about 18 hrs, the mixture was poured into NaH2PO4 (17.04 g, 142 mmol) in water and the phases were separated. The aqueous layer was extracted twice with EtOAc and the combined EtOAc extracts were concentrated. Excess 4-bromopyrazole was removed by chromatography eluting with DCM:THF (100:0 to 95:5). The material was also purified by chromatography eluting with ether:heptane to provide 2-((1r,3s)-1-(4-bromo-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile as a white solid (trans isomer, 2.19 g, 28 %)
[00258] 1H RMN (400 MHz, CDCl3) δ: 7,62 (s, 1 H), 7,55 (s, 1 H), 3,99 (tt, 1 H), 3,30 (s, 3 H), 3,12 (s, 2 H), 2,96 - 3,04 (m, 2 H), 2,44 - 2,51 (m, 2 H).[00258] 1H NMR (400 MHz, CDCl3) δ: 7.62 (s, 1 H), 7.55 (s, 1 H), 3.99 (tt, 1 H), 3.30 (s, 3 H), 3.12 (s, 2 H), 2.96 - 3.04 (m, 2 H), 2.44 - 2.51 (m, 2 H).
[00259] LCMS m/z = 270,0 [MH]+ (isótopo 79Br) e 2-((1s,3r)-1-(4- bromo-1H-pirazol-1-il)-3-metoxiciclobutil)acetonitrila como um óleo incolor (cis isômero, 5,00 g, 65 %).[00259] LCMS m/z = 270.0 [MH]+ (isotope 79Br) and 2-((1s,3r)-1-(4-bromo-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile as a colorless oil (cis isomer, 5.00 g, 65%).
[00260] 1H RMN (400 MHz, CDCl3) δ: 7,60 (s, 1 H), 7,53 (s, 1 H), 4,00 (quin, 1 H), 3,29 (s, 3 H), 2,99 (s, 2 H), 2,85 - 2,96 (m, 2 H), 2,56 - 2,67 (m, 2 H).[00260] 1H NMR (400 MHz, CDCl3) δ: 7.60 (s, 1 H), 7.53 (s, 1 H), 4.00 (quin, 1 H), 3.29 (s, 3 H), 2.99 (s, 2 H), 2.85 - 2.96 (m, 2 H), 2.56 - 2.67 (m, 2 H).
[00261] LCMS m/z = 270,0 [MH]+ (isótopo 79Br) Preparação 38 2-((1r,3s)-3-Metóxi-1-(4-(4,4,5,5-tetrametil-1,3,2-dioxaborolan-2-il)- 1H-pirazol-1-il)ciclobutil)acetonitrila. [00261] LCMS m/z = 270.0 [MH]+ (isotope 79Br) Preparation 38 2-((1r,3s)-3-Methoxy-1-(4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrile.
[00262] Uma mistura de 2-((1r,3s)-1-(4-bromo-1H-pirazol-1-il)-3- metoxiciclobutil)acetonitrila (Preparação 37, trans isômero, 3399 mg, 12,58 mmol), bis(pinacolato)diboro (3510 mg, 13,8 mmol) e acetato de potássio (3700 mg, 37,7 mmol) em 1,4-dioxano (33 mL) foi purgada com argônio durante cerca de 5 min, seguido pela adição de XPhos Pd G2 (1980 mg, 2,52 mmol) a cerca de 25 °C. A mistura foi aquecida a cerca de 65 °C durante cerca de 4 hrs. A mistura foi concentrada e o resíduo foi purificado por cromatografia para proporcionar um sólido. A este sólido ter sido adicionados EtOAc (10 mL) e heptano (40 mL), e a mistura foi agitada a cerca de 25 °C durante cerca de 30 min. O sólido foi filtrado e secado sob vácuo para proporcionar o composto título como um sólido branco (1,95 g, 49 %).[00262] A mixture of 2-((1r,3s)-1-(4-bromo-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile (Preparation 37, trans isomer, 3399 mg, 12.58 mmol ), bis(pinacolato)diboron (3510 mg, 13.8 mmol) and potassium acetate (3700 mg, 37.7 mmol) in 1,4-dioxane (33 mL) was purged with argon for about 5 min, followed by by adding XPhos Pd G2 (1980 mg, 2.52 mmol) at about 25 °C. The mixture was heated to about 65°C for about 4 hrs. The mixture was concentrated and the residue was purified by chromatography to provide a solid. To this solid were added EtOAc (10 mL) and heptane (40 mL), and the mixture was stirred at about 25°C for about 30 min. The solid was filtered and dried under vacuum to provide the title compound as a white solid (1.95 g, 49%).
[00263] 1H RMN (500 MHz, CDCl3) δ: 7,91 (s, 1 H), 7,87 (s, 1 H), 3,98 (tt, 1 H), 3,28 (s, 3 H), 3,17 (s, 2 H), 2,98 - 3,07 (m, 2 H), 2,45 - 2,53 (m, 2 H), 1,31 (s, 12 H).[00263] 1H NMR (500 MHz, CDCl3) δ: 7.91 (s, 1 H), 7.87 (s, 1 H), 3.98 (tt, 1 H), 3.28 (s, 3 H), 3.17 (s, 2 H), 2.98 - 3.07 (m, 2 H), 2.45 - 2.53 (m, 2 H), 1.31 (s, 12 H) .
[00264] LCMS m/z = 318,0 [MH]+ Preparação 39 2-((1r,3s)-1-(4-(6-Cloropirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)-3- metoxiciclobutil)acetonitrila [00264] LCMS m/z = 318.0 [MH]+ Preparation 39 2-((1r,3s)-1-(4-(6-Chloropyrazolo[1,5-a]pyrazin-4-yl)-1H -pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile
[00265] Uma solução de 2-((1r,3s)-3-metóxi-1-(4-(4,4,5,5-tetrametil- 1,3,2-dioxaborolan-2-il)-1H-pirazol-1-il)ciclobutil)acetonitrila (Preparação 38, 1950 mg, 6,15 mmol), 4,6-dicloropirazolo[1,5-a]pirazina (Preparação 4, 1160 mg, 6,15 mmol) e K3PO4 aq. a 2 M (9,22 mL) em 1,4- dioxano (25 mL) foi purgada com argônio durante cerca de 5 min, seguido pela adição de bis(tri-t-butilfosfina)paládio (0) (157 mg, 0,31 mmol) a cerca de 25 °C. Depois de cerca de 2 hrs, a mistura foi diluída com EtOAc, as fases foram separadas, e a fase aquosa foi extraída duas vezes com DCM. Os extratos de EtOAc e DCM combinados foram secados (Na2SO4) e concentrados para proporcionar um sólido que foi recristalizado a partir de uma mistura quente (cerca de 40 °C) de DCM e heptano para proporcionar o composto título como um sólido esbranquiçado (1,12 g, 53 %). O filtrado foi concentrado e purificado por cromatografia para proporcionar um composto título adicional (1,01 g, 47 %).[00265] A solution of 2-((1r,3s)-3-methoxy-1-(4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H- pyrazol-1-yl)cyclobutyl)acetonitrile (Preparation 38, 1950 mg, 6.15 mmol), 4,6-dichloropyrazolo[1,5-a]pyrazine (Preparation 4, 1160 mg, 6.15 mmol) and aq K3PO4 . at 2 M (9.22 mL) in 1,4-dioxane (25 mL) was purged with argon for about 5 min, followed by the addition of bis(tri-t-butylphosphine)palladium (0) (157 mg, 0 .31 mmol) at about 25 °C. After about 2 hrs, the mixture was diluted with EtOAc, the phases were separated, and the aqueous phase was extracted twice with DCM. The combined EtOAc and DCM extracts were dried (Na2SO4) and concentrated to provide a solid which was recrystallized from a hot (about 40°C) mixture of DCM and heptane to provide the title compound as an off-white solid (1. 12 g, 53%). The filtrate was concentrated and purified by chromatography to provide an additional title compound (1.01 g, 47%).
[00266] 1H RMN (500 MHz, CDCl3) δ: m 8,39 (d, 1 H), 8,38 (s, 1 H), 8,28 (s, 1 H), 8,09 (d, 1 H), 7,03 (dd, 1 H), 4,04 - 4,10 (m, 1 H), 3,33 (s, 3 H), 3,25 (s, 2 H), 3,09 - 3,17 (m, 2 H), 2,53 - 2,61 (m, 2 H).[00266] 1H NMR (500 MHz, CDCl3) δ: m 8.39 (d, 1 H), 8.38 (s, 1 H), 8.28 (s, 1 H), 8.09 (d, 1 H), 7.03 (dd, 1 H), 4.04 - 4.10 (m, 1 H), 3.33 (s, 3 H), 3.25 (s, 2 H), 3, 09 - 3.17 (m, 2 H), 2.53 - 2.61 (m, 2 H).
[00267] LCMS m/z = 343,1 [MH]+ (isótopo 35Cl) Preparação 40 3,5-Dibromo-1-(tetra-hidro-2H-piran-2-il)-1H-pirazol [00267] LCMS m/z = 343.1 [MH]+ (isotope 35Cl) Preparation 40 3,5-Dibromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole
[00268] A uma solução de 3,5-dibromopirazol* (CAS: 67460-86-0, 18,0 g, 79,7 mmol) e DHP (30 mL) foi adicionado CF3COOH (73 mg, 0,64 mmol). A mistura foi aquecida a cerca de 95 °C durante cerca de 12 hrs. A reação foi extinguida com NaOH (96 mg, 2,4 mmol) e em seguida concentrada. O resíduo foi purificado por cromatografia para proporcionar o composto título (11,5 g, 46 %).[00268] To a solution of 3,5-dibromopyrazole* (CAS: 67460-86-0, 18.0 g, 79.7 mmol) and DHP (30 mL) was added CF3COOH (73 mg, 0.64 mmol) . The mixture was heated to about 95°C for about 12 hrs. The reaction was quenched with NaOH (96 mg, 2.4 mmol) and then concentrated. The residue was purified by chromatography to provide the title compound (11.5 g, 46%).
[00269] *Veja: Justus Liebigs Annalen der Chemie 1959, 625, 55 - 65.[00269] *See: Justus Liebigs Annalen der Chemie 1959, 625, 55 - 65.
[00270] 1H RMN (400 MHz, CDCl3) δ: 6,35 (s, 1 H), 5,42 (d, 1 H), 4,05 (m, 1 H), 3,65 (m, 1 H), 2,38 - 2,48 (m, 1 H), 2,11 (m, 1 H), 1,90 (m, 1 H), 1,62 - 1,77 (m, 3H).[00270] 1H NMR (400 MHz, CDCl3) δ: 6.35 (s, 1 H), 5.42 (d, 1 H), 4.05 (m, 1 H), 3.65 (m, 1 H), 2.38 - 2.48 (m, 1 H), 2.11 (m, 1 H), 1.90 (m, 1 H), 1.62 - 1.77 (m, 3H).
[00271] LCMS m/z = 226,7 [MH-THP] + (isótopo 79Br, 81Br) Preparação 41 Ácido 3-bromo-1-(tetra-hidro-2H-piran-2-il)-1H-pirazol-5-carboxílico [00271] LCMS m/z = 226.7 [MH-THP] + (isotope 79Br, 81Br) Preparation 41 3-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol- acid 5-carboxylic
[00272] n-BuLi (2,5 M, 15,8 mL, 39,5 mmol) foi adicionado gota a gota a uma solução de 3,5-dibromo-1-(tetra-hidro-2H-piran-2-il)-1H- pirazol (Preparação 40, 9,4 g, 30,0 mmol) em THF (87 mL) a cerca de -78 °C. A mistura foi mantida a cerca de -78 °C durante cerca de 2 hrs. Uma solução de CO2 (preparada por borbulhamento de CO2 em THF anidroso (100 mL) durante 20 min a cerca de -70 °C e agitação a essa temperatura durante cerca de 1,5 hrs) foi adicionada gota a gota, ao mesmo tempo que mantendo a temperatura de reação interna abaixo de cerca de -65 °C. A mistura foi em seguida agitada a cerca de -70 °C durante cerca de 1 hr. A mistura foi ajustada a cerca de pH 4 com HCl aq. a 1 M a cerca de 0 °C e foi extraída com EtOAc (3 x 100 mL). Os extratos de EtOAc combinados foram lavados com salmoura (2 x 50 mL), secados (Na2SO4) e concentrados. O resíduo foi purificado por cromatografia para proporcionar o composto título como um sólido amarelo (5,0 g, 60 %).[00272] n-BuLi (2.5 M, 15.8 mL, 39.5 mmol) was added dropwise to a solution of 3,5-dibromo-1-(tetrahydro-2H-pyran-2- il)-1H-pyrazole (Preparation 40, 9.4 g, 30.0 mmol) in THF (87 mL) at about -78 °C. The mixture was maintained at about -78°C for about 2 hrs. A CO2 solution (prepared by bubbling CO2 in anhydrous THF (100 mL) for 20 min at about -70 °C and stirring at that temperature for about 1.5 hrs) was added dropwise, while keeping the internal reaction temperature below about -65 °C. The mixture was then stirred at about -70°C for about 1 hr. The mixture was adjusted to about pH 4 with aq. at 1 M at about 0°C and extracted with EtOAc (3 x 100 mL). The combined EtOAc extracts were washed with brine (2 x 50 mL), dried (Na2SO4) and concentrated. The residue was purified by chromatography to provide the title compound as a yellow solid (5.0 g, 60%).
[00273] 1H RMN (400 MHz, DMSO-d6) δ: 6,99 (s, 1 H), 6,17 (dd, 1 H), 3,90 (d, 1 H), 3,49 - 3,66 (m, 2 H), 2,12 - 2,28 (m, 1 H), 1,91 - 2,04 (m, 1 H), 1,83 - 1,92 (m, 1 H), 1,58 - 1,70 (m, 1 H), 1,45 - 1,57 (m, 2 H). Preparação 42 terc-Butil (3-bromo-1-(tetra-hidro-2H-piran-2-il)-1H-pirazol-5- il)carbamato [00273] 1H NMR (400 MHz, DMSO-d6) δ: 6.99 (s, 1 H), 6.17 (dd, 1 H), 3.90 (d, 1 H), 3.49 - 3 .66 (m, 2 H), 2.12 - 2.28 (m, 1 H), 1.91 - 2.04 (m, 1 H), 1.83 - 1.92 (m, 1 H) , 1.58 - 1.70 (m, 1 H), 1.45 - 1.57 (m, 2 H). Preparation 42 tert-Butyl (3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)carbamate
[00274] Difenilfosforil azida (10 g, 36,4 mmol) foi adicionada a uma solução de ácido 3-bromo-1-(tetra-hidro-2H-piran-2-il)-1H-pirazol-5- carboxílico (Preparação 41, 5 g, 18,17 mmol) e DIPEA (6,4 mL, 37,0 mmol) em t-butanol (60,6 mL). A mistura foi aquecida a cerca de 45 °C durante cerca de 30 min, e em seguida aquecida sob refluxo durante cerca de 5 hrs. A mistura foi diluída com EtOAc (300 mL) e lavada com NaHCO3 aq. saturado (3 x 100 mL), salmoura (2 x 100 mL), secada (Na2SO4) e concentrada. O resíduo foi purificado por cromatografia para proporcionar o composto título como um óleo amarelo leve (3,36 g, 53 %).[00274] Diphenylphosphoryl azide (10 g, 36.4 mmol) was added to a solution of 3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-carboxylic acid (Preparation 41.5 g, 18.17 mmol) and DIPEA (6.4 mL, 37.0 mmol) in t-butanol (60.6 mL). The mixture was heated to about 45°C for about 30 min, and then heated under reflux for about 5 hrs. The mixture was diluted with EtOAc (300 mL) and washed with aq. saturated (3 x 100 mL), brine (2 x 100 mL), dried (Na2SO4) and concentrated. The residue was purified by chromatography to provide the title compound as a light yellow oil (3.36 g, 53%).
[00275] 1H RMN (400 MHz, DMSO-d6) δ: 9,64 (br. s., 1 H), 6,26 (s, 1 H), 5,44 (dd, 1 H), 3,84 (d, 1 H), 3,55 - 3,70 (m, 1 H), 2,08 - 2,20 (m, 1 H), 1,91 - 2,00 (m, 1 H), 1,75 (dd, 1 H), 1,54 - 1,64 (m, 1 H), 1,48 - 1,53 (m, 2 H), 1,46 (s, 9 H).[00275] 1H NMR (400 MHz, DMSO-d6) δ: 9.64 (br. s., 1 H), 6.26 (s, 1 H), 5.44 (dd, 1 H), 3, 84 (d, 1 H), 3.55 - 3.70 (m, 1 H), 2.08 - 2.20 (m, 1 H), 1.91 - 2.00 (m, 1 H), 1.75 (dd, 1 H), 1.54 - 1.64 (m, 1 H), 1.48 - 1.53 (m, 2 H), 1.46 (s, 9 H).
[00276] LCMS m/z = 367,9 [MNa]+(isótopo 79Br) Preparação 43 3-Bromo-1-(tetra-hidro-2H-piran-2-il)-5-(diBoc)-amino-1H-pirazol [00276] LCMS m/z = 367.9 [MNa]+(isotope 79Br) Preparation 43 3-Bromo-1-(tetrahydro-2H-pyran-2-yl)-5-(diBoc)-amino-1H -pyrazole
[00277] DMAP (27 mg, 0,22 mmol) foi adicionado a uma solução de terc-butil (3-bromo-1-(tetra-hidro-2H-piran-2-il)-1H-pirazol-5- il)carbamato (Preparação 42, 390 mg, 1,13 mmol), di-terc-butil dicar-bonato (492 mg, 2,25 mmol) e TEA (0,47 mL, 3,38 mmol) em DCM (4 mL) a cerca de 20 °C. Depois de cerca de 18 hrs, a mistura foi concen-trada, e o resíduo foi purificado por cromatografia para proporcionar o composto título (450 mg, 89 %)[00277] DMAP (27 mg, 0.22 mmol) was added to a solution of tert-butyl (3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl )carbamate (Preparation 42, 390 mg, 1.13 mmol), di-tert-butyl dicarbonate (492 mg, 2.25 mmol) and TEA (0.47 mL, 3.38 mmol) in DCM (4 mL ) at around 20°C. After about 18 hrs, the mixture was concentrated, and the residue was purified by chromatography to provide the title compound (450 mg, 89%)
[00278] 1H RMN (400 MHz, CDCl3) δ: 6,42 (s, 1 H), 5,15 (m, 1 H), 4,02 (m, 1 H), 3,60 (m, 1 H), 2,40 (m, 1 H), 2,15 (m, 1 H), 1,88 (m, 1 H), 1,58 - 1,76 (m, 3 H), 1,48 (s, 18 H).[00278] 1H NMR (400 MHz, CDCl3) δ: 6.42 (s, 1 H), 5.15 (m, 1 H), 4.02 (m, 1 H), 3.60 (m, 1 H), 2.40 (m, 1 H), 2.15 (m, 1 H), 1.88 (m, 1 H), 1.58 - 1.76 (m, 3 H), 1.48 (s, 18 H).
[00279] LCMS m/z = 467,9 [MNa]+(isótopo 79Br) Preparação 44 2-((1r,3s)-1-(4-(6-(5-(DiBoc)-amino-1-(tetra-hidro-2H-piran-2-il)- pirazol-3-il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)-3- metoxiciclobutil)acetonitrila [00279] LCMS m/z = 467.9 [MNa]+(isotope 79Br) Preparation 44 2-((1r,3s)-1-(4-(6-(5-(DiBoc)-amino-1-( tetrahydro-2H-pyran-2-yl)-pyrazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile
[00280] Uma mistura de KOAc (110 mg, 1,06 mmol), bis(pinacolato)diboro (164 mg, 0,64 mmol), 3-bromo-1-(tetra-hidro-2H- piran-2-il)-5-(diBoc)-amino-1H-pirazol (Preparação 43,191 mg, 0,43 mmol) e XPhos Pd G2 (55 mg, 0,07 mmol) em 1,4-dioxano (3,5 mL) foi aquecida a cerca de 65 °C durante cerca de 3,5 hrs. A mistura foi res-friada a cerca de 25 °C e 2-((1r,3s)-1-(4-(6-cloropirazolo[1,5-a]pirazin- 4-il)-1H-pirazol-1-il)-3-metóxi-ciclobutil)acetonitrila (Preparação 39, 68 mg, 0,20 mmol) foi adicionado, e a mistura foi purgada com nitrogênio antes de K3PO4 aq. a 2 M (0,53 mL, 1,06 mmol) e XPhos Pd G2 (55 mg, 0,07 mmol) ter sido adicionados. A mistura foi aquecida a cerca de 80 °C durante cerca de 3 hrs. A reação foi extinguida com salmoura e extraída com EtOAc. O extrato de EtOAc foi concentrado, e o resíduo foi purificado por cromatografia para proporcionar o composto título como um sólido amarelo (91 mg, 32 %).[00280] A mixture of KOAc (110 mg, 1.06 mmol), bis(pinacolato)diboron (164 mg, 0.64 mmol), 3-bromo-1-(tetrahydro-2H-pyran-2-yl )-5-(diBoc)-amino-1H-pyrazole (Preparation 43.191 mg, 0.43 mmol) and XPhos Pd G2 (55 mg, 0.07 mmol) in 1,4-dioxane (3.5 mL) was heated at about 65°C for about 3.5 hrs. The mixture was cooled to about 25 °C and 2-((1r,3s)-1-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazole-1 -yl)-3-methoxy-cyclobutyl)acetonitrile (Preparation 39, 68 mg, 0.20 mmol) was added, and the mixture was purged with nitrogen before aq. at 2 M (0.53 mL, 1.06 mmol) and XPhos Pd G2 (55 mg, 0.07 mmol) were added. The mixture was heated to about 80°C for about 3 hrs. The reaction was quenched with brine and extracted with EtOAc. The EtOAc extract was concentrated, and the residue was purified by chromatography to provide the title compound as a yellow solid (91 mg, 32%).
[00281] 1H RMN (400 MHz, CDCl3) δ: 9,08 (s, 1 H), 8,39 (s, 1 H), 8,33 (s, 1 H), 8,09 (d, 1 H), 6,97 (d, 1 H), 6,90 (s, 1 H), 5,26 (dd, 1 H), 4,02 - 4,11 (m, 2 H), 3,64 (t, 1 H), 3,34 (s, 3 H), 3,25 (s, 2 H), 3,12 - 3,20 (m, 2 H), 2,55 - 2,62 (m, 2 H), 2,17 - 2,25 (m, 1 H), 1,93 (dd, 1 H), 1,58 - 1,82 (m, 4 H), 1,45 (s, 18 H).[00281] 1H NMR (400 MHz, CDCl3) δ: 9.08 (s, 1 H), 8.39 (s, 1 H), 8.33 (s, 1 H), 8.09 (d, 1 H), 6.97 (d, 1 H), 6.90 (s, 1 H), 5.26 (dd, 1 H), 4.02 - 4.11 (m, 2 H), 3.64 (t, 1 H), 3.34 (s, 3 H), 3.25 (s, 2 H), 3.12 - 3.20 (m, 2 H), 2.55 - 2.62 (m , 2 H), 2.17 - 2.25 (m, 1 H), 1.93 (dd, 1 H), 1.58 - 1.82 (m, 4 H), 1.45 (s, 18 H).
[00282] LCMS m/z = 674,5 [MH]+ Preparação 45 2-((1r,3s)-1-(4-(6-(5-Amino-1H-pirazol-3-il)pirazolo[1,5-a]pirazin-4- il)-1H-pirazol-1-il)-3-metoxiciclobutil)acetonitrila [00282] LCMS m/z = 674.5 [MH]+ Preparation 45 2-((1r,3s)-1-(4-(6-(5-Amino-1H-pyrazol-3-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile
[00283] TFA (2 mL) foi adicionado a 2-((1r,3s)-1-(4-(6-(5-(diBoc)- amino-1-(tetra-hidro-2H-piran-2-il)-pirazol-3-il)pirazolo[1,5-a]pirazin-4- il)-1H-pirazol-1-il)-3-metoxiciclobutil)-acetonitrila (Preparação 44, 91 mg, 0,13 mmol) em DCM anidroso (1 mL) a cerca de 20 °C. Depois de cerca de 1 hr, a mistura foi concentrada. DCM foi adicionado, seguido por NaHCO3 aq. saturado até que a solução pH tornou-se básica. As fases foram separadas, e a fase aquosa foi extraída duas vezes com DCM. Os extratos de DCM combinados foram secados (Na2SO4), con-centrados, e o resíduo foi purificado por cromatografia para proporcionar o composto título (50 mg, 95 %).[00283] TFA (2 mL) was added to 2-((1r,3s)-1-(4-(6-(5-(diBoc)-amino-1-(tetrahydro-2H-pyran-2- yl)-pyrazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)-acetonitrile (Preparation 44, 91 mg, 0.13 mmol ) in anhydrous DCM (1 mL) at about 20 °C. After about 1 hr, the mixture was concentrated. DCM was added, followed by aq. saturated until the pH solution became basic. The phases were separated, and the aqueous phase was extracted twice with DCM. The combined DCM extracts were dried (Na2SO4), concentrated, and the residue was purified by chromatography to provide the title compound (50 mg, 95%).
[00284] 1H RMN (400 MHz, CDCl3) δ: 8,53 (s, 1 H), 8,40 (s, 1 H), 8,25 (s, 1 H), 8,06 (s, 1 H), 6,96 (br. s., 1 H), 6,01 (br. s., 1 H), 4,33 (br. s., 1 H), 4,05 (m, 1 H), 3,31 (s, 3 H), 3,25 (s, 2 H), 3,11 (dd, 2 H), 2,55 (dd, 2 H).[00284] 1H NMR (400 MHz, CDCl3) δ: 8.53 (s, 1 H), 8.40 (s, 1 H), 8.25 (s, 1 H), 8.06 (s, 1 H), 6.96 (br. s., 1 H), 6.01 (br. s., 1 H), 4.33 (br. s., 1 H), 4.05 (m, 1 H ), 3.31 (s, 3 H), 3.25 (s, 2 H), 3.11 (dd, 2 H), 2.55 (dd, 2 H).
[00285] LCMS m/z = 390,3 [MH]+ Exemplo 5 N-(3-(4-(1-((1r,3s)-1-(Cianometil)-3-metoxiciclobutil)-1H-pirazol-4- il)pirazolo[1,5-a]pirazin-6-il)-1H-pirazol-5-il)acetamida [00285] LCMS m/z = 390.3 [MH]+ Example 5 N-(3-(4-(1-((1r,3s)-1-(Cyanomethyl)-3-methoxycyclobutyl)-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-5-yl)acetamide
[00286] 2-((1r,3s)-1-(4-(6-(5-Amino-1H-pirazol-3-il)pirazolo[1,5- a]pirazin-4-il)-1H-pirazol-1-il)-3-metóxi-ciclobutil)acetonitrila (Prepara ção 45, 39 mg, 0,1 mmol) foi colocado em um tubo de reação, o qual foi em seguida evacuado e recarregado três vezes com nitrogênio. A isto foi adicionado DCM anidroso (1 mL). O tubo foi resfriado a cerca de 0 °C antes de N-metilmorfolina (11 mg, 0,11 mmol) e cloreto de acetila (8,6 mg, 0,11 mmol) ter sido adicionados. A mistura foi permitida aquecer a cerca de 25 °C durante cerca de 18 hrs. A mistura foi concentrada e o resíduo foi dissolvido em MeOH (2 mL). K2CO3 (30 mg, 0,22 mmol) foi adicionado a cerca de 0 °C. Depois de cerca de 3 hrs, a mistura foi filtrada através de Celite®. O filtrado foi concentrado e o resíduo foi purificado por cromatografia para proporcionar o com- posto título (30 mg, 63 %).[00286] 2-((1r,3s)-1-(4-(6-(5-Amino-1H-pyrazol-3-yl)pyrazolo[1,5- a]pyrazin-4-yl)-1H- pyrazol-1-yl)-3-methoxy-cyclobutyl)acetonitrile (Preparation 45, 39 mg, 0.1 mmol) was placed in a reaction tube, which was then evacuated and recharged three times with nitrogen. To this was added anhydrous DCM (1 mL). The tube was cooled to about 0 °C before N-methylmorpholine (11 mg, 0.11 mmol) and acetyl chloride (8.6 mg, 0.11 mmol) were added. The mixture was allowed to heat to about 25°C for about 18 hrs. The mixture was concentrated and the residue was dissolved in MeOH (2 ml). K2CO3 (30 mg, 0.22 mmol) was added at about 0 °C. After about 3 hrs, the mixture was filtered through Celite®. The filtrate was concentrated and the residue was purified by chromatography to provide the title compound (30 mg, 63%).
[00287] 1H RMN (400 MHz, CD3OD) δ: 8,80 (s, 1 H), 8,75 (s, 1 H), 8,40 (s, 1 H), 8,09 (d, 1 H), 7,23 (d, 1 H), 6,88 (s, 1 H), 4,02 - 4,12 (m, 1 H), 3,81 (s, 3 H), 3,34 (s, 2 H), 3,15 - 3,24 (m, 2 H), 2,48 - 2,59 (m, 2 H), 2,21 (s, 3 H).[00287] 1H NMR (400 MHz, CD3OD) δ: 8.80 (s, 1 H), 8.75 (s, 1 H), 8.40 (s, 1 H), 8.09 (d, 1 H), 7.23 (d, 1 H), 6.88 (s, 1 H), 4.02 - 4.12 (m, 1 H), 3.81 (s, 3 H), 3.34 (s, 2 H), 3.15 - 3.24 (m, 2 H), 2.48 - 2.59 (m, 2 H), 2.21 (s, 3 H).
[00288] LCMS m/z = 432,2 [MH]+ Preparação 46 Etil 5-(4-(1-((1r,3s)-1-(cianometil)-3-metoxiciclobutil)-1H-pirazol-4- il)pirazolo[1,5-a]pirazin-6-il)-1H-pirazol-3-carboxilato [00288] LCMS m/z = 432.2 [MH]+ Preparation 46 Ethyl 5-(4-(1-((1r,3s)-1-(cyanomethyl)-3-methoxycyclobutyl)-1H-pyrazol-4- il)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-3-carboxylate
[00289] Uma solução de 2-((1r,3s)-1-(4-(6-cloropirazolo[1,5- a]pirazin-4-il)-1H-pirazol-1-il)-3-metoxiciclobutil)acetonitrila (Prepara-ção 39, 200 mg, 0,58 mmol) e etil 3-(tributilestanil)-1H-pirazol-5- carboxilato (Preparação 31, 300 mg, 0,70 mmol) em 1,4-dioxano (5,8 mL) foi purgada com nitrogênio e XPhos Pd G2 (45,9 mg, 0,058 mmol) adicionado a cerca de 25 °C. A reação foi aquecida a cerca de 80 °C durante cerca de 16 hrs. A mistura resfriada foi purificada por croma- tografia para proporcionar o composto título como um sólido amarelo (220 mg, 84 %).[00289] A solution of 2-((1r,3s)-1-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl )acetonitrile (Preparation 39, 200 mg, 0.58 mmol) and ethyl 3-(tributylstanyl)-1H-pyrazol-5-carboxylate (Preparation 31, 300 mg, 0.70 mmol) in 1,4-dioxane ( 5.8 mL) was purged with nitrogen and XPhos Pd G2 (45.9 mg, 0.058 mmol) added at about 25 °C. The reaction was heated to about 80°C for about 16 hrs. The cooled mixture was purified by chromatography to provide the title compound as a yellow solid (220 mg, 84%).
[00290] 1H RMN (400 MHz, DMSO-d6) δ: 14,09 (s, 1 H), 9,39 (s, 1 H), 9,10 (s, 1 H), 8,72 (s, 1 H), 8,30 (d, 1 H), 7,59 (d, 1 H), 7,53 (d, 1 H), 4,33 (q, 2 H), 4,01 (dd, 1 H), 3,44 (s, 3 H), 3,22 (s, 2 H), 3,14 - 3,20 (m, 2 H), 2,43 - 2,48 (m, 2 H), 1,34 (t, 3 H).[00290] 1H NMR (400 MHz, DMSO-d6) δ: 14.09 (s, 1 H), 9.39 (s, 1 H), 9.10 (s, 1 H), 8.72 (s , 1 H), 8.30 (d, 1 H), 7.59 (d, 1 H), 7.53 (d, 1 H), 4.33 (q, 2 H), 4.01 (dd , 1 H), 3.44 (s, 3 H), 3.22 (s, 2 H), 3.14 - 3.20 (m, 2 H), 2.43 - 2.48 (m, 2 H), 1.34 (t, 3 H).
[00291] LCMS m/z = 447,2 [MH]+ Exemplo 6 5-(4-(1-((1r,3s)-1-(Cianometil)-3-metoxiciclobutil)-1H-pirazol-4- il)pirazolo[1,5-a]pirazin-6-il)-N-metil-1H-pirazol-3-carboxamida [00291] LCMS m/z = 447.2 [MH]+ Example 6 5-(4-(1-((1r,3s)-1-(Cyanomethyl)-3-methoxycyclobutyl)-1H-pyrazol-4-yl )pyrazolo[1,5-a]pyrazin-6-yl)-N-methyl-1H-pyrazol-3-carboxamide
[00292] Uma solução de etil 5-(4-(1-((1r,3s)-1-(cianometil)-3- metoxiciclobutil)-1H-pirazol-4-il)pirazolo[1,5-a]pirazin-6-il)-1H-pirazol-3- carboxilato (Preparação 46, 100 mg, 0,22 mmol) em 30 % de MeNH2 em solução de EtOH (35 mL) foi vedado em um tubo de micro-ondas a cerca de 20 °C. Depois de cerca de 16 hrs, a mistura foi concentrada e o resíduo foi purificado por HPLC para proporcionar o composto título como um sólido branco (62 mg, 58 %).[00292] A solution of ethyl 5-(4-(1-((1r,3s)-1-(cyanomethyl)-3-methoxycyclobutyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin -6-yl)-1H-pyrazol-3-carboxylate (Preparation 46, 100 mg, 0.22 mmol) in 30% MeNH2 in EtOH solution (35 mL) was sealed in a microwave tube at ca. 20°C. After about 16 hrs, the mixture was concentrated and the residue was purified by HPLC to provide the title compound as a white solid (62 mg, 58%).
[00293] 1H RMN (400 MHz, CD3OD) δ: 9,00 (s, 1 H), 8,91 (s, 1 H), 8,57 (s, 1 H), 8,18 (s, 1 H), 7,37 (br. s., 1 H), 7,26 (s, 1 H), 4,61 (s, 1 H), 4,04 - 4,15 (m, 1 H), 3,37 (s, 3 H), 3,33 (s, 2 H), 3,18 - 3,26 (m, 2 H), 2,95 (s, 3 H), 2,56 (dd, 2 H).[00293] 1H NMR (400 MHz, CD3OD) δ: 9.00 (s, 1 H), 8.91 (s, 1 H), 8.57 (s, 1 H), 8.18 (s, 1 H), 7.37 (br. s., 1 H), 7.26 (s, 1 H), 4.61 (s, 1 H), 4.04 - 4.15 (m, 1 H), 3.37 (s, 3 H), 3.33 (s, 2 H), 3.18 - 3.26 (m, 2 H), 2.95 (s, 3 H), 2.56 (dd, 2H).
[00294] LCMS m/z = 432,1 [M+H]+ Preparação 47 terc-Butil 3-(cianometil)-3-(4-(6-(1-metil-1H-pirazol-4-il)pirazolo[1,5- a]pirazin-4-il)-1H-pirazol-1-il)azetidina-1-carboxilato [00294] LCMS m/z = 432.1 [M+H]+ Preparation 47 tert-Butyl 3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazole [1,5- a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate
[00295] A um frasconete foram adicionados 4-cloro-6-(1-metil-1H- pirazol-4-il)pirazolo[1,5-a]pirazina (Preparação 11, 150 mg), terc-butil 3-(cianometil)-3-(4-(4,4,5,5-tetrametil-1,3,2-dioxaborolan-2-il)-1H- pirazol-1-il)azetidina-1-carboxilato (Preparação 28, 374 mg, 0,96 mmol), Na2CO3 aq. a 2 M (0,96 mL) e 1,4-dioxano (4 mL). A mistura foi purgada com argônio durante cerca de 5 min, seguido pela adição de PdCl2 (dppf) (93,7 mg, 0,13 mmol). A mistura foi aquecida a cerca de 120 °C durante cerca de 1 hr sob irradiação de micro-ondas. A mistura foi diluída com EtOAc, lavada com água, secada (Na2SO4) e concentrada. O resíduo foi purificado por cromatografia para proporcionar o composto título como um sólido amarelo (233 mg, 79 %).[00295] To a vial were added 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (Preparation 11, 150 mg), tert-butyl 3-( cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (Preparation 28, 374 mg, 0.96 mmol), aq. Na2CO3. at 2 M (0.96 mL) and 1,4-dioxane (4 mL). The mixture was purged with argon for about 5 min, followed by the addition of PdCl2 (dppf) (93.7 mg, 0.13 mmol). The mixture was heated to about 120°C for about 1 hr under microwave irradiation. The mixture was diluted with EtOAc, washed with water, dried (Na2SO4) and concentrated. The residue was purified by chromatography to provide the title compound as a yellow solid (233 mg, 79%).
[00296] 1H RMN (400 MHz, DMSO-d6) δ: 9,03 (s, 1 H), 8,95 (s, 1 H), 8,53 (s, 1 H), 8,37 (s, 1 H), 8,20 (d, 1 H), 8,16 (s, 1 H), 7,46 (s, 1 H), 4,54 (d, 2 H), 4,25 (d, 3 H), 3,91 (s, 3 H), 3,67 (s, 2 H), 1,42 (s, 9 H).[00296] 1H NMR (400 MHz, DMSO-d6) δ: 9.03 (s, 1 H), 8.95 (s, 1 H), 8.53 (s, 1 H), 8.37 (s , 1 H), 8.20 (d, 1 H), 8.16 (s, 1 H), 7.46 (s, 1 H), 4.54 (d, 2 H), 4.25 (d , 3 H), 3.91 (s, 3 H), 3.67 (s, 2 H), 1.42 (s, 9 H).
[00297] LCMS m/z = 460,2 [MH]+ Preparação 48 2-(3-(4-(6-(1-Metil-1H-pirazol-4-il)pirazolo[1,5-a]pirazin-4-il)-1H- pirazol-1-il)azetidin-3-il)acetonitrila [00297] LCMS m/z = 460.2 [MH]+ Preparation 48 2-(3-(4-(6-(1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin -4-yl)-1H- pyrazol-1-yl)azetidin-3-yl)acetonitrile
[00298] TFA (1 mL) foi adicionado a terc-butil 3-(cianometil)-3-(4-(6- (1-metil-1H-pirazol-4-il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1- il)azetidina-1-carboxilato (Preparação 47, 233 mg, 0,51 mmol) em DCM (5 mL) a cerca de 25 °C. Depois de cerca de 90 min, a mistura foi concentrada. O resíduo foi concentrado duas vezes com tolueno, em seguida secado sob vácuo. O resíduo foi dissolvido em MeOH e passado através de um leito de resina de carbonato suportada por po-límero. A solução eluída foi concentrada para proporcionar o composto título (200 mg, cerca de 100 %) o qual foi usado sem outra purificação.[00298] TFA (1 mL) was added to tert-butyl 3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin -4-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (Preparation 47, 233 mg, 0.51 mmol) in DCM (5 mL) at about 25 °C. After about 90 min, the mixture was concentrated. The residue was concentrated twice with toluene, then dried under vacuum. The residue was dissolved in MeOH and passed through a bed of polymer-supported carbonate resin. The eluted solution was concentrated to provide the title compound (200 mg, about 100%) which was used without further purification.
[00299] 1H RMN (400 MHz, DMSO-d6) δ: 9,12 (s, 1 H), 9,06 (s, 1 H), 8,58 (s, 1 H), 8,39 (s, 1 H), 8,22 (d, 1 H), 8,17 (s, 1 H), 7,50 (d, 1 H), 4,68 - 4,77 (m, 2 H), 4,35 - 4,40 (m, 2 H), 3,93 (s, 2 H), 3,91 (s, 3 H).[00299] 1H NMR (400 MHz, DMSO-d6) δ: 9.12 (s, 1 H), 9.06 (s, 1 H), 8.58 (s, 1 H), 8.39 (s , 1 H), 8.22 (d, 1 H), 8.17 (s, 1 H), 7.50 (d, 1 H), 4.68 - 4.77 (m, 2 H), 4 .35 - 4.40 (m, 2 H), 3.93 (s, 2 H), 3.91 (s, 3 H).
[00300] LCMS m/z = 360,5 [MH]+ Exemplo 7 2,2'-(3-(4-(6-(1-Metil-1H-pirazol-4-il)pirazolo[1,5-a]pirazin-4-il)-1H- pirazol-1-il)azetidina-1,3-diil)diacetonitrila [00300] LCMS m/z = 360.5 [MH]+ Example 7 2,2'-(3-(4-(6-(1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidine-1,3-diyl)diacetonitrile
[00301] DIPEA (132 μL, 0,76 mmol) foi adicionado a uma solução de 2-(3-(4-(6-(1-metil-1H-pirazol-4-il)pirazolo[1,5-a]pirazin-4-il)-1H- pirazol-1-il)azetidin-3-il)acetonitrila (Preparação 48, 91 mg, 0,25 mmol) em DMF (2 mL). Bromoacetonitrila (36 mg, 0,30 mmol) foi adicionado a cerca de 25 °C. Depois de cerca de 18 hrs, a reação foi extinguida com NH4OH conc. e agitada a cerca de 25 °C durante cerca de 10 min. A mistura foi concentrada e o resíduo foi diluído com DCM. O DCM foi lavado duas vezes com NH4Cl aq. saturado, em seguida duas vezes com Na2CO3 aq. saturada. O DCM foi secado (Na2SO4) e concentrado. O resíduo foi purificado por cromatografia para proporcionar o composto título como um sólido esbranquiçado (68 mg, 68 %).[00301] DIPEA (132 μL, 0.76 mmol) was added to a solution of 2-(3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a ]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (Preparation 48, 91 mg, 0.25 mmol) in DMF (2 mL). Bromoacetonitrile (36 mg, 0.30 mmol) was added at about 25 °C. After about 18 hrs, the reaction was quenched with conc. NH4OH. and stirred at about 25°C for about 10 min. The mixture was concentrated and the residue was diluted with DCM. The DCM was washed twice with aq. saturated, then twice with aq. Na2CO3. saturated. The DCM was dried (Na2SO4) and concentrated. The residue was purified by chromatography to provide the title compound as an off-white solid (68 mg, 68%).
[00302] 1H RMN (400 MHz, CD3OD) δ: 8,77 (s, 1 H), 8,74 (s, 1 H), 8,45 (s, 1 H), 8,25 (s, 1 H), 8,08 - 8,10 (m, 2 H), 7,25 (d, 1 H), 4,01 (d, 2 H), 3,98 (s, 3 H), 3,86 (d, 2 H), 3,78 (s, 2 H), 3,54 (s, 2 H).[00302] 1H NMR (400 MHz, CD3OD) δ: 8.77 (s, 1 H), 8.74 (s, 1 H), 8.45 (s, 1 H), 8.25 (s, 1 H), 8.08 - 8.10 (m, 2 H), 7.25 (d, 1 H), 4.01 (d, 2 H), 3.98 (s, 3 H), 3.86 (d, 2H), 3.78 (s, 2H), 3.54 (s, 2H).
[00303] LCMS m/z = 399,3 [MH]+ Exemplo 8 2-(3-(4-(6-(1-Metil-1H-pirazol-4-il)pirazolo[1,5-a]pirazin-4-il)-1H- pirazol-1-il)-1-(metilsulfonil)azetidin-3-il)acetonitrila [00303] LCMS m/z = 399.3 [MH]+ Example 8 2-(3-(4-(6-(1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin -4-yl)-1H- pyrazol-1-yl)-1-(methylsulfonyl)azetidin-3-yl)acetonitrile
[00304] A uma solução de 2-(3-(4-(6-(1-metil-1H-pirazol-4- il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)azetidin-3-il)acetonitrila (Preparação 48, 120 mg, 0,27 mmol) e TEA (331 mg, 3,27 mmol) em DCM (20 mL) foi adicionado cloreto de metanossulfonil (313 mg, 2,73 mmol) a cerca de 0 °C. A mistura foi em seguida agitada a cerca de 10 °C durante cerca de 1 hr antes de ser concentrada. O resíduo foi puri-ficado usando HPLC para proporcionar o composto título como um sólido branco (39 mg, 33 %).[00304] To a solution of 2-(3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol- methanesulfonyl chloride (313 mg, 2 .73 mmol) at about 0 °C. The mixture was then stirred at about 10°C for about 1 hr before being concentrated. The residue was purified using HPLC to provide the title compound as a white solid (39 mg, 33%).
[00305] 1H RMN (400 MHz, DMSO-d6) δ: 9,05 (s, 1 H), 8,99 (s, 1 H), 8,57 (s, 1 H), 8,37 (s, 1 H), 8,21 (d, 1 H), 8,17 (s, 1 H), 7,47 (d, 1 H), 4,65 (d, 2 H), 4,30 (d, 2 H), 3,91 (s, 3 H), 3,70 (s, 2 H), 3,14 (s, 3 H).[00305] 1H NMR (400 MHz, DMSO-d6) δ: 9.05 (s, 1 H), 8.99 (s, 1 H), 8.57 (s, 1 H), 8.37 (s , 1 H), 8.21 (d, 1 H), 8.17 (s, 1 H), 7.47 (d, 1 H), 4.65 (d, 2 H), 4.30 (d , 2 H), 3.91 (s, 3 H), 3.70 (s, 2 H), 3.14 (s, 3 H).
[00306] LCMS m/z = 437,9 [MH]+ Exemplo 9 2-(1-(Ciclopropilsulfonil)-3-(4-(6-(1-metil-1H-pirazol-4- il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)azetidin-3-il)acetonitrila [00306] LCMS m/z = 437.9 [MH]+ Example 9 2-(1-(Cyclopropylsulfonyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile
[00307] A uma mistura de 2-(3-(4-(6-(1-metil-1H-pirazol-4- il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)azetidin-3-il)acetonitrila (Preparação 48, 100 mg, 0,25 mmol) em DCM (10 mL) foram adicio-nados TEA (153 mg, 1,52 mmol) e cloreto de ciclopropanossulfonila (107 mg, 0,76 mmol) a cerca de 0 °C. A mistura foi agitada a cerca de 20 °C durante cerca de 16 hrs, em seguida concentrada. O resíduo foi purificado por HPLC para proporcionar o composto título como um sólido branco (60 mg, 46 %).[00307] A mixture of 2-(3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol- 1-yl)azetidin-3-yl)acetonitrile (Preparation 48, 100 mg, 0.25 mmol) in DCM (10 mL) were added TEA (153 mg, 1.52 mmol) and cyclopropanesulfonyl chloride (107 mg , 0.76 mmol) at about 0 °C. The mixture was stirred at about 20°C for about 16 hrs, then concentrated. The residue was purified by HPLC to provide the title compound as a white solid (60 mg, 46%).
[00308] 1H RMN (400 MHz, DMSO-d6) δ: 9,05 (s, 1 H), 9,00 (s, 1 H), 8,57 (s, 1 H), 8,37 (s, 1 H), 8,21 (d, 1 H), 8,16 (s, 1 H), 7,46 (d, 1 H), 4,69 (d, 2 H), 4,32 (d, 2 H), 3,91 (s, 3 H), 3,70 (s, 2 H), 2,85 (m, 1 H), 0,96 - 1,09 (m, 4 H).[00308] 1H NMR (400 MHz, DMSO-d6) δ: 9.05 (s, 1 H), 9.00 (s, 1 H), 8.57 (s, 1 H), 8.37 (s , 1 H), 8.21 (d, 1 H), 8.16 (s, 1 H), 7.46 (d, 1 H), 4.69 (d, 2 H), 4.32 (d , 2 H), 3.91 (s, 3 H), 3.70 (s, 2 H), 2.85 (m, 1 H), 0.96 - 1.09 (m, 4 H).
[00309] LCMS m/z = 464,0 [MH]+ Exemplo 10 2-(3-(4-(6-(1-Metil-1H-pirazol-4-il)pirazolo[1,5-a]pirazin-4-il)-1H- pirazol-1-il)-1-propionilazetidin-3-il)acetonitrila [00309] LCMS m/z = 464.0 [MH]+ Example 10 2-(3-(4-(6-(1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin -4-yl)-1H- pyrazol-1-yl)-1-propionylazetidin-3-yl)acetonitrile
[00310] A uma solução de 2-(3-(4-(6-(1-metil-1H-pirazol-4- il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)azetidin-3-il)acetonitrila (Preparação 48, 90 mg, 0,23 mmol) em DCM (5 mL) foram adicionados TEA (69 mg, 0,68 mmol) e anidrido propiônico (59 mg, 0,45 mmol). A reação foi agitada a cerca de 20 °C durante cerca de 30 min, em seguida concentrada, e o resíduo foi purificado por HPLC para proporcionar o composto título como um sólido branco (28 mg, 30 %).[00310] To a solution of 2-(3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol- 1-yl)azetidin-3-yl)acetonitrile (Preparation 48, 90 mg, 0.23 mmol) into DCM (5 mL) were added TEA (69 mg, 0.68 mmol) and propionic anhydride (59 mg, 0. 45 mmol). The reaction was stirred at about 20°C for about 30 min, then concentrated, and the residue was purified by HPLC to provide the title compound as a white solid (28 mg, 30%).
[00311] 1H RMN (400 MHz, DMSO-d6) δ: 9,05 (s, 1 H), 8,97 (s, 1 H), 8,55 (s, 1 H), 8,37 (s, 1 H), 8,21 (d, 1 H), 8,16 (s, 1 H), 7,46 (d, 1 H), 4,80 (d, 1 H), 4,52 (dd, 2 H), 4,23 (d, 1 H), 3,91 (s, 3 H), 3,70 (s, 2 H), 2,16 (q, 2 H), 0,99 (t, 3 H).[00311] 1H NMR (400 MHz, DMSO-d6) δ: 9.05 (s, 1 H), 8.97 (s, 1 H), 8.55 (s, 1 H), 8.37 (s , 1 H), 8.21 (d, 1 H), 8.16 (s, 1 H), 7.46 (d, 1 H), 4.80 (d, 1 H), 4.52 (dd , 2 H), 4.23 (d, 1 H), 3.91 (s, 3 H), 3.70 (s, 2 H), 2.16 (q, 2 H), 0.99 (t , 3 H).
[00312] LCMS m/z 416,0 [MH]+ Preparação 49 2-(3-(Benzilóxi)ciclobutilideno)acetonitrila [00312] LCMS m/z 416.0 [MH]+ Preparation 49 2-(3-(Benzyloxy)cyclobutylidene)acetonitrile
[00313] LiBr (0,270 g, 3,12 mmol) foi colocado sob vácuo, em seguida recarregado com nitrogênio e THF (28 mL) foi adicionado, seguido por (EtO)2POCH2CN (0,53 mL, 3,12 mmol) e TEA (0,79 mL, 5,67 mmol). A solução resultante foi agitada a cerca de 20 °C durante cerca de 45 min, em seguida uma solução de 3-(benzilóxi)ciclobutanona (500 mg, 2,84 mmol) em THF seco (3 mL) foi adicionada. Depois de cerca de 5 hrs, a mistura foi vertida em EtOAc (100 mL), e o EtOAc foi lavado três vezes com NH4Cl aq. saturado (3 x 50 mL) e com salmoura (25 mL). O extrato de EtOAc foi secado (MgSO4) e concentrado. O resíduo foi cromatografado para proporcionar o composto título (480 mg, 85 %).[00313] LiBr (0.270 g, 3.12 mmol) was placed under vacuum, then recharged with nitrogen and THF (28 mL) was added, followed by (EtO)2POCH2CN (0.53 mL, 3.12 mmol) and TEA (0.79 mL, 5.67 mmol). The resulting solution was stirred at about 20°C for about 45 min, then a solution of 3-(benzyloxy)cyclobutanone (500 mg, 2.84 mmol) in dry THF (3 mL) was added. After about 5 hrs, the mixture was poured into EtOAc (100 mL), and the EtOAc was washed three times with aq. saturated (3 x 50 mL) and with brine (25 mL). The EtOAc extract was dried (MgSO4) and concentrated. The residue was chromatographed to provide the title compound (480 mg, 85%).
[00314] 1H RMN (400 MHz, CDCl3) δ: 7,29 - 7,43 (m, 5 H), 5,24 (quin, 1 H), 4,45 - 4,53 (m, 2 H), 4,19 (quin, 1 H), 3,18 - 3,29 (m, 1 H), 3,03 - 3,13 (m, 1 H), 2,86 - 3,00 (m, 2 H). Preparação 50 2-(3-Hidroxiciclobutil)acetonitrila [00314] 1H NMR (400 MHz, CDCl3) δ: 7.29 - 7.43 (m, 5 H), 5.24 (quin, 1 H), 4.45 - 4.53 (m, 2 H) , 4.19 (quin, 1 H), 3.18 - 3.29 (m, 1 H), 3.03 - 3.13 (m, 1 H), 2.86 - 3.00 (m, 2 H). Preparation 50 2-(3-Hydroxycyclobutyl)acetonitrile
[00315] Hidróxido de paládio sobre carbono (20 % de Pd, umidade, 430 mg) foi adicionado a uma solução de 2-(3- (benzilóxi)ciclobutilideno)acetonitrila (Preparação 49, 430 mg, 2,16 mmol) em THF (6,5 mL). A mistura foi pressurizada sob hidrogênio (7,03 kg/cm2 (100 psi)) em um reator de aço e agitada a cerca de 20 °C durante cerca de 1 hr. Hidróxido de paládio sobre carbono adicional (20 % de Pd, umidade, 430 mg) foi adicionado, e a mistura foi repres- surizada sob hidrogênio (100 psi) e agitada durante cerca de 1,5 hrs a mais. A mistura foi diluída com EtOAc, filtrada através de Celite®, e o filtrado foi concentrado para proporcionar o composto título como um óleo incolor (240 mg, 100 %) como uma mistura de cis e trans isôme- ros.[00315] Palladium hydroxide on carbon (20% Pd, moisture, 430 mg) was added to a solution of 2-(3-(benzyloxy)cyclobutylidene)acetonitrile (Preparation 49, 430 mg, 2.16 mmol) in THF (6.5 mL). The mixture was pressurized under hydrogen (7.03 kg/cm2 (100 psi)) in a steel reactor and stirred at about 20 °C for about 1 hr. Additional palladium hydroxide on carbon (20% Pd, moisture, 430 mg) was added, and the mixture was repressurized under hydrogen (100 psi) and stirred for about 1.5 hrs longer. The mixture was diluted with EtOAc, filtered through Celite®, and the filtrate was concentrated to provide the title compound as a colorless oil (240 mg, 100%) as a mixture of cis and trans isomers.
[00316] Isômero 1 : 1H RMN (400 MHz, CDCl3) δ: 4,52 (quin, 1 H), 2,63 - 2,74 (m, 2 H), 2,19 - 2,28 (m, 4 H), 2,07 - 2,17 (m, 1 H), 1,83 (br. s, 1 H).[00316] Isomer 1: 1H NMR (400 MHz, CDCl3) δ: 4.52 (quin, 1 H), 2.63 - 2.74 (m, 2 H), 2.19 - 2.28 (m, 4 H), 2.07 - 2.17 (m, 1 H), 1.83 (br. s, 1 H).
[00317] Isômero 2 : 1H RMN (400 MHz, CDCl3) δ: 4,14 - 4,25 (m, 1 H), 2,55 - 2,64 (m, 2 H), 2,48 (dd, 4 H), 1,83 (br. s, 1 H), 1,67 - 1,79 (m, 1 H). Preparação 51 2-(3-Oxociclobutil)acetonitrila [00317] Isomer 2: 1H NMR (400 MHz, CDCl3) δ: 4.14 - 4.25 (m, 1 H), 2.55 - 2.64 (m, 2 H), 2.48 (dd, 4 H), 1.83 (br. s, 1 H), 1.67 - 1.79 (m, 1 H). Preparation 51 2-(3-Oxocyclobutyl)acetonitrile
[00318] A uma solução de 2-(3-hidroxiciclobutil)acetonitrila (Preparação 50, 50 mg, 0,45 mmol) em THF seco (1,8 mL) foi adicionado pe- riodinano de Dess-Martin (CAS: 87413-09-0, 216 mg, 0,49 mmol). O frasconete foi vedado sob atmosfera ambiente e agitada a cerca de 50 °C durante cerca de 2 hrs. A mistura foi diluída com Et2O (10 mL) seguido por NaHCO3 aq. saturado (4 mL). Penta-hidrato de tiossulfato de sódio (954 mg, 3,82 mmol) foi adicionado, e a mistura foi agitada vigo-rosamente durante cerca de 10 min até que todos os sólidos tenham se dissolvido. As fases foram separadas, e a fase aquosa extraída mais uma vez com Et2O. Os extratos de Et2O combinados foram secados (MgSO4) e concentrados. O resíduo foi purificado por cromato- grafia para proporcionar o composto título como um óleo incolor (27 mg, 55 %).[00318] To a solution of 2-(3-hydroxycyclobutyl)acetonitrile (Preparation 50, 50 mg, 0.45 mmol) in dry THF (1.8 mL) was added Dess-Martin periodinane (CAS: 87413- 09-0, 216 mg, 0.49 mmol). The vial was sealed under ambient atmosphere and stirred at about 50°C for about 2 hrs. The mixture was diluted with Et2O (10 mL) followed by aq. saturated (4 mL). Sodium thiosulfate pentahydrate (954 mg, 3.82 mmol) was added, and the mixture was stirred vigorously for about 10 min until all solids had dissolved. The phases were separated, and the aqueous phase was extracted once again with Et2O. The combined Et2O extracts were dried (MgSO4) and concentrated. The residue was purified by chromatography to provide the title compound as a colorless oil (27 mg, 55%).
[00319] 1H RMN (400 MHz, CDCl3) δ: 3,23 - 3,37 (m, 2 H), 2,89 - 3,01 (m, 2 H), 2,75 - 2,89 (m, 1 H), 2,69 (d, 2 H).[00319] 1H NMR (400 MHz, CDCl3) δ: 3.23 - 3.37 (m, 2 H), 2.89 - 3.01 (m, 2 H), 2.75 - 2.89 (m , 1 H), 2.69 (d, 2 H).
[00320] 13C RMN (101 MHz, CDCl3) δ: 203,6, 117,6,52,3, 23,1, 20,6. Preparação 52 2-(3-(Cianometil)ciclobutilideno)acetonitrila [00320] 13C NMR (101 MHz, CDCl3) δ: 203.6, 117.6,52.3, 23.1, 20.6. Preparation 52 2-(3-(Cyanomethyl)cyclobutylidene)acetonitrile
[00321] O composto título foi preparado (75mg, 89 %) usando o método de Preparação 35 usando 2-(3-oxociclobutil)acetonitrila (Preparação 51, 70 mg, 0,64 mmol), (EtO)2POCH2CN (213 mg, 1,15 mmol), LiBr (100 mg, 1,15 mmol) e TEA (0,27 mL, 1,92 mmol). O composto título foi usado diretamente na próxima reação (Exemplo 11 e 12).[00321] The title compound was prepared (75mg, 89%) using the Preparation 35 method using 2-(3-oxocyclobutyl)acetonitrile (Preparation 51, 70 mg, 0.64 mmol), (EtO)2POCH2CN (213 mg, 1.15 mmol), LiBr (100 mg, 1.15 mmol) and TEA (0.27 mL, 1.92 mmol). The title compound was used directly in the next reaction (Example 11 and 12).
[00322] 1H RMN (400 MHz, CDCl3) δ: 5,25 (m, 1 H), 3,10 - 3,30 (m, 2 H), 2,80 (m, 3 H), 2,60 (m, 2 H).[00322] 1H NMR (400 MHz, CDCl3) δ: 5.25 (m, 1 H), 3.10 - 3.30 (m, 2 H), 2.80 (m, 3 H), 2.60 (m, 2 H).
[00323] GCMS m/z = 132 [M]+ Preparação 53 6-(1-Metil-1H-pirazol-4-il)-4-(1H-pirazol-4-il)pirazolo[1,5-a]pirazina [00323] GCMS m/z = 132 [M]+ Preparation 53 6-(1-Methyl-1H-pyrazol-4-yl)-4-(1H-pyrazol-4-yl)pyrazolo[1,5-a] pyrazine
[00324] Pd(dppf)Cl2 (5,01 g, 6,85 mmol) foi adicionado a uma mistu ra de 4-cloro-6-(1-metil-1H-pirazol-4-il)pirazolo[1,5-a]pirazina (Prepa-ração 11, 8 g, 34 mmol), terc-butil 4-(4,4,5,5-tetrametil-1,3,2- dioxaborolan-2-il)-1H-pirazol-1-carboxilato (12,1 g, 41,1 mmol) e K2CO3 aq. a 2 M (34,2 mL) em 1,4-dioxano (30 mL) e tolueno (30 mL) a cerca de 10 °C, ao mesmo tempo que uma corrente de nitrogênio foi borbulhado através da solução. A mistura foi agitada a cerca de 100 °C durante cerca de 16 hrs, em seguida mantida a cerca de 10 °C du- rante cerca de 48 hrs. A mistura foi filtrada, e o filtrado foi concentrado. O resíduo foi purificado por cromatografia para proporcionar o composto título como um óleo cinza (6,3 g, 69 %).[00324] Pd(dppf)Cl2 (5.01 g, 6.85 mmol) was added to a mixture of 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1.5 -a]pyrazine (Preparation 11.8 g, 34 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole- 1-carboxylate (12.1 g, 41.1 mmol) and aq. at 2 M (34.2 mL) in 1,4-dioxane (30 mL) and toluene (30 mL) at about 10 °C, while a stream of nitrogen was bubbled through the solution. The mixture was stirred at about 100°C for about 16 hrs, then held at about 10°C for about 48 hrs. The mixture was filtered, and the filtrate was concentrated. The residue was purified by chromatography to provide the title compound as a gray oil (6.3 g, 69%).
[00325] 1H RMN (400 MHz, DMSO-d6) δ: 8,97 (s, 1 H), 8,72 (s, 1 H), 8,40 (s, 1 H), 8,35 (s, 1 H), 8,15 (d, 1 H), 8,12 (s, 1 H), 7,36 (d, 1 H), 3,91 (s, 3 H).[00325] 1H NMR (400 MHz, DMSO-d6) δ: 8.97 (s, 1 H), 8.72 (s, 1 H), 8.40 (s, 1 H), 8.35 (s , 1 H), 8.15 (d, 1 H), 8.12 (s, 1 H), 7.36 (d, 1 H), 3.91 (s, 3 H).
[00326] LCMS m/z = 265,8 [MH]+ Exemplo 11 2,2'-((1s,3s)-1-(4-(6-(1-Metil-1H-pirazol-4-il)pirazolo[1,5-a]pirazin-4- il)-1H-pirazol-1-il)ciclobutano-1,3-diil)diacetonitrila (cis isômero) e Exemplo 12 2,2'-((1r,3r)-1-(4-(6-(1-Metil-1H-pirazol-4-il)pirazolo[1,5-a]pirazin-4- il)-1H-pirazol-1-il)ciclobutano-1,3-diil)diacetonitrila (trans isômero) [00326] LCMS m/z = 265.8 [MH]+ Example 11 2,2'-((1s,3s)-1-(4-(6-(1-Methyl-1H-pyrazol-4-yl) pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1,3-diyl)diacetonitrile (cis isomer) and Example 12 2,2'-((1r,3r)-1-(4-(6-(1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl) -1H-pyrazol-1-yl)cyclobutane-1,3-diyl)diacetonitrile (trans isomer)
[00327] DBU (34 mg, 0,22 mmol) foi adicionado a uma suspensão de 2-(3-(cianometil)ciclobutilideno)acetonitrila (Preparação 52, 32 mg, 0,24 mmol) e 6-(1-metil-1H-pirazol-4-il)-4-(1H-pirazol-4-il)pirazolo[1,5- a]pirazina (Preparação 53, 53 mg, 0,20 mmol) em MeCN (4,8 mL). A mistura foi aquecida a cerca de 50 °C durante cerca de 16 horas, em seguida concentrada. O resíduo foi purificado por cromatografia para proporcionar uma mistura dos compostos título como mistura 1:1 de cis / trans isômeros (80 mg, 83 %). Os isômeros foram separados por HPLC para proporcionar 2,2'-((1s,3s)-1-(4-(6-(1-metil-1H-pirazol-4- il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)ciclobutano-1,3- diil)diacetonitrila como um sólido (cis isômero, 27 mg, 36 %).[00327] DBU (34 mg, 0.22 mmol) was added to a suspension of 2-(3-(cyanomethyl)cyclobutylidene)acetonitrile (Preparation 52, 32 mg, 0.24 mmol) and 6-(1-methyl- 1H-pyrazol-4-yl)-4-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (Preparation 53, 53 mg, 0.20 mmol) in MeCN (4.8 mL). The mixture was heated at about 50°C for about 16 hours, then concentrated. The residue was purified by chromatography to provide a mixture of the title compounds as a 1:1 mixture of cis/trans isomers (80 mg, 83%). The isomers were separated by HPLC to provide 2,2'-((1s,3s)-1-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin -4-yl)-1H-pyrazol-1-yl)cyclobutane-1,3-diyl)diacetonitrile as a solid (cis isomer, 27 mg, 36%).
[00328] 1H RMN (500 MHz, 9:1 CDCl3-CD3OD) δ: 8,45 (s, 1 H), 8,35 (s, 1 H), 8,25 (s, 1 H), 7,99 (d, 1 H), 7,95 (s, 1 H), 7,92 (s, 1 H), 6,93 (s, 1 H), 3,95 (s, 3 H), 3,72 (s, 2 H), 3,18 (s, 2 H), 2,81 - 2,91 (m, 2 H), 2,72 - 2,81 (m, 1 H), 2,72 - 2,81 (m, 1 H), 2,64 - 2,72 (m, 2 H), 2,61 (d, 2 H).[00328] 1H NMR (500 MHz, 9:1 CDCl3-CD3OD) δ: 8.45 (s, 1 H), 8.35 (s, 1 H), 8.25 (s, 1 H), 7, 99 (d, 1 H), 7.95 (s, 1 H), 7.92 (s, 1 H), 6.93 (s, 1 H), 3.95 (s, 3 H), 3, 72 (s, 2 H), 3.18 (s, 2 H), 2.81 - 2.91 (m, 2 H), 2.72 - 2.81 (m, 1 H), 2.72 - 2.81 (m, 1 H), 2.64 - 2.72 (m, 2 H), 2.61 (d, 2 H).
[00329] LCMS m/z = 399,1 [MH]+ e 2,2'-((1r,3r)-1-(4-(6-(1-metil-1H- pirazol-4-il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)ciclo-butano-1,3- diil)diacetonitrila como um sólido (trans isômero, 14 mg, 18 %).[00329] LCMS m/z = 399.1 [MH]+ and 2,2'-((1r,3r)-1-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazole [1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1,3-diyl)diacetonitrile as a solid (trans isomer, 14 mg, 18%).
[00330] 1H RMN (500 MHz, CDCl3) δ: 8,49 (s, 1 H), 8,46 (s, 1 H), 8,32 (s, 1 H), 8,05 (d, 1 H), 7,96 (m, 2 H), 6,95 (d, 1 H), 4,00 (s, 3 H), 3,75 (br. s., 1 H), 3,15 - 3,25 (m, 2 H), 3,11 (s, 2 H), 2,88 (tt, 1 H), 2,64 (d, 2 H), 2,48 - 2,59 (m, 2 H).[00330] 1H NMR (500 MHz, CDCl3) δ: 8.49 (s, 1 H), 8.46 (s, 1 H), 8.32 (s, 1 H), 8.05 (d, 1 H), 7.96 (m, 2 H), 6.95 (d, 1 H), 4.00 (s, 3 H), 3.75 (br. s., 1 H), 3.15 - 3.25 (m, 2 H), 3.11 (s, 2 H), 2.88 (tt, 1 H), 2.64 (d, 2 H), 2.48 - 2.59 (m, 2 H).
[00331] LCMS m/z = 399,1 [MH]+ Preparação 54 2-(3-(Benzilóxi)ciclobutilideno)acetonitrila [00331] LCMS m/z = 399.1 [MH]+ Preparation 54 2-(3-(Benzyloxy)cyclobutylidene)acetonitrile
[00332] A uma solução de (EtO)2P(O)CH2CN (24,1 g, 136 mmol) em THF seco (500 mL) foi adicionado LiBr (11,8 g, 136 mmol) e TEA (18,4 g, 182 mmol), e a mistura resultante foi agitada a cerca de 20 °C durante cerca de 1 hr. A isto foi adicionado 3-(benzilóxi)ciclobutan-1- ona (16,00 g, 90,8 mmol). A mistura foi agitada a cerca de 20 °C du- rante cerca de 20 hrs. A mistura foi filtrada, e o filtrado foi concentrado. O resíduo foi purificado por cromatografia para proporcionar o composto título como um líquido amarelo pálido (18 g, 99 %).[00332] To a solution of (EtO)2P(O)CH2CN (24.1 g, 136 mmol) in dry THF (500 mL) was added LiBr (11.8 g, 136 mmol) and TEA (18.4 g , 182 mmol), and the resulting mixture was stirred at about 20°C for about 1 hr. To this was added 3-(benzyloxy)cyclobutan-1-one (16.00 g, 90.8 mmol). The mixture was stirred at about 20°C for about 20 hrs. The mixture was filtered, and the filtrate was concentrated. The residue was purified by chromatography to provide the title compound as a pale yellow liquid (18 g, 99%).
[00333] 1H RMN (400 MHz, CDCl3) δ: 7,29 - 7,40 (m, 5 H), 5,24 (dt, 1 H), 4,45 - 4,53 (m, 2 H), 4,19 (quin, 1 H), 3,19 - 3,29 (m, 1 H), 3,03 - 3,13 (m, 1 H), 2,86 - 3,00 (m, 2 H).[00333] 1H NMR (400 MHz, CDCl3) δ: 7.29 - 7.40 (m, 5 H), 5.24 (dt, 1 H), 4.45 - 4.53 (m, 2 H) , 4.19 (quin, 1 H), 3.19 - 3.29 (m, 1 H), 3.03 - 3.13 (m, 1 H), 2.86 - 3.00 (m, 2 H).
[00334] LCMS m/z = 200,1 [MH]+ Preparação 55 2-(3-(Benzilóxi)-1-(4-(6-(1-metil-1H-pirazol-4-il)pirazolo[1,5- a]pirazin-4-il)-1H-pirazol-1-il)ciclobutil)acetonitrila (mistura de cis e trans isômeros) [00334] LCMS m/z = 200.1 [MH]+ Preparation 55 2-(3-(Benzyloxy)-1-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1 ,5- a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrile (mixture of cis and trans isomers)
[00335] DBU (1,448 g, 9,4 mmol) foi adicionado a uma solução de 6-(1-metil-1H-pirazol-4-il)-4-(1H-pirazol-4-il)pirazolo[1,5-a]pirazina (Preparação 53, 313 mg, 1,18 mmol) e 2-(3- (benzilóxi)ciclobutilideno)acetonitrila (Preparação 54, 470 mg, 2,36 mmol) em MeCN (6,38 mL). A mistura foi agitada a cerca de 20 °C du-rante cerca de 18 hrs, em seguida foi vertida em solução de NaH2PO4 aq. para manter um pH de cerca de 5. A mistura foi extraída três vezes com DCM. Os extratos de DCM combinados foram concentrados, e o resíduo foi purificado por cromatografia para proporcionar o composto título (474 mg, 86 %).[00335] DBU (1.448 g, 9.4 mmol) was added to a solution of 6-(1-methyl-1H-pyrazol-4-yl)-4-(1H-pyrazol-4-yl)pyrazolo[1, 5-a]pyrazine (Preparation 53, 313 mg, 1.18 mmol) and 2-(3-(benzyloxy)cyclobutylidene)acetonitrile (Preparation 54, 470 mg, 2.36 mmol) in MeCN (6.38 mL). The mixture was stirred at about 20°C for about 18 hrs, then poured into aq. to maintain a pH of about 5. The mixture was extracted three times with DCM. The combined DCM extracts were concentrated, and the residue was purified by chromatography to provide the title compound (474 mg, 86%).
[00336] 1H RMN (400 MHz, CD3OD) δ: 8,67 - 8,72 (m, 2 H), 8,63 (s, 1 H), 8,39 (s, 1 H), 8,22 (s, 1 H), 8,04 - 8,10 (m, 2 H), 7,25 - 7,42 (m, 5 H), 4,53 (s, 2 H), 4,24 - 4,34 (m, 1 H), 3,97 (s, 3 H), 3,29 (s, 2 H), 2,92 - 3,02 (m, 2 H), 2,77 - 2,88 (m, 2 H).[00336] 1H NMR (400 MHz, CD3OD) δ: 8.67 - 8.72 (m, 2 H), 8.63 (s, 1 H), 8.39 (s, 1 H), 8.22 (s, 1 H), 8.04 - 8.10 (m, 2 H), 7.25 - 7.42 (m, 5 H), 4.53 (s, 2 H), 4.24 - 4 .34 (m, 1 H), 3.97 (s, 3 H), 3.29 (s, 2 H), 2.92 - 3.02 (m, 2 H), 2.77 - 2.88 (m, 2 H).
[00337] LCMS m/z = 465,3 [MH]+ Exemplo 13 2-((1s,3r)-3-Hidróxi-1-(4-(6-(1-metil-1H-pirazol-4-il)pirazolo[1,5- a]pirazin-4-il)-1H-pirazol-1-il)ciclobutil)acetonitrila (cis isômero) Exemplo 14 PF-06877900 2-((1r,3s)-3-Hidróxi-1-(4-(6-(1-metil-1H-pirazol-4-il)pirazolo[1,5- a]pirazin-4-il)-1H-pirazol-1-il)ciclobutil)acetonitrila (trans isômero) [00337] LCMS m/z = 465.3 [MH]+ Example 13 2-((1s,3r)-3-Hydroxy-1-(4-(6-(1-methyl-1H-pyrazol-4-yl )pyrazolo[1,5- a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrile (cis isomer) Example 14 PF-06877900 2-((1r,3s)-3-Hydroxy-1-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4 -yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrile (trans isomer)
[00338] Iodeto de sódio foi secado com uma pistola térmica a todo calor durante 5 min, em seguida resfriada a cerca de 25 °C sob nitrogênio antes do uso. O NaI seco (1,21 g, 8,1 mmol) foi adicionado a cerca de 20 °C a uma solução agitada de (2-(3-(benzilóxi)-1-(4-(6-(1- metil-1H-pirazol-4-il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1- il)ciclobutil)acetonitrila (Preparação 55, 377 mg, 0,81 mmol) em MeCN (12 mL), seguido por TMSCl (1,05 mL, 8,1 mmol). A mistura foi agitada a cerca de 50 °C durante cerca de 18 hrs. Uma porção adicional de ambos os NaI e TMSCl foram adicionados, e a mistura foi mantida a cerca de 50 °C durante cerca de 8 hrs adicionais. A mistura resfriada foi vertida em NaHCO3 aq. saturado gelado contendo penta-hidrato de tiossulfato de sódio (10,1 g, 40,6 mmol) e extraída três vezes com EtOAc. Os extratos de EtOAc combinados foram concentrados para proporcionar uma mistura dos dois compostos título. Esta mistura foi purificada por cromatografia para proporcionar 2-((1s,3r)-3-hidróxi-1- (4-(6-(1-metil-1H-pirazol-4-il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1- il)ciclobutil)acetonitrila (trans isômero, 80 mg, 26 %)[00338] Sodium iodide was dried with a heat gun at full heat for 5 min, then cooled to about 25 °C under nitrogen before use. Dry NaI (1.21 g, 8.1 mmol) was added at about 20 °C to a stirred solution of (2-(3-(benzyloxy)-1-(4-(6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrile (Preparation 55, 377 mg, 0.81 mmol) in MeCN (12 mL), followed by TMSCl (1.05 mL, 8.1 mmol). The mixture was stirred at about 50 °C for about 18 hrs. An additional portion of both NaI and TMSCl were added, and the mixture was added. held at about 50°C for about 8 additional hrs. The cooled mixture was poured into ice-cold saturated aq. NaHCO3 containing sodium thiosulfate pentahydrate (10.1 g, 40.6 mmol) and extracted three times with EtOAc. The combined EtOAc extracts were concentrated to provide a mixture of the two title compounds. This mixture was purified by chromatography to provide 2-((1s,3r)-3-hydroxy-1-(4-(6-(1-methyl). -1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrile (trans isomer, 80 mg, 26%)
[00339] 1H RMN (400 MHz, CD3OD) δ: 8,72 (s, 1 H), 8,71 (s, 1 H), 8,42 (s, 1 H), 8,24 (s, 1 H), 8,05 - 8,10 (m, 2 H), 7,24 (d, 1 H), 4,34 - 4,44 (m, 1 H), 3,98 (s, 3 H), 3,35 (s, 2 H), 3,22 - 3,28 (m, 2 H), 2,49 (dd, 2 H).[00339] 1H NMR (400 MHz, CD3OD) δ: 8.72 (s, 1 H), 8.71 (s, 1 H), 8.42 (s, 1 H), 8.24 (s, 1 H), 8.05 - 8.10 (m, 2 H), 7.24 (d, 1 H), 4.34 - 4.44 (m, 1 H), 3.98 (s, 3 H) , 3.35 (s, 2 H), 3.22 - 3.28 (m, 2 H), 2.49 (dd, 2 H).
[00340] LCMS m/z = 375,4 [MH]+ e 2-((1r,3s)-3-hidróxi-1-(4-(6-(1- metil-1H-pirazol-4-il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1- il)ciclobutil)acetonitrila (cis isômero, 180 mg, 59 %).[00340] LCMS m/z = 375.4 [MH]+ e 2-((1r,3s)-3-hydroxy-1-(4-(6-(1-methyl-1H-pyrazol-4-yl) pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrile (cis isomer, 180 mg, 59%).
[00341] 1H RMN (400 MHz, CD3OD) δ: 8,67 (s, 1 H), 8,62 (s, 1 H), 8,38 (s, 1 H), 8,21 (s, 1 H), 8,07 (d, 1 H), 8,05 (s, 1 H), 8,04 - 8,06 (m, 1 H), 7,21 (d, 1 H), 4,41 (quin, 1 H), 3,97 (s, 3 H), 3,28 (s, 2 H), 2,95 - 3,04 (m, 2 H), 2,68 - 2,78 (m, 2 H).[00341] 1H NMR (400 MHz, CD3OD) δ: 8.67 (s, 1 H), 8.62 (s, 1 H), 8.38 (s, 1 H), 8.21 (s, 1 H), 8.07 (d, 1 H), 8.05 (s, 1 H), 8.04 - 8.06 (m, 1 H), 7.21 (d, 1 H), 4.41 (quin, 1 H), 3.97 (s, 3 H), 3.28 (s, 2 H), 2.95 - 3.04 (m, 2 H), 2.68 - 2.78 (m , 2H).
[00342] LCMS m/z = 375,4 [MH]+ Exemplo 15 2-((1r,3s)-3-Metóxi-1-(4-(6-(1-metil-1H-pirazol-4-il)pirazolo[1,5- a]pirazin-4-il)-1H-pirazol-1-il)ciclobutil)acetonitrila (trans isômero) Exemplo 16 2-((1s,3r)-3-Metóxi-1-(4-(6-(1-metil-1H-pirazol-4-il)pirazolo[1,5- a]pirazin-4-il)-1H-pirazol-1-il)ciclobutil)acetonitrila (cis isômero) [00342] LCMS m/z = 375.4 [MH]+ Example 15 2-((1r,3s)-3-Methoxy-1-(4-(6-(1-methyl-1H-pyrazol-4-yl )pyrazolo[1,5- a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrile (trans isomer) Example 16 2-((1s,3r)-3-Methoxy-1-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-4-yl) -1H-pyrazol-1-yl)cyclobutyl)acetonitrile (cis isomer)
[00343] Uma solução de uma mistura de 2-((1s,3r)-3-hidróxi-1-(4-(6- (1-metil-1H-pirazol-4-il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1- il)ciclobutil)acetonitrila e 2-((1r,3s)-3-Hidróxi-1-(4-(6-(1-metil-1H-pirazol- 4-il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)ciclobutil)acetonitrila (Exemplos 13 e 14, mistura de cis e trans isômeros, 48 mg, 0,13 mmol) em THF (0,2 mL) foi sequencialmente tratada com brometo de tetrabutilamônio (TBAB, 126 mg, 0,38 mmol), NaOH aq. a 1 M (1,02 mL) e dimetil sulfato (6 μL). O frasconete de reação foi vedado e agitado vigorosamente a cerca de 20 °C durante cerca de 1 hr. Dimetil sulfato adicional (14 μL) e TBAB (10 mg) foram adicionados, e a reação foi mantida a cerca de 20 °C durante cerca de 2 hrs. A mistura foi extraída três vezes com EtOAc e os extratos de EtOAc combinados foram secados (Na2SO4) e concentrados. O resíduo foi purificado por cromatografia para proporcionar uma mistura de cis e trans isômeros. Outra purificação por HPLC proporcionou 2-((1r,3s)-3-metóxi-1-(4-(6- (1-metil-1H-pirazol-4-il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1- il)ciclobutil)acetonitrila como um sólido (trans isômero, 10 mg, 20 %)[00343] A solution of a mixture of 2-((1s,3r)-3-hydroxy-1-(4-(6- (1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a ]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrile and 2-((1r,3s)-3-Hydroxy-1-(4-(6-(1-methyl-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrile (Examples 13 and 14, mixture of cis and trans isomers, 48 mg, 0.13 mmol ) in THF (0.2 mL) was sequentially treated with tetrabutylammonium bromide (TBAB, 126 mg, 0.38 mmol), aq. at 1 M (1.02 mL) and dimethyl sulfate (6 μL). The reaction vial was sealed and shaken vigorously at about 20°C for about 1 hr. Additional dimethyl sulfate (14 μL) and TBAB (10 mg) were added, and the reaction was maintained at about 20 °C for about 2 hrs. The mixture was extracted three times with EtOAc and the combined EtOAc extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography to provide a mixture of cis and trans isomers. Further HPLC purification provided 2-((1r,3s)-3-methoxy-1-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4 -yl)-1H-pyrazol-1- yl)cyclobutyl)acetonitrile as a solid (trans isomer, 10 mg, 20%)
[00344] 1H RMN (400 MHz, CD3CN) δ: 8,61 (d, 1 H), 8,55 (s, 1 H), 8,38 (s, 1 H), 8,12 (s, 1 H), 8,05 (d, 1 H), 7,99 (s, 1 H), 7,13 (d, 1 H), 3,99 - 4,08 (m, 1 H), 3,93 (s, 3 H), 3,27 (s, 5 H), 3,13 - 3,21 (m, 2 H), 2,45 - 2,53 (m, 2 H).[00344] 1H NMR (400 MHz, CD3CN) δ: 8.61 (d, 1 H), 8.55 (s, 1 H), 8.38 (s, 1 H), 8.12 (s, 1 H), 8.05 (d, 1 H), 7.99 (s, 1 H), 7.13 (d, 1 H), 3.99 - 4.08 (m, 1 H), 3.93 (s, 3 H), 3.27 (s, 5 H), 3.13 - 3.21 (m, 2 H), 2.45 - 2.53 (m, 2 H).
[00345] LCMS m/z = 389,1 [MH]+ e 2-((1s,3r)-3-metóxi-1-(4-(6-(1- metil-1H-pirazol-4-il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1- il)ciclobutil)acetonitrila como um sólido (cis isômero, 17 mg, 33 %).[00345] LCMS m/z = 389.1 [MH]+ e 2-((1s,3r)-3-methoxy-1-(4-(6-(1-methyl-1H-pyrazol-4-yl) pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrile as a solid (cis isomer, 17 mg, 33%).
[00346] 1H RMN (400 MHz, CD3CN) δ: 8,60 (d, 1 H), 8,49 (s, 1 H), 8,36 (s, 1 H), 8,12 (s, 1 H), 8,04 (d, 1 H), 7,98 (s, 1 H), 7,12 (dd, 1 H), 4,03 (quin, 1 H), 3,92 (s, 3 H), 3,26 (s, 3 H), 3,19 (s, 2 H), 2,89 - 2,97 (m, 2 H), 2,65 - 2,74 (m, 2 H).[00346] 1H NMR (400 MHz, CD3CN) δ: 8.60 (d, 1 H), 8.49 (s, 1 H), 8.36 (s, 1 H), 8.12 (s, 1 H), 8.04 (d, 1 H), 7.98 (s, 1 H), 7.12 (dd, 1 H), 4.03 (quin, 1 H), 3.92 (s, 3 H), 3.26 (s, 3 H), 3.19 (s, 2 H), 2.89 - 2.97 (m, 2 H), 2.65 - 2.74 (m, 2 H) .
[00347] LCMS m/z = 389,1 [MH]+ Preparação 56 Benzil (R)-2-metil-3-oxoazetidina-1-carboxilato [00347] LCMS m/z = 389.1 [MH]+ Preparation 56 Benzyl (R)-2-methyl-3-oxoazetidine-1-carboxylate
[00348] Uma solução de N,4-dimetil-N-nitrosobenzenossulfonamida (Diazald®, 21,25 g, 99,19 mmol) em Et2O (150 mL) foi adicionado gota a gota a uma solução de KOH (6 g, 106,9 mmol) e 2-(2- etoxietóxi)etanol (30 mL) e água (10 mL) a cerca de 70 °C. A mistura foi aquecida a cerca de 70 °C e uma solução etérea de diazometano foi coletado como um líquido amarelo por destilação (100 mL, estimado conter 66 mmol de diazometano) usando um condensador de gelo seco / acetona e usado imediatamente na Parte 2.[00348] A solution of N,4-dimethyl-N-nitrosobenzenesulfonamide (Diazald®, 21.25 g, 99.19 mmol) in Et2O (150 mL) was added dropwise to a solution of KOH (6 g, 106 .9 mmol) and 2-(2-ethoxyethoxy)ethanol (30 mL) and water (10 mL) at about 70 °C. The mixture was heated to about 70 °C and an ethereal diazomethane solution was collected as a yellow liquid by distillation (100 mL, estimated to contain 66 mmol diazomethane) using a dry ice/acetone condenser and used immediately in Part 2.
[00349] Cloroformiato de etil (2,430 g, 22,4 mmol) foi adicionado gota a gota a uma solução de Cbz-D-alanina (5,00 g, 22,4 mmol) e TEA (2,27 mg, 22,4 mmol) em THF (50 mL) a cerca de - 15 °C. A mistura de reação foi aquecida a cerca de 0 °C, e a solução de diazometano da Parte 1 (100 mL, cerca de 66 mmol) foi adicionada gota a gota e agitada a cerca de 20 °C durante cerca de 16 hrs. A mistura de rea- ção foi extinguida com água (10 mL) e extraída com EtOAc (2 x 30 mL). Os extratos de EtOAc combinados foram secados (Na2SO4) e concentrados. O resíduo foi purificado por cromatografia para propor-cionar o intermediário de diazo-cetona (4,5 g, 81 %) como um sólido branco. O material foi usado na Parte 3.[00349] Ethyl chloroformate (2.430 g, 22.4 mmol) was added dropwise to a solution of Cbz-D-alanine (5.00 g, 22.4 mmol) and TEA (2.27 mg, 22.4 mmol) 4 mmol) in THF (50 mL) at about - 15 °C. The reaction mixture was heated to about 0 °C, and the diazomethane solution from Part 1 (100 mL, about 66 mmol) was added dropwise and stirred at about 20 °C for about 16 hrs. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2 x 30 mL). The combined EtOAc extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography to provide the diazo-ketone intermediate (4.5 g, 81%) as a white solid. The material was used in Part 3.
[00350] A uma solução do intermediário de diazo-cetona da Parte 2 (4,50 g, 18,2 mmol) em DCM (450 mL) foram adicionados TEA (18 mg, 0,18 mmol) e Rh2(OAc)4 (40 mg, 0,091 mmol) a cerca de 0 °C. A mistura foi agitada durante cerca de 16 hrs a cerca de 25 °C. A mistura foi extinguida com água (50 mL), e a fase de DCM foi separada e concen-trada. O resíduo foi purificado por cromatografia para proporcionar o composto título como um sólido branco (1,20 g, 30 %). 1H RMN (400 MHz, CDCl3) δ: 7,34 - 7,38 (m, 5 H), 5,18 (m, 2 H), 5,03 (m, 1 H), 4,65 - 4,81 (m, 2 H), 1,49 (d, 3 H). GCMS m/z = 219 [M]+ Preparação 57 Benzil (R)-3-(cianometileno)-2-metilazetidina-1-carboxilato [00350] To a solution of the diazo-ketone intermediate from Part 2 (4.50 g, 18.2 mmol) in DCM (450 mL) were added TEA (18 mg, 0.18 mmol) and Rh2(OAc)4 (40 mg, 0.091 mmol) at about 0 °C. The mixture was stirred for about 16 hrs at about 25°C. The mixture was quenched with water (50 mL), and the DCM phase was separated and concentrated. The residue was purified by chromatography to provide the title compound as a white solid (1.20 g, 30%). 1H NMR (400 MHz, CDCl3) δ: 7.34 - 7.38 (m, 5 H), 5.18 (m, 2 H), 5.03 (m, 1 H), 4.65 - 4, 81 (m, 2 H), 1.49 (d, 3 H). GCMS m/z = 219 [M]+ Preparation 57 Benzyl (R)-3-(cyanomethylene)-2-methylazetidine-1-carboxylate
[00351] A uma mistura de LiBr (166 mg, 1,92 mmol) e TEA (277 mg, 2,74 mmol) em THF (10 mL) foi adicionado (EtO)2P(O)CH2CN (339 mg, 1,92 mmol) a cerca de 25 °C. Depois de cerca de 2,5 hrs, benzil (R)-2- metil-3-oxoazetidina-1-carboxilato (Preparação 56, 300 mg, 1,37 mmol) em THF (2 mL) foi adicionado a cerca de 25 °C, e a mistura foi agitada durante cerca de 16 hrs. A mistura foi concentrada, e o resíduo foi puri-ficado por cromatografia para proporcionar o composto título como mis-tura de isômeros de olefina E/Z como óleo incolor (290 mg, 87 %).[00351] To a mixture of LiBr (166 mg, 1.92 mmol) and TEA (277 mg, 2.74 mmol) in THF (10 mL) was added (EtO)2P(O)CH2CN (339 mg, 1. 92 mmol) at about 25 °C. After about 2.5 hrs, benzyl(R)-2-methyl-3-oxoazetidine-1-carboxylate (Preparation 56, 300 mg, 1.37 mmol) in THF (2 mL) was added at about 25° C, and the mixture was stirred for about 16 hrs. The mixture was concentrated, and the residue was purified by chromatography to provide the title compound as a mixture of E/Z olefin isomers as colorless oil (290 mg, 87%).
[00352] 1H RMN (400 MHz, CDCl3) δ: 7,33 - 7,40 (m, 5 H), 5,36 (m, 1 H), 5,10 - 5,17 (m, 2 H), 4,97 (m, 1 H), 4,63 - 4,77 (m, 2 H), 1,50 - 1,67 (m, 3 H). Preparação 58 Benzil (2R)-3-(cianometil)-2-metil-3-(4-(6-(1-metil-1H-pirazol-4- il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)azetidina-1-carboxilato [00352] 1H NMR (400 MHz, CDCl3) δ: 7.33 - 7.40 (m, 5 H), 5.36 (m, 1 H), 5.10 - 5.17 (m, 2 H) , 4.97 (m, 1 H), 4.63 - 4.77 (m, 2 H), 1.50 - 1.67 (m, 3 H). Preparation 58 Benzyl (2R)-3-(cyanomethyl)-2-methyl-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4- il)-1H-pyrazol-1-yl)azetidine-1-carboxylate
[00353] A uma solução de 6-(1-metil-1H-pirazol-4-il)-4-(1H-pirazol- 4-il)pirazolo[1,5-a]pirazina (Preparação 53, 268 mg, 1,01 mmol) em MeCN (15 mL) foram adicionados benzil (R)-3-(cianometileno)-2- metilazetidina-1-carboxilato (Preparação 57, 294 mg, 1,21 mmol) e DBU (77 mg, 0,51 mmol) a cerca de 15 °C. A mistura foi agitada a cerca de 25 °C durante cerca de 7 hrs antes de ser diluída com EtOAc (50 mL) e lavada com ácido cítrico aq. a 1 M (15 mL) seguido por salmoura (15 mL). O extrato de EtOAc foi concentrado, e o resíduo foi purificado por cromatografia para proporcionar o composto título como uma goma amarela (500 mg, 97 %).[00353] To a solution of 6-(1-methyl-1H-pyrazol-4-yl)-4-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (Preparation 53, 268 mg, 1.01 mmol) in MeCN (15 mL) were added benzyl (R)-3-(cyanomethylene)-2-methylazetidine-1-carboxylate (Preparation 57, 294 mg, 1.21 mmol) and DBU (77 mg, 0 .51 mmol) at about 15 °C. The mixture was stirred at about 25°C for about 7 hrs before being diluted with EtOAc (50 mL) and washed with aq. at 1 M (15 mL) followed by brine (15 mL). The EtOAc extract was concentrated, and the residue was purified by chromatography to provide the title compound as a yellow gum (500 mg, 97%).
[00354] 1H RMN (400 MHz, CDCl3) δ: 8,49 (s, 1 H), 8,33 (s, 1 H), 8,32 (s, 1 H), 8,05 (d, 1 H), 7,96 (s, 1 H), 7,95 (s, 1 H), 7,33 - 7,40 (m, 5 H), 6,93 (d, 2 H), 5,15 (s, 2 H), 4,87 (m, 1 H), 4,61 (d, 1 H), 4,26 (d, 1 H), 4,01 (s, 3 H), 3,27 (s, 2 H), 1,69 (d, 3 H).[00354] 1H NMR (400 MHz, CDCl3) δ: 8.49 (s, 1 H), 8.33 (s, 1 H), 8.32 (s, 1 H), 8.05 (d, 1 H), 7.96 (s, 1 H), 7.95 (s, 1 H), 7.33 - 7.40 (m, 5 H), 6.93 (d, 2 H), 5.15 (s, 2 H), 4.87 (m, 1 H), 4.61 (d, 1 H), 4.26 (d, 1 H), 4.01 (s, 3 H), 3.27 (s, 2H), 1.69 (d, 3H).
[00355] LCMS m/z = 530,1 [M+Na]+ Preparação 59 2-((2R)-2-Metil-3-(4-(6-(1-metil-1H-pirazol-4-il)pirazolo[1,5-a]pirazin- 4-il)-1H-pirazol-1-il)azetidin-3-il)acetonitrila [00355] LCMS m/z = 530.1 [M+Na]+ Preparation 59 2-((2R)-2-Methyl-3-(4-(6-(1-methyl-1H-pyrazol-4-yl )pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile
[00356] A uma mistura de NaI (2,36 g, 15,8 mmol) em MeCN (16 mL) foi adicionado TMSCl (2 mL, 15,8 mmol) a cerca de 0 °C. A mistura foi agitada a cerca de 15 °C durante cerca de 4 hrs. Uma solução de benzil (2R)-3-(cianometil)-2-metil-3-(4-(6-(1-metil-1H-pirazol-4- il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)azetidina-1-carboxilato (Preparação 58, 400 mg, 0,79 mmol) em MeCN (4 mL) foi adicionada a cerca de 0 °C. A agitação foi continuada a cerca de 15 °C durante cerca de 3 hrs. A mistura foi resfriada a cerca de 10 °C e extinguida pela adição de TEA (2 mL). A mistura foi concentrada. O resíduo foi dissolvido em EtOAc (20 mL) e MeOH (2 mL), e os sólidos presentes foram removidos por filtração. O filtrado foi concentrado, e o resíduo foi purificado por TLC para proporcionar o composto título como um sólido amarelo (200 mg, 68 %).[00356] To a mixture of NaI (2.36 g, 15.8 mmol) in MeCN (16 mL) was added TMSCl (2 mL, 15.8 mmol) at about 0 °C. The mixture was stirred at about 15°C for about 4 hrs. A solution of benzyl (2R)-3-(cyanomethyl)-2-methyl-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4 -yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (Preparation 58, 400 mg, 0.79 mmol) in MeCN (4 mL) was added at about 0 °C. Stirring was continued at about 15°C for about 3 hrs. The mixture was cooled to about 10 °C and quenched by adding TEA (2 mL). The mixture was concentrated. The residue was dissolved in EtOAc (20 mL) and MeOH (2 mL), and the solids present were removed by filtration. The filtrate was concentrated, and the residue was purified by TLC to provide the title compound as a yellow solid (200 mg, 68%).
[00357] 1H RMN (400 MHz, DMSO-d6) δ: 9,06 (s, 1 H), 9,03 (s, 1 H), 8,59 (s, 1 H), 8,39 (s, 1 H), 8,22 (d, 1 H), 8,16 (s, 1 H), 7,47 (s, 1 H), 5,09 (m, 1 H), 4,74 (d, 1 H), 4,24 (d, 1 H), 3,91 (s, 3 H), 2,99 (s, 2 H), 1,65 (d, 3 H).[00357] 1H NMR (400 MHz, DMSO-d6) δ: 9.06 (s, 1 H), 9.03 (s, 1 H), 8.59 (s, 1 H), 8.39 (s , 1 H), 8.22 (d, 1 H), 8.16 (s, 1 H), 7.47 (s, 1 H), 5.09 (m, 1 H), 4.74 (d , 1 H), 4.24 (d, 1 H), 3.91 (s, 3 H), 2.99 (s, 2 H), 1.65 (d, 3 H).
[00358] LCMS m/z = 374,0 [MH]+ Exemplo 17 2-((2R,3S)-2-Metil-3-(4-(6-(1-metil-1H-pirazol-4-il)pirazolo[1,5- a]pirazin-4-il)-1H-pirazol-1-il)-1-(2,2,2-trifluoroetil)azetidin-3- il)acetonitrila [00358] LCMS m/z = 374.0 [MH]+ Example 17 2-((2R,3S)-2-Methyl-3-(4-(6-(1-methyl-1H-pyrazol-4-yl )pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-1-(2,2,2-trifluoroethyl)azetidin-3-yl)acetonitrile
[00359] A uma solução de 2-((2R)-2-metil-3-(4-(6-(1-metil-1H- pirazol-4-il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)azetidin-3- il)acetonitrila (Preparação 59, 200 mg, 0,43 mmol) em DMF (5 mL) foram adicionados 2,2,2-trifluoroetil trifluorometanossulfonato (298 mg, 1,29 mmol) e DIPEA (332 mg, 2,57 mmol). A mistura foi agitada a cerca de 10 °C durante cerca de 36 hrs antes de ser diluída com EtOAc (30 mL) e lavada com salmoura (15 mL). O extrato de EtOAc foi concentrado, e o resíduo foi purificado por HPLC para proporcionar o composto título como uma mistura de diastereômeros (80 mg, 41 %) como um sólido branco. Outra purificação por HPLC proporcionou o composto título como um sólido branco (41,8 mg, 21 %, 94,7 % ee).[00359] To a solution of 2-((2R)-2-methyl-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4 -yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (Preparation 59, 200 mg, 0.43 mmol) in DMF (5 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (298 mg , 1.29 mmol) and DIPEA (332 mg, 2.57 mmol). The mixture was stirred at about 10°C for about 36 hrs before being diluted with EtOAc (30 mL) and washed with brine (15 mL). The EtOAc extract was concentrated, and the residue was purified by HPLC to provide the title compound as a mixture of diastereomers (80 mg, 41%) as a white solid. Further purification by HPLC provided the title compound as a white solid (41.8 mg, 21%, 94.7% ee).
[00360] 1H RMN (400 MHz, CD3CN) δ: 8,59 (s, 1 H), 8,45 (s, 1 H), 8,36 (s, 1 H), 8,10 (s, 1 H), 8,04 (d, 1 H), 7,98 (s, 1 H), 7,09 - 7,13 (m, 1 H), 3,92 - 3,96 (m, 1 H), 3,91 (s, 3 H), 3,84 - 3,89 (m, 1 H), 3,77 - 3,84 (m, 1 H), 3,38 (s, 2 H), 3,28 - 3,43 (m, 1 H), 3,15 (dq, 1 H), 1,36 (d, 3 H).[00360] 1H NMR (400 MHz, CD3CN) δ: 8.59 (s, 1 H), 8.45 (s, 1 H), 8.36 (s, 1 H), 8.10 (s, 1 H), 8.04 (d, 1 H), 7.98 (s, 1 H), 7.09 - 7.13 (m, 1 H), 3.92 - 3.96 (m, 1 H) , 3.91 (s, 3 H), 3.84 - 3.89 (m, 1 H), 3.77 - 3.84 (m, 1 H), 3.38 (s, 2 H), 3 .28 - 3.43 (m, 1 H), 3.15 (dq, 1 H), 1.36 (d, 3 H).
[00361] LCMS m/z = 456,2 [MH]+ Exemplo 18 2-((1r,3r)-1-(4-(6-(1-Metil-1H-pirazol-4-il)pirazolo[1,5-a]pirazin-4-il)- 1H-pirazol-1-il)-3-(1H-pirazol-5-il)ciclobutil)acetonitrila [00361] LCMS m/z = 456.2 [MH]+ Example 18 2-((1r,3r)-1-(4-(6-(1-Methyl-1H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)- 1H-pyrazol-1-yl)-3-(1H-pyrazin-5-yl)cyclobutyl)acetonitrile
[00362] A uma solução de LiBr (70 mg, 0,81 mmol), TEA (205 μL, 1,47 mmol) em THF (10 mL), foi adicionado (EtO)2P(O)CH2CN (143 mg, 0,81 mmol). A mistura foi agitada a cerca de 20 °C durante cerca de 30 min. 3-(1H-Pirazol-5-il)ciclobutan-1-ona (Preparação 99, 100 mg, 0,74 mmol) foi adicionado, e a mistura foi mantida a cerca de 20 °C durante cerca de 18 hrs. Cerca de 30 % da solução de reação fo- ram retirados e 6-(1-metil-1H-pirazol-4-il)-4-(1H-pirazol-4- il)pirazolo[1,5-a]pirazina (Preparação 53, 58 mg, 0,22 mmol) e DBU (110 μL, 0,73 mmol) em MeCN (5 mL) foram adicionados. Agitação a cerca de 20 °C foi mantida durante cerca de 20 hrs. A mistura foi concentrada, e o resíduo foi purificado por cromatografia para proporcionar o composto título (6 mg, 6 %).[00362] To a solution of LiBr (70 mg, 0.81 mmol), TEA (205 μL, 1.47 mmol) in THF (10 mL), (EtO)2P(O)CH2CN (143 mg, 0 .81 mmol). The mixture was stirred at about 20°C for about 30 min. 3-(1H-Pyrazol-5-yl)cyclobutan-1-one (Preparation 99, 100 mg, 0.74 mmol) was added, and the mixture was maintained at about 20 °C for about 18 hrs. About 30% of the reaction solution was removed and 6-(1-methyl-1H-pyrazol-4-yl)-4-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine ( Preparation 53, 58 mg, 0.22 mmol) and DBU (110 μL, 0.73 mmol) in MeCN (5 mL) were added. Stirring at about 20°C was maintained for about 20 hrs. The mixture was concentrated, and the residue was purified by chromatography to provide the title compound (6 mg, 6%).
[00363] 1H RMN (500 MHz, CD3OD) δ: 8,85 (s, 1 H), 8,73 (s, 1 H), 8,46 (s, 1 H), 8,26 (s, 1 H), 8,10 (s, 2 H), 7,60 (br. s., 1 H), 7,28 (d, 1 H), 6,32 (d, 1 H), 3,95 - 4,04 (m, 3 H), 3,69 - 3,78 (m, 1 H), 3,33 - 3,43 (m, 2 H), 2,77 - 2,89 (m, 2 H).[00363] 1H NMR (500 MHz, CD3OD) δ: 8.85 (s, 1 H), 8.73 (s, 1 H), 8.46 (s, 1 H), 8.26 (s, 1 H), 8.10 (s, 2 H), 7.60 (br. s., 1 H), 7.28 (d, 1 H), 6.32 (d, 1 H), 3.95 - 4.04 (m, 3 H), 3.69 - 3.78 (m, 1 H), 3.33 - 3.43 (m, 2 H), 2.77 - 2.89 (m, 2 H ).
[00364] LCMS m/z = 425,4 [MH]+ Exemplo 19 (1s,3s)-3-(Cianometil)-3-(4-(6-(1-metil-1H-pirazol-4-il)pirazolo[1,5- a]pirazin-4-il)-1H-pirazol-1-il)ciclobutano-1-carbonitrila [00364] LCMS m/z = 425.4 [MH]+ Example 19 (1s,3s)-3-(Cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl) pyrazolo[1,5- a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile
[00365] A uma solução de (1s,3s)-3-(cianometil)-3-(4-(4,4,5,5- tetrametil-1,3,2-dioxaborolan-2-il)-1H-pirazol-1-il)ciclobutano-1- carbonitrila (Preparação 91, 539 mg, 1,72 mmol) e 4-cloro-6-(1-metil- 1H-pirazol-4-il)pirazolo[1,5-a]pirazina (Preparação 11, 350 mg, 1,5 mmol) em 1,4-dioxano (7,5 mL) foi adicionado K3PO4 aq. a 2 M (2,25 mL) a cerca de 25 °C. A mistura foi colocada sob nitrogênio, em seguida XPhos Pd G2 (11,8 mg, 0,0150 mmol) foi adicionado. A mistura foi aquecida a cerca de 40 °C durante cerca de 6 h, em seguida foi aquecida a cerca de 80 °C para dissolver o produto precipitado. A camada aquosa foi removida, ao mesmo tempo que mantendo a temperatura a cerca de 80 °C, em seguida a fase de 1,4-dioxano foi adicionada a EtOH (70 mL, previamente pré-aquecida a cerca de 50 °C). A mistura foi agitada durante cerca de 10 min a cerca de 50 °C antes de ser removida do aquecimento. Agitação a cerca de 25 °C foi continuada durante cerca de 18 h. O sólido foi filtrado e lavado com EtOH (2 x 25 mL) e secado sob vácuo para proporcionar o composto título como um sólido branco (483 mg, 84 %).[00365] To a solution of (1s,3s)-3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazol-1-yl)cyclobutane-1-carbonitrile (Preparation 91, 539 mg, 1.72 mmol) and 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a ]pyrazine (Preparation 11, 350 mg, 1.5 mmol) in 1,4-dioxane (7.5 mL) was added aq. at 2 M (2.25 mL) at about 25 °C. The mixture was placed under nitrogen, then XPhos Pd G2 (11.8 mg, 0.0150 mmol) was added. The mixture was heated to about 40°C for about 6 h, then heated to about 80°C to dissolve the precipitated product. The aqueous layer was removed, while maintaining the temperature at about 80 °C, then the 1,4-dioxane phase was added to EtOH (70 mL, previously preheated to about 50 °C). The mixture was stirred for about 10 min at about 50°C before being removed from heating. Stirring at about 25°C was continued for about 18 h. The solid was filtered and washed with EtOH (2 x 25 mL) and dried under vacuum to provide the title compound as a white solid (483 mg, 84%).
[00366] ponto de fusão 217 - 220 °C[00366] melting point 217 - 220 °C
[00367] 1H RMN (400 MHz, DMSO-d6) δ: 9,02 (s, 1 H), 8,87 (s, 1 H), 8,51 (s, 1 H), 8,37 (s, 1 H), 8,20 (s, 1 H), 8,16 (s, 1 H), 7,45 (s, 1 H), 3,92 (s, 3 H), 3,65 - 3,59 (m, 1 H), 3,57 (s, 2 H), 3,26 - 3,16 (m, 2 H), 2,88 (m, 2H).[00367] 1H NMR (400 MHz, DMSO-d6) δ: 9.02 (s, 1 H), 8.87 (s, 1 H), 8.51 (s, 1 H), 8.37 (s , 1 H), 8.20 (s, 1 H), 8.16 (s, 1 H), 7.45 (s, 1 H), 3.92 (s, 3 H), 3.65 - 3 .59 (m, 1H), 3.57 (s, 2H), 3.26 - 3.16 (m, 2H), 2.88 (m, 2H).
[00368] 13C RMN (101 MHz, DMSO-d6) δ: 145,21, 142,50, 140,09, 137,15, 133,80, 131,39, 129,54, 129,24, 121,94, 121,03, 120,33, 117,69, 114,55, 99,94, 59,62, 39,28, 36,90, 27,42, 14,64.[00368] 13C NMR (101 MHz, DMSO-d6) δ: 145.21, 142.50, 140.09, 137.15, 133.80, 131.39, 129.54, 129.24, 121.94 , 121.03, 120.33, 117.69, 114.55, 99.94, 59.62, 39.28, 36.90, 27.42, 14.64.
[00369] LCMS m/z = 384,2 [MH]+ Exemplo 20 (1r,3r)-3-(Cianometil)-3-(4-(6-(1-metil-1H-pirazol-4-il)pirazolo[1,5- a]pirazin-4-il)-1H-pirazol-1-il)ciclobutano-1-carbonitrila [00369] LCMS m/z = 384.2 [MH]+ Example 20 (1r,3r)-3-(Cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl) pyrazolo[1,5- a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile
[00370] A uma solução de (1r,3r)-3-(cianometil)-3-(4-(4,4,5,5- tetrametil-1,3,2-dioxaborolan-2-il)-1H-pirazol-1-il)ciclobutano-1- carbonitrila (Preparação 91, 3,38 g, 10,8 mmol) e 4-cloro-6-(1-metil- 1H-pirazol-4-il)pirazolo[1,5-a]pirazina (Preparação 11, 2,20 g, 9,4 mmol) em 1,4-dioxano (47,1 mL) foi adicionado K3PO4 aq. a 2 M (14,1 mL). Nitrogênio foi borbulhado através da mistura durante cerca de 5 min a cerca de 25 °C, em seguida XPhos Pd G2 (37,0 mg, 0,047 mmol) foi adicionado. A mistura foi aquecida a cerca de 40 °C durante cerca de 18 h, em seguida foi aquecida a cerca de 80 °C para dissolver o produto precipitado. A camada aquosa foi removida, ao mesmo tempo que mantendo a temperatura a cerca de 80 °C, em seguida a fase de 1,4-dioxano foi adicionada ao EtOH (471 mL, previamente pré- aquecido a cerca de 50 °C). A mistura foi agitada durante cerca de 10 min a cerca de 50 °C antes de ser removida do aquecimento. A agitação a cerca de 25 °C foi continuada durante cerca de 6 h. O sólido foi filtrado e lavado com EtOH (2 x 25 mL), água (2 x 50 mL) e EtOH (2 x 25 mL). O precipitado foi secado sob vácuo para proporcionar o composto título como um sólido branco (3,61 g, 74 %).[00370] To a solution of (1r,3r)-3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazol-1-yl)cyclobutane-1-carbonitrile (Preparation 91, 3.38 g, 10.8 mmol) and 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1.5 -a]pyrazine (Preparation 11, 2.20 g, 9.4 mmol) in 1,4-dioxane (47.1 mL) was added aq. at 2 M (14.1 mL). Nitrogen was bubbled through the mixture for about 5 min at about 25 °C, then XPhos Pd G2 (37.0 mg, 0.047 mmol) was added. The mixture was heated to about 40°C for about 18 h, then heated to about 80°C to dissolve the precipitated product. The aqueous layer was removed, while maintaining the temperature at about 80 °C, then the 1,4-dioxane phase was added to EtOH (471 mL, previously preheated to about 50 °C). The mixture was stirred for about 10 min at about 50°C before being removed from heating. Stirring at about 25°C was continued for about 6 h. The solid was filtered and washed with EtOH (2 x 25 mL), water (2 x 50 mL) and EtOH (2 x 25 mL). The precipitate was dried under vacuum to provide the title compound as a white solid (3.61 g, 74%).
[00371] O composto título (500 mg, 1,30 mmol) foi aquecido em 1,4- dioxano (6,5 mL) a cerca de 80 °C até que todo material tenha sido dissolvido. 1,2-Bis(difenilfosfino)etano (7,8 mg, 0,019 mmol) foi adicio-nado e o aquecimento a cerca de 80 °C foi continuado durante cerca de 4 hrs, em seguida a fase de 1,4-dioxano foi adicionada ao EtOH (58,7 mL, previamente pré-aquecido a cerca de 50 °C). Um adicional de 6,5 mL de EtOH pré-aquecido foi usado para enxaguar a vaso de reação. A mistura foi removida do aquecimento. A agitação a cerca de 25 °C foi continuada durante cerca de 18 h. O sólido foi filtrado e lavado com EtOH (2 x 5 mL), água (5 mL), em seguida EtOH (3 x 5 mL). O precipitado foi secado sob vácuo para proporcionar o composto título como um sólido branco (450 mg, 90 %).[00371] The title compound (500 mg, 1.30 mmol) was heated in 1,4-dioxane (6.5 mL) at about 80 °C until all material was dissolved. 1,2-Bis(diphenylphosphine)ethane (7.8 mg, 0.019 mmol) was added and heating at about 80 °C was continued for about 4 hrs, then the 1,4-dioxane phase was added to EtOH (58.7 mL, previously preheated to around 50 °C). An additional 6.5 mL of preheated EtOH was used to rinse the reaction vessel. The mixture was removed from heating. Stirring at about 25°C was continued for about 18 h. The solid was filtered and washed with EtOH (2 x 5 mL), water (5 mL), then EtOH (3 x 5 mL). The precipitate was dried under vacuum to provide the title compound as a white solid (450 mg, 90%).
[00372] Ponto de fusão 213 - 215 °C[00372] Melting point 213 - 215 °C
[00373] 1H RMN (400 MHz, DMSO-d6) δ: 9,02 (s, 1 H) 8,92 (s, 1 H) 8,52 (s, 1 H) 8,37 (s, 1 H) 8,19 (s, 1 H) 8,16 (s, 1 H) 7,45 (s, 1 H) 3,91 (s, 3 H) 3,55 - 3,65 (m, 1 H) 3,52 (s, 2 H) 3,22 - 3,38 (m, 2 H) 2,85 - 3,00 (m, 2 H).[00373] 1H NMR (400 MHz, DMSO-d6) δ: 9.02 (s, 1 H) 8.92 (s, 1 H) 8.52 (s, 1 H) 8.37 (s, 1 H ) 8.19 (s, 1 H) 8.16 (s, 1 H) 7.45 (s, 1 H) 3.91 (s, 3 H) 3.55 - 3.65 (m, 1 H) 3.52 (s, 2 H) 3.22 - 3.38 (m, 2 H) 2.85 - 3.00 (m, 2 H).
[00374] 13C RMN (126 MHz, DMSO-d6) δ: 145,17, 142,46, 140,20, 137,13, 133,78, 131,38, 129,82, 129,51, 122,28, 121,13, 120,33, 117,30, 114,54, 99,91, 61,51, 39,26, 36,26, 29,65, 16,05.[00374] 13C NMR (126 MHz, DMSO-d6) δ: 145.17, 142.46, 140.20, 137.13, 133.78, 131.38, 129.82, 129.51, 122.28 , 121.13, 120.33, 117.30, 114.54, 99.91, 61.51, 39.26, 36.26, 29.65, 16.05.
[00375] LCMS m/z = 384,1 [MH]+. Preparação 60 (1r,3r)-3-(Cianometil)-3-(3-metil-4-(4,4,5,5-tetrametil-1,3,2- dioxaborolan-2-il)-1H-pirazol-1-il)ciclobutano-1-carbonitrila (trans isômero) (1s,3s)-3-(Cianometil)-3-(3-metil-4-(4,4,5,5-tetrametil-1,3,2- dioxaborolan-2-il)-1H-pirazol-1-il)ciclobutano-1-carbonitrila (cis isômero) [00375] LCMS m/z = 384.1 [MH]+. Preparation 60 (1r,3r)-3-(Cyanomethyl)-3-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole -1-yl)cyclobutane-1-carbonitrile (trans isomer) (1s,3s)-3-(Cyanomethyl)-3-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1 -yl)cyclobutane-1-carbonitrile (cis isomer)
[00376] A uma solução de 3-metil-4-(4,4,5,5-tetrametil-1,3,2- dioxaborolan-2-il)-1H-pirazol (600 mg, 2,88 mmol) e 3- (cianometileno)ciclobutano-1-carbonitrila (Preparação 27, 341 mg, 2,88 mmol) em MeCN (28,8 mL) foi adicionado DBU (439 mg, 2,88 mmol) a cerca de 20 °C. Depois de cerca de 18 hrs a cerca de 20 °C, a mistura foi vertida em EtOAc e K2HPO4 aq. a 10 %. O EtOAc foi sepa-rado, e a fase aquosa foi extraída mais duas vezes com EtOAc. Os extratos de EtOAc combinados foram lavados com salmoura, secados (Na2SO4) e concentrados. O resíduo foi purificado por cromatografia de coluna para proporcionar (1r,3r)-3-(cianometil)-3-(3-metil-4-(4,4,5,5- tetrametil-1,3,2-dioxaborolan-2-il)-1H-pirazol-1-il)ciclobutano-1- carbonitrila (trans isômero, 325 mg, 35 %)[00376] To a solution of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (600 mg, 2.88 mmol) and 3-(cyanomethylene)cyclobutane-1-carbonitrile (Preparation 27, 341 mg, 2.88 mmol) in MeCN (28.8 mL) was added DBU (439 mg, 2.88 mmol) at about 20 °C. After about 18 hrs at about 20°C, the mixture was poured into EtOAc and aq. to 10%. The EtOAc was separated, and the aqueous phase was extracted twice more with EtOAc. The combined EtOAc extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by column chromatography to provide (1r,3r)-3-(cyanomethyl)-3-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile (trans isomer, 325 mg, 35%)
[00377] 1H RMN (400 MHz, CDCl3) δ: 7,79 (s, 1 H), 3,17 - 3,28 (m, 3 H), 3,16 (s, 2 H), 2,81 - 2,89 (m, 2 H), 2,39 (s, 3 H), 1,32 (s, 12 H).[00377] 1H NMR (400 MHz, CDCl3) δ: 7.79 (s, 1 H), 3.17 - 3.28 (m, 3 H), 3.16 (s, 2 H), 2.81 - 2.89 (m, 2 H), 2.39 (s, 3 H), 1.32 (s, 12 H).
[00378] LCMS m/z = 327,2 [MH]+ e (1s,3s)-3-(cianometil)-3-(3-metil- 4-(4,4,5,5-tetrametil-1,3,2-dioxaborolan-2-il)-1H-pirazol-1- il)ciclobutano-1-carbonitril (cis isômero, 171 mg, 18 %).[00378] LCMS m/z = 327.2 [MH]+ e (1s,3s)-3-(cyanomethyl)-3-(3-methyl- 4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitril (cis isomer, 171 mg, 18%).
[00379] 1H RMN (400 MHz, CDCl3) δ: 7,75 (s, 1 H), 3,18 - 3,28 (m, 1 H), 3,08 - 3,18 (m, 2 H), 3,05 (s, 2 H), 2,93 - 3,02 (m, 2 H), 2,39 (s, 3 H), 1,32 (s, 12 H).[00379] 1H NMR (400 MHz, CDCl3) δ: 7.75 (s, 1 H), 3.18 - 3.28 (m, 1 H), 3.08 - 3.18 (m, 2 H) , 3.05 (s, 2 H), 2.93 - 3.02 (m, 2 H), 2.39 (s, 3 H), 1.32 (s, 12 H).
[00380] LCMS m/z = 327,2 [MH]+ Exemplo 21 (1r,3r)-3-(Cianometil)-3-(3-metil-4-(6-(1-metil-1H-pirazol-4- il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)ciclobutano-1- carbonitrila [00380] LCMS m/z = 327.2 [MH]+ Example 21 (1r,3r)-3-(Cyanomethyl)-3-(3-methyl-4-(6-(1-methyl-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile
[00381] A uma solução de (1r,3r)-3-(cianometil)-3-(3-metil-4- (4,4,5,5-tetrametil-1,3,2-dioxaborolan-2-il)-1H-pirazol-1-il)ciclobutano- 1-carbonitrila (Preparação 60, trans isômero, 209 mg, 0,64 mmol) em 1,4-dioxano (4,3 mL) foi adicionado 4-cloro-6-(1-metil-1H-pirazol-4- il)pirazolo[1,5-a]pirazina (Preparação 11, 150 mg, 0,64 mmol) e K3PO4 aq. a 2 M (0,96 mL). A mistura foi purgada com nitrogênio durante cerca de 5 min, em seguida XPhos Pd G2 (101 mg, 0,13 mmol) foi adicionado. A mistura foi aquecida a cerca de 40 °C durante cerca de 2 hrs, em seguida concentradas. O resíduo foi dissolvido em EtOAc, e o EtOAc foi lavado com água. A fase aquosa foi extraída mais duas vezes com EtOAc, em seguida uma vez com DCM. Os extratos de EtO- Ac e DCM combinados foram secados (Na2SO4), concentrados, e o resíduo foi purificado por cromatografia para proporcionar um sólido o qual foi recristalizado a partir de MeCN para proporcionar o composto título (120 mg, 47 %).[00381] To a solution of (1r,3r)-3-(cyanomethyl)-3-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )-1H-pyrazol-1-yl)cyclobutane- 1-carbonitrile (Preparation 60, trans isomer, 209 mg, 0.64 mmol) in 1,4-dioxane (4.3 mL) was added 4-chloro-6- (1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (Preparation 11, 150 mg, 0.64 mmol) and aq. at 2 M (0.96 mL). The mixture was purged with nitrogen for about 5 min, then XPhos Pd G2 (101 mg, 0.13 mmol) was added. The mixture was heated to about 40°C for about 2 hrs, then concentrated. The residue was dissolved in EtOAc, and the EtOAc was washed with water. The aqueous phase was extracted twice more with EtOAc, then once with DCM. The combined EtO-Ac and DCM extracts were dried (Na2SO4), concentrated, and the residue was purified by chromatography to provide a solid which was recrystallized from MeCN to provide the title compound (120 mg, 47%).
[00382] 1H RMN (400 MHz, DMSO-d6) δ: 9,00 (s, 1 H), 8,74 (s, 1 H), 8,26 (s, 1 H), 8,18 (s, 1 H), 8,08 (s, 1 H), 7,32 (s, 1 H), 3,91 (s, 3 H), 3,55 (quin, 1 H), 3,48 (s, 2 H), 3,22 - 3,30 (m, 2 H), 2,84 - 2,93 (m, 2 H), 2,63 (s, 3 H).[00382] 1H NMR (400 MHz, DMSO-d6) δ: 9.00 (s, 1 H), 8.74 (s, 1 H), 8.26 (s, 1 H), 8.18 (s , 1 H), 8.08 (s, 1 H), 7.32 (s, 1 H), 3.91 (s, 3 H), 3.55 (quin, 1 H), 3.48 (s , 2 H), 3.22 - 3.30 (m, 2 H), 2.84 - 2.93 (m, 2 H), 2.63 (s, 3 H).
[00383] LCMS m/z = 398,3 [MH]+ Preparação 61 4-Bromo-1-metil-3-(((tetra-hidro-2H-piran-2-il)óxi)metil)-1H-pirazol [00383] LCMS m/z = 398.3 [MH]+ Preparation 61 4-Bromo-1-methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazole
[00384] A uma solução de 4-bromo-1-metil-1H-pirazol-3-metanol (720 mg, 3,77 mmol) em THF (30 mL) foi adicionado DHP (951 mg, 11,3 mmol) e PTSA (14 mg, 0,075 mmol). A solução foi agitada a cerca de 50 °C durante cerca de 16 hrs. A mistura foi concentrada, e o resíduo foi purificado por cromatografia para proporcionar o composto título como um óleo incolor (1,0 g, 84 %).[00384] To a solution of 4-bromo-1-methyl-1H-pyrazol-3-methanol (720 mg, 3.77 mmol) in THF (30 mL) was added DHP (951 mg, 11.3 mmol) and PTSA (14 mg, 0.075 mmol). The solution was stirred at about 50°C for about 16 hrs. The mixture was concentrated, and the residue was purified by chromatography to provide the title compound as a colorless oil (1.0 g, 84%).
[00385] 1H RMN (400 MHz, CDCl3) δ: 7,37 (s, 1 H), 4,81 (t, 1 H), 4,74 (d, 1 H), 4,46 (d, 1 H), 3,96 - 4,03 (m, 1 H), 3,88 (s, 3 H), 3,56 - 3,63 (m, 1 H), 1,80 - 1,93 (m, 1 H), 1,59 - 1,78 (m, 3 H), 1,48 - 1,57 (m, 2 H).[00385] 1H NMR (400 MHz, CDCl3) δ: 7.37 (s, 1 H), 4.81 (t, 1 H), 4.74 (d, 1 H), 4.46 (d, 1 H), 3.96 - 4.03 (m, 1 H), 3.88 (s, 3 H), 3.56 - 3.63 (m, 1 H), 1.80 - 1.93 (m , 1 H), 1.59 - 1.78 (m, 3 H), 1.48 - 1.57 (m, 2 H).
[00386] LCMS m/z = 190,7 [MH-THP]+ Preparação 62 (1s,3s)-3-(Cianometil)-3-(4-(6-(1-metil-3-(((tetra-hidro-2H-piran-2- il)óxi)metil)-1H-pirazol-4-il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1- il)ciclobutano-1-carbonitrila [00386] LCMS m/z = 190.7 [MH-THP]+ Preparation 62 (1s,3s)-3-(Cyanomethyl)-3-(4-(6-(1-methyl-3-(((tetra -hydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1 -carbonitrile
[00387] A uma solução de 4-bromo-1-metil-3-(((tetra-hidro-2H-piran- 2-il)óxi)metil)-1H-pirazol (Preparação 61, 200 mg, 0,73 mmol) em 1,4- dioxano (10 mL) foram adicionados KOAc (313 mg, 3,19 mmol), e bis(pinacolato)diboro (405 mg, 1,59 mmol). A mistura foi purgada com nitrogênio durante cerca de 5 min antes da adição de Pd(dppf)Cl2 (78 mg, 0,11 mmol). A mistura foi aquecida a cerca de 90 °C durante cerca de 18 hrs. A mistura foi concentrada para proporcionar uma amostra impura de 1-metil-3-(((tetra-hidro-2H-piran-2-il)óxi)metil)-4-(4,4,5,5- tetrametil-1,3,2-dioxaborolan-2-il)-1H-pirazol como um óleo preto (234 mg), o qual foi usado na Parte 2 abaixo de sem outra purificação.[00387] To a solution of 4-bromo-1-methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazole (Preparation 61, 200 mg, 0.73 mmol) in 1,4-dioxane (10 mL) were added KOAc (313 mg, 3.19 mmol), and bis(pinacolato)diboron (405 mg, 1.59 mmol). The mixture was purged with nitrogen for about 5 min before adding Pd(dppf)Cl2 (78 mg, 0.11 mmol). The mixture was heated to about 90°C for about 18 hrs. The mixture was concentrated to provide an impure sample of 1-methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1H-pyrazole as a black oil (234 mg), which was used in Part 2 below without further purification.
[00388] Uma mistura de (1r,3r)-3-(4-(6-cloropirazolo[1,5-a]pirazin-4- il)-1H-pirazol-1-il)-3-(cianometil)ciclobutano-1-carbonitrila (Preparação 75, 85 mg, 0,25 mmol), 1-metil-3-(((tetra-hidro-2H-piran-2-il)óxi)metil)- 4-(4,4,5,5-tetrametil-1,3,2-dioxaborolan-2-il)-1H-pirazol (Parte 1,81 mg, 0,25 mmol), e K3PO4 aq. a 2 M (1,0 mL) em 1,4-dioxano (3,0 mL) foi purgada com argônio durante cerca de 2 min, depois dos quais XPhos Pd G2 (39 mg, 0,050 mmol) foi adicionado. A mistura de reação foi aquecida a cerca de 45 °C durante cerca de 45 min. A fase de 1,4- dioxano foi separada da fase aquosa, a qual foi extraída também com EtOAc (5 mL). Os extratos de 1,4-dioxano e EtOAc combinados foram secados (Na2SO4) e concentradas. O resíduo o qual foi purificado por cromatografia para proporcionar o composto título (50 mg, 40 %).[00388] A mixture of (1r,3r)-3-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)cyclobutane -1-carbonitrile (Preparation 75, 85 mg, 0.25 mmol), 1-methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)- 4-(4.4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Part 1.81 mg, 0.25 mmol), and aq. 2 M (1.0 mL) in 1,4-dioxane (3.0 mL) was purged with argon for about 2 min, after which XPhos Pd G2 (39 mg, 0.050 mmol) was added. The reaction mixture was heated to about 45 °C for about 45 min. The 1,4-dioxane phase was separated from the aqueous phase, which was also extracted with EtOAc (5 mL). The combined 1,4-dioxane and EtOAc extracts were dried (Na2SO4) and concentrated. The residue which was purified by chromatography to provide the title compound (50 mg, 40%).
[00389] 1H RMN (400 MHz, CDCl3) δ: 8,92 (s, 1 H), 8,45 (s, 1 H), 8,33 (s, 1 H), 8,07 - 8,10 (m, 1 H), 8,00 (s, 1 H), 6,96 (d, 1 H), 5,02 (d, 1 H), 4,87 - 4,91 (m, 1 H), 4,70 (m, 1 H), 4,59 (d, 1 H), 4,51 (d, 1 H), 3,99 (s, 3 H), 3,51 - 3,62 (m, 2 H), 3,34 - 3,44 (m, 1 H), 3,29 (s, 2 H), 2,99 (m, 2 H), 1,80 - 1,96 (m, 3 H), 1,68 - 1,80 (m, 3 H).[00389] 1H NMR (400 MHz, CDCl3) δ: 8.92 (s, 1 H), 8.45 (s, 1 H), 8.33 (s, 1 H), 8.07 - 8.10 (m, 1 H), 8.00 (s, 1 H), 6.96 (d, 1 H), 5.02 (d, 1 H), 4.87 - 4.91 (m, 1 H) , 4.70 (m, 1 H), 4.59 (d, 1 H), 4.51 (d, 1 H), 3.99 (s, 3 H), 3.51 - 3.62 (m , 2 H), 3.34 - 3.44 (m, 1 H), 3.29 (s, 2 H), 2.99 (m, 2 H), 1.80 - 1.96 (m, 3 H), 1.68 - 1.80 (m, 3 H).
[00390] LCMS m/z = 498,3 [MH]+ Exemplo 22 (1r,3r)-3-(Cianometil)-3-(4-(6-(3-(hidroximetil)-1-metil-1H-pirazol-4- il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)ciclobutano-1- carbonitrila [00390] LCMS m/z = 498.3 [MH]+ Example 22 (1r,3r)-3-(Cyanomethyl)-3-(4-(6-(3-(hydroxymethyl)-1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile
[00391] PTSA (10 mg, 0,052 mmol) foi adicionado à solução de (1s,3s)-3-(cianometil)-3-(4-(6-(1-metil-3-(((tetra-hidro-2H-piran-2- il)óxi)metil)-1H-pirazol-4-il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1- il)ciclobutano-1-carbonitrila (Preparação 62, 50 mg, 0,10 mmol) em MeOH (10 mL). A mistura de reação foi mantida a cerca de 20 °C du- rante cerca de 18 hrs. O sólido precipitado foi filtrado para proporcionar o composto título (20 mg, 48 %).[00391] PTSA (10 mg, 0.052 mmol) was added to the solution of (1s,3s)-3-(cyanomethyl)-3-(4-(6-(1-methyl-3-(((tetrahydro- 2H-pyran-2-yl)oxy)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile ( Preparation 62, 50 mg, 0.10 mmol) in MeOH (10 mL). The reaction mixture was maintained at about 20 ° C for about 18 hrs. The precipitated solid was filtered to provide the title compound (20 mg, 48%).
[00392] 1H RMN (400 MHz, DMSO-d6) δ: 9,00 (s, 1 H), 8,91 (s, 1 H), 8,48 (s, 1 H), 8,35 (s, 1 H), 8,22 (d, 1 H), 7,47 (d, 1 H), 5,41 (br. s., 1 H), 4,66 (s, 2 H), 3,88 (s, 3 H), 3,54 - 3,62 (m, 1 H), 3,52 (s, 2 H), 3,28 - 3,34 (m, 2 H), 2,90 - 2,98 (m, 2 H).[00392] 1H NMR (400 MHz, DMSO-d6) δ: 9.00 (s, 1 H), 8.91 (s, 1 H), 8.48 (s, 1 H), 8.35 (s , 1 H), 8.22 (d, 1 H), 7.47 (d, 1 H), 5.41 (br. s., 1 H), 4.66 (s, 2 H), 3, 88 (s, 3 H), 3.54 - 3.62 (m, 1 H), 3.52 (s, 2 H), 3.28 - 3.34 (m, 2 H), 2.90 - 2.98 (m, 2H).
[00393] LCMS m/z = 414,4 [MH]+ Preparação 63 (1r,3r)-3-(Cianometil)-3-(4-(6-(1-metil-3-nitro-1H-pirazol-4- il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)ciclobutano-1- carbonitrila [00393] LCMS m/z = 414.4 [MH]+ Preparation 63 (1r,3r)-3-(Cyanomethyl)-3-(4-(6-(1-methyl-3-nitro-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile
[00394] A uma solução de 4-bromo-1-metil-3-nitro-1H-pirazol (200 mg, 0,97 mmol) em 1,4-dioxano (10 mL) foram adicionados KOAc (285 mg, 2,90 mmol), e bis(pinacolato)diboro (368 mg, 1,45 mmol). A mistura foi purgada com nitrogênio durante cerca de 5 min, depois dos quais Pd(dppf)Cl2 (70,8 mg, 0,097 mmol) foi adicionado. A mistura foi aquecida a cerca de 90 °C durante cerca de 18 h. A mistura foi concentrada para proporcionar 1-metil-3-nitro-4-(4,4,5,5-tetrametil-1,3,2- dioxaborolan-2-il)-1H-pirazol impuro como um óleo preto, o qual foi usado sem outra purificação na Parte 2.[00394] To a solution of 4-bromo-1-methyl-3-nitro-1H-pyrazole (200 mg, 0.97 mmol) in 1,4-dioxane (10 mL) was added KOAc (285 mg, 2. 90 mmol), and bis(pinacolato)diboron (368 mg, 1.45 mmol). The mixture was purged with nitrogen for about 5 min, after which Pd(dppf)Cl2 (70.8 mg, 0.097 mmol) was added. The mixture was heated to about 90°C for about 18 h. The mixture was concentrated to provide crude 1-methyl-3-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a black oil, the which was used without further purification in Part 2.
[00395] Uma mistura de (1r,3r)-3-(4-(6-cloropirazolo[1,5-a]pirazin-4- il)-1H-pirazol-1-il)-3-(cianometil)ciclobutano-1-carbonitrila (Preparação 75, 130 mg, 0,38 mmol), 1-metil-3-nitro-4-(4,4,5,5-tetrametil-1,3,2- dioxaborolan-2-il)-1H-pirazol (Parte 1, 97 mg, 0,38 mmol) e K3PO4 aq. a 2 M (2,0 mL) em 1,4-dioxano (6,0 mL) foi purgada com argônio durante cerca de 2 min, depois dos quais XPhos Pd G2 (60,6 mg, 0,077 mmol) foi adicionado. A mistura foi aquecida a cerca de 45 °C durante cerca de 45 min. A fase de 1,4-dioxano foi separada da fase aquosa, a qual foi extraída também com EtOAc (10 mL). Os extratos de 1,4- dioxano e EtOAc combinados foram secados (Na2SO4) e concentrados. O resíduo foi purificado por cromatografia para proporcionar o composto título (120 mg, 72 %).[00395] A mixture of (1r,3r)-3-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)cyclobutane -1-carbonitrile (Preparation 75, 130 mg, 0.38 mmol), 1-methyl-3-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (Part 1, 97 mg, 0.38 mmol) and aq. 2 M (2.0 mL) in 1,4-dioxane (6.0 mL) was purged with argon for about 2 min, after which XPhos Pd G2 (60.6 mg, 0.077 mmol) was added. The mixture was heated to about 45°C for about 45 min. The 1,4-dioxane phase was separated from the aqueous phase, which was also extracted with EtOAc (10 mL). The combined 1,4-dioxane and EtOAc extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography to provide the title compound (120 mg, 72%).
[00396] 1H RMN (400 MHz, DMSO-d6) δ: 9,10 (s, 1 H), 8,90 (s, 1 H), 8,56 (s, 1 H), 8,43 (s, 1 H), 8,32 (d, 1 H), 7,56 (br. s., 1 H), 4,05 (s, 3 H), 3,54 - 3,60 (m, 1 H), 3,51 (s, 2 H), 3,18 - 3,29 (m, 2 H), 2,88 - 2,98 (m, 2 H).[00396] 1H NMR (400 MHz, DMSO-d6) δ: 9.10 (s, 1 H), 8.90 (s, 1 H), 8.56 (s, 1 H), 8.43 (s , 1 H), 8.32 (d, 1 H), 7.56 (br. s., 1 H), 4.05 (s, 3 H), 3.54 - 3.60 (m, 1 H ), 3.51 (s, 2 H), 3.18 - 3.29 (m, 2 H), 2.88 - 2.98 (m, 2 H).
[00397] LCMS m/z = 429,4 [MH]+ Exemplo 23 (1r,3r)-3-(4-(6-(3-Amino-1-metil-1H-pirazol-4-il)pirazolo[1,5- a]pirazin-4-il)-1H-pirazol-1-il)-3-(cianometil)ciclobutano-1- carbonitrila [00397] LCMS m/z = 429.4 [MH]+ Example 23 (1r,3r)-3-(4-(6-(3-Amino-1-methyl-1H-pyrazol-4-yl)pyrazolo[ 1,5- a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)cyclobutane-1-carbonitrile
[00398] A uma solução de (1r,3r)-3-(cianometil)-3-(4-(6-(1-metil-3- nitro-1H-pirazol-4-il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1- il)ciclobutano-1-carbonitrila (Preparação 63, 120 mg, 0,28 mmol) em EtOH (3 mL) e água (0,5 mL) foram adicionados NH4Cl (90 mg, 1,68 mmol) e pó de ferro (50 mg, 0,90 mmol). A reação foi agitada a cerca de 60 °C durante cerca de 18 hrs, depois dos quais porções adicionais de pó de ferro e NH4Cl foram adicionados. A mistura foi aquecida a cerca de 100 °C durante cerca de 3 hrs. A mistura foi concentrada e EtOH quente (20 mL) foi adicionado. Os sólidos não dissolvidos foram removidos por filtração. O filtrado foi concentrado, e o resíduo foi purificado por cromatografia para proporcionar o composto título como um sólido branco (10 mg, 9 %).[00398] To a solution of (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-3-nitro-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile (Preparation 63, 120 mg, 0.28 mmol) in EtOH (3 mL) and water (0.5 mL) were added NH4Cl (90 mg, 1.68 mmol) and iron powder (50 mg, 0.90 mmol). The reaction was stirred at about 60 °C for about 18 hrs, after which additional portions of iron powder and NH4Cl were added. The mixture was heated to about 100°C for about 3 hrs. The mixture was concentrated and hot EtOH (20 mL) was added. Undissolved solids were removed by filtration. The filtrate was concentrated, and the residue was purified by chromatography to provide the title compound as a white solid (10 mg, 9%).
[00399] 1H RMN (400 MHz, CD3OD) δ: 8,74 (s, 1 H), 8,67 (s, 1 H), 8,40 (s, 1 H), 8,08 (d, 1 H), 7,94 (s, 1 H), 7,24 (d, 1 H), 3,77 (s, 3 H), 3,47 - 3,55 (m, 1 H), 3,43 (s, 2 H), 3,34 - 3,41 (m, 2 H), 2,98 (dd, 2 H).[00399] 1H NMR (400 MHz, CD3OD) δ: 8.74 (s, 1 H), 8.67 (s, 1 H), 8.40 (s, 1 H), 8.08 (d, 1 H), 7.94 (s, 1 H), 7.24 (d, 1 H), 3.77 (s, 3 H), 3.47 - 3.55 (m, 1 H), 3.43 (s, 2 H), 3.34 - 3.41 (m, 2 H), 2.98 (dd, 2 H).
[00400] LCMS m/z = 399,4 [MH]+ Preparação 64 3,5-Dibromo-1-metil-1H-pirazol [00400] LCMS m/z = 399.4 [MH]+ Preparation 64 3,5-Dibromo-1-methyl-1H-pyrazole
[00401] Uma solução de 3,5-dibromopirazol (6,5 g, 28,7 mmol) em THF (30 mL) foi adicionado gota a gota a uma suspensão resfriada com gelo de NaH (2,88 g, 60 % em mineral óleo, 71,9 mmol) em THF (45 mL). A mistura foi agitada a cerca de 0 °C durante cerca de 1 hr. Iodometano (5,37 mL, 86,3 mmol) foi adicionado, e a mistura foi agitada a cerca de 0 °C durante cerca de 3 hrs, em seguida a agitação foi continuada a cerca de 15 °C durante cerca de 2 hrs. A mistura foi vertida em NH4Cl aq. saturado (20 mL) e extraída com EtOAc (40 mL). O extrato de EtOAc foi lavado com salmoura (20 mL), secado (Na2SO4) e concentrado. O resíduo foi purificado por cromatografia para proporcionar o composto título como um óleo incolor (5,5 g, 79 %).[00401] A solution of 3,5-dibromopyrazole (6.5 g, 28.7 mmol) in THF (30 mL) was added dropwise to an ice-cooled suspension of NaH (2.88 g, 60% in mineral oil, 71.9 mmol) in THF (45 mL). The mixture was stirred at about 0°C for about 1 hr. Iodomethane (5.37 mL, 86.3 mmol) was added, and the mixture was stirred at about 0°C for about 3 hrs, then stirring was continued at about 15°C for about 2 hrs. The mixture was poured into aq. saturated (20 mL) and extracted with EtOAc (40 mL). The EtOAc extract was washed with brine (20 mL), dried (Na2SO4) and concentrated. The residue was purified by chromatography to provide the title compound as a colorless oil (5.5 g, 79%).
[00402] 1H RMN (400 MHz, CDCl3) δ: 6,31 (s, 1 H), 3,87 (s, 3 H).[00402] 1H NMR (400 MHz, CDCl3) δ: 6.31 (s, 1 H), 3.87 (s, 3 H).
[00403] LCMS m/z = 240,6 [MH]+(isótopo 79Br, 81Br) Preparação 65 Ácido 3-bromo-1-metil-1H-pirazol-5-carboxílico [00403] LCMS m/z = 240.6 [MH]+(isotope 79Br, 81Br) Preparation 65 3-Bromo-1-methyl-1H-pyrazol-5-carboxylic acid
[00404] Uma solução de 3,5-dibromo-1-metil-1H-pirazol (Preparação 64, 3,0 g, 12,5 mmol) em THF (30 mL) foi tratado gota a gota com n-BuLi (2,5 M, 6,25 mL, 15,6 mmol) a cerca de -70 °C. Depois de cerca de 30 min nesta temperatura, uma solução de CO2 em THF (30 mL) foi adicio-nada gota a gota, ao mesmo tempo que mantendo a temperatura interna abaixo de cerca de -65 °C. A mistura foi agitada a esta temperatura du-rante cerca de 1 hr. A mistura de reação foi em seguida vertida em HCl aq. a 1 M (50 mL), e a mistura foi parcialmente concentrada para remo-ver a maior parte da THF. A camada aquosa foi extraída com DCM (50 mL). O extrato de DCM foi secado (Na2SO4) e concentrado para propor-cionar o composto título como um sólido amarelo (2,1 g, 81 %).[00404] A solution of 3,5-dibromo-1-methyl-1H-pyrazole (Preparation 64, 3.0 g, 12.5 mmol) in THF (30 mL) was treated dropwise with n-BuLi (2 .5 M, 6.25 mL, 15.6 mmol) at about -70 °C. After about 30 min at this temperature, a solution of CO2 in THF (30 mL) was added dropwise, while keeping the internal temperature below about -65 °C. The mixture was stirred at this temperature for about 1 hr. The reaction mixture was then poured into aq. to 1 M (50 mL), and the mixture was partially concentrated to remove most of the THF. The aqueous layer was extracted with DCM (50 ml). The DCM extract was dried (Na2SO4) and concentrated to provide the title compound as a yellow solid (2.1 g, 81%).
[00405] 1H RMN (400 MHz, DMSO-d6) δ: 13,70 (br s, 1 H), 6,95 (s, 1 H), 4,04 (s, 3H).[00405] 1H NMR (400 MHz, DMSO-d6) δ: 13.70 (br s, 1 H), 6.95 (s, 1 H), 4.04 (s, 3H).
[00406] LCMS m/z = 206,9 [MH]+ (isótopo 81Br) Preparação 66 terc-Butil (3-bromo-1-metil-1H-pirazol-5-il)carbamato [00406] LCMS m/z = 206.9 [MH]+ (isotope 81Br) Preparation 66 tert-Butyl (3-bromo-1-methyl-1H-pyrazol-5-yl)carbamate
[00407] Difenilfosforil azida (18,8 g, 68,5 mmol) foi adicionado a uma solução de ácido 5-bromo-2-metil-2H-pirazol-3-carboxílico (Preparação 65, 7,02 g, 34,2 mmol) e DIPEA (11,9 mL, 68,5 mmol) em t- butanol (114 mL). A mistura foi agitada a cerca de 45 °C durante cerca de 30 min, em seguida aquecida sob refluxo durante cerca de 5 hrs. A mistura resfriada foi diluída com EtOAc (60 mL) e lavada com NaHCO3 aq. saturado (2 x 30 mL) e salmoura (20 mL). O extrato de EtOAc foi concentrado, e o resíduo foi purificado por cromatografia para propor- cionar o composto título como um sólido amarelo (4,80 g, 51 %).[00407] Diphenylphosphoryl azide (18.8 g, 68.5 mmol) was added to a solution of 5-bromo-2-methyl-2H-pyrazol-3-carboxylic acid (Preparation 65, 7.02 g, 34.2 mmol) and DIPEA (11.9 mL, 68.5 mmol) in t-butanol (114 mL). The mixture was stirred at about 45°C for about 30 min, then heated under reflux for about 5 hrs. The cooled mixture was diluted with EtOAc (60 mL) and washed with aq. saturated (2 x 30 mL) and brine (20 mL). The EtOAc extract was concentrated, and the residue was purified by chromatography to provide the title compound as a yellow solid (4.80 g, 51%).
[00408] 1H RMN (400 MHz, DMSO-d6) δ: 6,28 (br s, 1 H), 6,18 (s, 1 H), 3,73 (s, 3 H), 1,50 (s, 9H).[00408] 1H NMR (400 MHz, DMSO-d6) δ: 6.28 (br s, 1 H), 6.18 (s, 1 H), 3.73 (s, 3 H), 1.50 ( s, 9H).
[00409] LCMS m/z = 221,7 [MH-C4H8]+ (isótopo 81Br) Preparação 67 3-Bromo-1-metil-5-(diBoc)-amino-1H-pirazol [00409] LCMS m/z = 221.7 [MH-C4H8]+ (isotope 81Br) Preparation 67 3-Bromo-1-methyl-5-(diBoc)-amino-1H-pyrazole
[00410] Di-terc-butil dicarbonato (1,58 g, 7,24 mmol) foi adicionado a uma solução de terc-butil (3-bromo-1-metil-1H-pirazol-5-il)carbamato (Preparação 66, 2,0 g, 7,24 mmol), TEA (4,04 mL, 29,0 mmol), e DMAP (177 mg, 1,45 mmol) em DCM (40 mL). A mistura foi agitada a cerca de 20 °C durante cerca de 18 hrs. Água (25 mL) foi adicionada, e a mistura foi extraída com DCM (2 x 30 mL). Os extratos de DCM combinados foram concentrados, e o resíduo foi purificado cromato- grafia para proporcionar o composto título (1,85 g, 67) %.[00410] Di-tert-butyl dicarbonate (1.58 g, 7.24 mmol) was added to a solution of tert-butyl (3-bromo-1-methyl-1H-pyrazol-5-yl)carbamate (Preparation 66 , 2.0 g, 7.24 mmol), TEA (4.04 mL, 29.0 mmol), and DMAP (177 mg, 1.45 mmol) in DCM (40 mL). The mixture was stirred at about 20°C for about 18 hrs. Water (25 mL) was added, and the mixture was extracted with DCM (2 x 30 mL). The combined DCM extracts were concentrated, and the residue was purified by chromatography to provide the title compound (1.85 g, 67%) %.
[00411] 1H RMN (400 MHz, CDCl3) δ: 6,06 - 6,20 (m, 1 H), 3,64 (s, 3 H), 1,44 (s, 18 H).[00411] 1H NMR (400 MHz, CDCl3) δ: 6.06 - 6.20 (m, 1 H), 3.64 (s, 3 H), 1.44 (s, 18 H).
[00412] LCMS m/z = 378,2 [MH]+(isótopo 81Br) Exemplo 24 2-((1r,3s)-1-(4-(6-(5-Amino-1-metil-1H-pirazol-3-il)pirazolo[1,5- a]pirazin-4-il)-1H-pirazol-1-il)-3-metoxiciclobutil)acetonitrila [00412] LCMS m/z = 378.2 [MH]+(isotope 81Br) Example 24 2-((1r,3s)-1-(4-(6-(5-Amino-1-methyl-1H-pyrazole -3-yl)pyrazolo[1,5- a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile
[00413] Uma mistura de 3-bromo-1-metil-5-(diBoc)-amino-1H- pirazol (Preparação 67, 1200 mg, 3,19 mmol), KOAc (988 mg, 9,57 mmol) e bis(pinacolato)diboro (1210 mg, 4,78 mmol) em 1,4-dioxano (15 mL) foi purgada com argônio durante cerca de 5 minutos antes de XPhos Pd G2 (502 mg, 0,64 mmol) foi adicionado. A mistura de reação foi aquecida a cerca de 65 °C durante cerca de 3,5 hrs, em seguida 2- ((1s,3r)-1-(4-(6-cloropirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)-3- metoxiciclo-butil)acetonitrila (Preparação 100, 1090 mg, 3,19 mmol), K3PO4 aq. a 2 M (4,78 mL) e XPhos Pd G2 (502 mg, 0,64 mmol) foram adicionados. A mistura foi purgada com argônio novamente, em seguida aquecida a cerca de 80 °C durante cerca de 1 hr. EtOAc foi adicionado e as fases foram separadas. A fase aquosa foi extraída mais duas vezes com EtOAc e os extratos de EtOAc combinados foram concentrados. O resíduo foi purificado por cromatografia para proporcionar uma mistura de intermediários de mono- e di-BOC (710 mg, 36 %) a qual foi usada na Parte 2.[00413] A mixture of 3-bromo-1-methyl-5-(diBoc)-amino-1H-pyrazole (Preparation 67, 1200 mg, 3.19 mmol), KOAc (988 mg, 9.57 mmol) and bis (pinacolato)diboron (1210 mg, 4.78 mmol) in 1,4-dioxane (15 mL) was purged with argon for about 5 minutes before XPhos Pd G2 (502 mg, 0.64 mmol) was added. The reaction mixture was heated to about 65°C for about 3.5 hrs, then 2-((1s,3r)-1-(4-(6-chloropyrazolo[1,5-a]pyrazin-4 -yl)-1H-pyrazol-1-yl)-3-methoxycyclo-butyl)acetonitrile (Preparation 100, 1090 mg, 3.19 mmol), K3PO4 aq. at 2 M (4.78 mL) and XPhos Pd G2 (502 mg, 0.64 mmol) were added. The mixture was purged with argon again, then heated to about 80 °C for about 1 hr. EtOAc was added and the phases were separated. The aqueous phase was extracted twice more with EtOAc and the combined EtOAc extracts were concentrated. The residue was purified by chromatography to provide a mixture of mono- and di-BOC intermediates (710 mg, 36%) which was used in Part 2.
[00414] TFA (6 mL, 80 mmol) adicionado a uma solução dos inter-mediários de mono- e di-BOC da Parte 1 (710 mg, 1,18 mmol) em DCM (6 mL) a cerca de 20 °C. Depois de cerca de 1 hr, a mistura foi concentrada. DCM foi adicionado, seguido por NaHCO3 aq. saturado suficiente para tornar o pH da solução básico. As fases foram separadas, e a fase aquosa foi extraída mais duas vezes com DCM. Os extratos de DCM combinados foram secados (Na2SO4) e concentrados. Uma reação equivalente usando o composto da Parte 1 (220 mg, 0,36 mmol) e TFA (2 mL, 30 mmol) em DCM (2 mL) foi combinada com a material a partir da reação anterior, e as amostras combinadas foram purificadas por cromatografia para proporcionar o composto título como uma goma clara (470 mg, 99 %).[00414] TFA (6 mL, 80 mmol) added to a solution of the mono- and di-BOC intermediates from Part 1 (710 mg, 1.18 mmol) in DCM (6 mL) at about 20 °C . After about 1 hr, the mixture was concentrated. DCM was added, followed by aq. saturated enough to make the pH of the solution basic. The phases were separated, and the aqueous phase was extracted twice more with DCM. The combined DCM extracts were dried (Na2SO4) and concentrated. An equivalent reaction using the compound from Part 1 (220 mg, 0.36 mmol) and TFA (2 mL, 30 mmol) in DCM (2 mL) was combined with the material from the previous reaction, and the combined samples were purified. by chromatography to provide the title compound as a clear gum (470 mg, 99%).
[00415] 1H RMN (400 MHz, DMSO-d6) δ: 8,81 (s, 1 H), 8,73 (s, 1 H), 8,40 (s, 1 H), 8,21 (d, 1 H), 7,44 (d, 1 H), 5,33 (br. s, 2 H), 3,94 - 4,02 (m, 1 H), 3,62 (s, 3 H), 3,44 (s, 2 H), 3,21 (s, 3 H), 3,14 - 3,20 (m, 2 H), 2,39 - 2,45 (m, 2 H).[00415] 1H NMR (400 MHz, DMSO-d6) δ: 8.81 (s, 1 H), 8.73 (s, 1 H), 8.40 (s, 1 H), 8.21 (d , 1 H), 7.44 (d, 1 H), 5.33 (br. s, 2 H), 3.94 - 4.02 (m, 1 H), 3.62 (s, 3 H) , 3.44 (s, 2 H), 3.21 (s, 3 H), 3.14 - 3.20 (m, 2 H), 2.39 - 2.45 (m, 2 H).
[00416] LCMS m/z = 404,5 [MH]+ Preparação 68 Dietil 4-bromo-1H-pirazol-3,5-dicarboxilato [00416] LCMS m/z = 404.5 [MH]+ Preparation 68 Diethyl 4-bromo-1H-pyrazol-3,5-dicarboxylate
[00417] Uma mistura de dietil éster de ácido 1H-pirazol-3,5- dicarboxílico (4,0 g, 18,85 mmol) e N-bromossuccinimida (4,03 g, 22,6 mmol) em uma mistura de ácido nítrico conc. e ácido acético glacial (12,0 mL, 5:95 v / v) foi aquecida por irradiação de micro-ondas a cerca de 120 °C durante cerca de 20 minutos. Um total de 13,0 g (61,26 mmol) de material de partida dietil éster de ácido 1H-pirazol-3,5- dicarboxílico foi processado desta maneira em bateladas paralelas. As misturas de reação cruas marrons resultantes foram combinadas, vertidas em água (260 mL) e tratadas com NaHCO3 suficiente para tornar o pH da solução básico. A mistura foi extraída com EtOAc (3 x 300 mL). Os extratos de EtOAc combinados foram secados (Na2SO4) e concentrados para proporcionar o composto título como um sólido esbranquiçado (17,0 g, 95 %).[00417] A mixture of 1H-pyrazol-3,5-dicarboxylic acid diethyl ester (4.0 g, 18.85 mmol) and N-bromosuccinimide (4.03 g, 22.6 mmol) in a mixture of acid nitric conc. and glacial acetic acid (12.0 mL, 5:95 v/v) was heated by microwave irradiation at about 120 °C for about 20 minutes. A total of 13.0 g (61.26 mmol) of 1H-pyrazol-3,5-dicarboxylic acid diethyl ester starting material was processed in parallel batches in this manner. The resulting raw brown reaction mixtures were combined, poured into water (260 mL) and treated with enough NaHCO3 to make the pH of the solution basic. The mixture was extracted with EtOAc (3 x 300 mL). The combined EtOAc extracts were dried (Na2SO4) and concentrated to provide the title compound as an off-white solid (17.0 g, 95%).
[00418] 1H RMN (400 MHz, CDCl3) δ: 8,79 (br. s., 1 H), 4,44 (q, 4 H), 1,42 (t, 6 H).[00418] 1H NMR (400 MHz, CDCl3) δ: 8.79 (br. s., 1 H), 4.44 (q, 4 H), 1.42 (t, 6 H).
[00419] LCMS m/z = 290,7 [MH]+(isótopo 79Br) Preparação 69 Dietil 4-bromo-1-(2-(1-metil-1H-pirazol-4-il)-2-oxoetil)-1H-pirazol- 3,5-dicarboxilato [00419] LCMS m/z = 290.7 [MH]+(isotope 79Br) Preparation 69 Diethyl 4-bromo-1-(2-(1-methyl-1H-pyrazol-4-yl)-2-oxoethyl)- 1H-pyrazole- 3,5-dicarboxylate
[00420] Uma solução de dietil éster de ácido 4-bromo-1H-pirazol- 3,5-dicarboxílico (Preparação 68, 9,66 g, 33,18 mmol) e 2-bromo-1-(1- metil-1H-pirazol-4-il)-etanona (Preparação 6, 6,0 g, 29,55 mmol) em MeCN (140 mL) foi tratada com K2CO3 (5,31 g, 38,40 mmol), e a mistura de reação foi agitada a cerca de 25 °C durante cerca de 16 hrs. Água (100 mL) foi adicionada, e a mistura foi extraída com EtOAc (3 x 100 mL). Os extratos de EtOAc combinados foram secados (Na2SO4) e concentrados. O resíduo foi purificado por cromatografia para proporcionar o composto título como um sólido branco (10,0 g, 82 %).[00420] A solution of 4-bromo-1H-pyrazol-3,5-dicarboxylic acid diethyl ester (Preparation 68, 9.66 g, 33.18 mmol) and 2-bromo-1-(1-methyl-1H -pyrazol-4-yl)-ethanone (Preparation 6, 6.0 g, 29.55 mmol) in MeCN (140 mL) was treated with K2CO3 (5.31 g, 38.40 mmol), and the reaction mixture was stirred at about 25°C for about 16 hrs. Water (100 mL) was added, and the mixture was extracted with EtOAc (3 x 100 mL). The combined EtOAc extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography to provide the title compound as a white solid (10.0 g, 82%).
[00421] 1H RMN (400 MHz, CDCl3) δ: 7,95 (s, 1 H), 7,92 (s, 1 H), 5,82 (s, 2 H), 4,43 (q, 2 H), 4,36 (q, 2 H), 3,96 (s, 3 H), 1,45 (t, 3 H), 1,35 (t, 3 H).[00421] 1H NMR (400 MHz, CDCl3) δ: 7.95 (s, 1 H), 7.92 (s, 1 H), 5.82 (s, 2 H), 4.43 (q, 2 H), 4.36 (q, 2 H), 3.96 (s, 3 H), 1.45 (t, 3 H), 1.35 (t, 3 H).
[00422] LCMS m/z = 436,8 [MNa]+ (isótopo 81Br) Preparação 70 Dietil 4-metil-1-(2-(1-metil-1H-pirazol-4-il)-2-oxoetil)-1H-pirazol-3,5- dicarboxilato [00422] LCMS m/z = 436.8 [MNa]+ (isotope 81Br) Preparation 70 Diethyl 4-methyl-1-(2-(1-methyl-1H-pyrazol-4-yl)-2-oxoethyl)- 1H-pyrazole-3,5-dicarboxylate
[00423] Uma mistura de K2CO3 (11,0 g, 79,9 mmol) e dietil éster de ácido 4-bromo-1H-[2-(1-metil-1H-pirazol-4-il)-2-oxo-etil]-1H-pirazol-3,5- dicarboxílico (Preparação 69, 11,0 g, 26,62 mmol) em DMF (133,0 mL) foi purgada com nitrogênio a cerca de 25 °C, depois do que Pd(dppf)Cl2 (1950 mg, 2,66 mmol) e trimetilboroxina (10,0 g, 79,9 mmol) foram adici-onados, e a solução foi aquecida a cerca de 110 °C durante cerca de 5 hrs. A reação resfriada foi diluída com EtOAc (100 mL), e a mistura resultante foi lavada com salmoura (2 x 100 mL), secada (Na2SO4) e concentrada. O resíduo foi purificado por cromatografia para proporcionar o composto título como um sólido amarelo (5,45 g, 50 %).[00423] A mixture of K2CO3 (11.0 g, 79.9 mmol) and 4-bromo-1H-[2-(1-methyl-1H-pyrazol-4-yl)-2-oxo-acid diethyl ester ethyl]-1H-pyrazol-3,5-dicarboxylic acid (Preparation 69, 11.0 g, 26.62 mmol) in DMF (133.0 mL) was purged with nitrogen at about 25 °C, after which Pd( dppf)Cl2 (1950 mg, 2.66 mmol) and trimethylboroxine (10.0 g, 79.9 mmol) were added, and the solution was heated to about 110 ° C for about 5 hrs. The cooled reaction was diluted with EtOAc (100 mL), and the resulting mixture was washed with brine (2 x 100 mL), dried (Na2SO4) and concentrated. The residue was purified by chromatography to provide the title compound as a yellow solid (5.45 g, 50%).
[00424] 1H RMN (400 MHz, CDCl3) δ: 7,92 (s, 1 H), 7,90 (s, 1 H), 5,78 (s, 2 H), 4,41 (q, 2 H), 4,28 (q, 2 H), 3,95 (s, 3 H), 2,58 (s, 3 H), 1,39 (t, 3 H), 1,31 (t, 3 H).[00424] 1H NMR (400 MHz, CDCl3) δ: 7.92 (s, 1 H), 7.90 (s, 1 H), 5.78 (s, 2 H), 4.41 (q, 2 H), 4.28 (q, 2 H), 3.95 (s, 3 H), 2.58 (s, 3 H), 1.39 (t, 3 H), 1.31 (t, 3 H).
[00425] LCMS m/z = 348,9 [MH]+ Preparação 71 Etil 4-hidróxi-3-metil-6-(1-metil-1H-pirazol-4-il)pirazolo[1,5- a]pirazina-2-carboxilato [00425] LCMS m/z = 348.9 [MH]+ Preparation 71 Ethyl 4-hydroxy-3-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine -2-carboxylate
[00426] Dietil éster de ácido 4-metil-[2-(1-metil-1H-pirazol-4-il)-2- oxo-etil]-1H-pirazol-3,5-dicarboxílico (Preparação 70, 5,35 g, 15,36 mmol) foi misturado com EtOH seco (15 mL) e concentrado. O sólido resultante foi dissolvido em EtOH (40 mL) e NH4OAc (3,55 g, 46,1 mmol) foi adicionado. A mistura de reação foi aquecida a cerca de 130 °C em uma autoclave durante cerca de 8 hrs. Depois de resfriar, a mistura foi filtrada, e o precipitado foi secado para proporcionar o composto título como um sólido esbranquiçado (3,40 g, 73 %).[00426] 4-Methyl-[2-(1-methyl-1H-pyrazol-4-yl)-2-oxo-ethyl]-1H-pyrazol-3,5-dicarboxylic acid diethyl ester (Preparation 70, 5, 35 g, 15.36 mmol) was mixed with dry EtOH (15 mL) and concentrated. The resulting solid was dissolved in EtOH (40 mL) and NH4OAc (3.55 g, 46.1 mmol) was added. The reaction mixture was heated to about 130 °C in an autoclave for about 8 hrs. After cooling, the mixture was filtered, and the precipitate was dried to provide the title compound as an off-white solid (3.40 g, 73%).
[00427] 1H RMN (400 MHz, DMSO-d6) δ: 11,45 (br. s., 1 H), 8,27 (s, 1 H), 8,08 (s, 1 H), 8,02 (s, 1 H), 4,31 (m, 2 H), 3,87 (s, 3 H), 2,61 (s, 3 H), 1,24 - 1,40 (m, 3 H).[00427] 1H NMR (400 MHz, DMSO-d6) δ: 11.45 (br. s., 1 H), 8.27 (s, 1 H), 8.08 (s, 1 H), 8, 02 (s, 1 H), 4.31 (m, 2 H), 3.87 (s, 3 H), 2.61 (s, 3 H), 1.24 - 1.40 (m, 3 H ).
[00428] LCMS m/z = 301,8 [MH]+ Preparação 72 Ácido 4-hidróxi-3-metil-6-(1-metil-1H-pirazol-4-il)-pirazolo[1,5-a]pi razina-2-carboxílico [00428] LCMS m/z = 301.8 [MH]+ Preparation 72 4-Hydroxy-3-methyl-6-(1-methyl-1H-pyrazol-4-yl)-pyrazolo[1,5-a] acid pirazine-2-carboxylic acid
[00429] Mono-hidrato de hidróxido de lítio (1,42 g, 33,9 mmol) foi adi-cionado a uma suspensão de etil éster de ácido 4-hidróxi-3-metil-6-(1- metil-1H-pirazol-4-il)-pirazolo[1,5-a]pirazina-2-carboxílico (Preparação 71, 3,40 g, 11,3 mmol) em THF (50 mL), MeOH (50 mL) e água (25 mL). A mistura foi agitada a cerca de 60 °C durante cerca de 4 hrs. A mistura resfriada foi concentrada e água (50 mL) foi adicionada. O pH da mistura foi ajustado a cerca de 2 pela adição de HCl aq. a 12 M. O precipitado resultante foi filtrado e lavado com água (50 mL), em seguida secado sob vácuo para proporcionar o composto título como um sólido.[00429] Lithium hydroxide monohydrate (1.42 g, 33.9 mmol) was added to a suspension of 4-hydroxy-3-methyl-6-(1-methyl-1H- pyrazol-4-yl)-pyrazolo[1,5-a]pyrazine-2-carboxylic acid (Preparation 71, 3.40 g, 11.3 mmol) in THF (50 mL), MeOH (50 mL) and water (25 mL). The mixture was stirred at about 60°C for about 4 hrs. The cooled mixture was concentrated and water (50 mL) was added. The pH of the mixture was adjusted to about 2 by adding aq. at 12 M. The resulting precipitate was filtered and washed with water (50 ml), then dried under vacuum to provide the title compound as a solid.
[00430] 1H RMN (400 MHz, DMSO-d6) δ: 12,90 - 13,20 (br. s, 1 H), 11,40 (s, 1 H), 8,30 (s, 1 H), 8,02 (m, 2 H), 3,90 (s, 3 H), 2,60 (s, 3 H).[00430] 1H NMR (400 MHz, DMSO-d6) δ: 12.90 - 13.20 (br. s, 1 H), 11.40 (s, 1 H), 8.30 (s, 1 H) , 8.02 (m, 2 H), 3.90 (s, 3 H), 2.60 (s, 3 H).
[00431] LCMS m/z = 301,8 [MH]+, 323,8 [MNa]+ Preparação 73 3-Metil-6-(1-metil-1H-pirazol-4-il)-pirazolo[1,5-a]pirazin-4-ol [00431] LCMS m/z = 301.8 [MH]+, 323.8 [MNa]+ Preparation 73 3-Methyl-6-(1-methyl-1H-pyrazol-4-yl)-pyrazolo[1.5 -a]pyrazin-4-ol
[00432] Ácido 4-hidróxi-3-metil-6-(1-metil-1H-pirazol-4-il)- pirazolo[1,5-a]pirazina-2-carboxílico (Preparação 72, 2,58 g, 9,44 mmol) foi adicionado em porções ao sulfolano pré-aquecido (18,9 mL) a cerca de 280 °C. Uma vez que a adição foi concluída, a mistura foi agitada durante um adicional de 1 hr a cerca de 280 °C. A mistura res-friada foi purificada diretamente por cromatografia em sílica gel (eluin- do com éter de petróleo:EtOAc (100:0 a 50:50), em seguida DCM:MeOH (91:9)) para proporcionar o composto título como um sóli- do amarelo (1,50 g, 69 %).[00432] 4-Hydroxy-3-methyl-6-(1-methyl-1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyrazine-2-carboxylic acid (Preparation 72, 2.58 g, 9.44 mmol) was added in portions to preheated sulfolane (18.9 mL) at about 280 °C. Once the addition was complete, the mixture was stirred for an additional 1 hr at about 280°C. The cooled mixture was purified directly by silica gel chromatography (eluting with petroleum ether:EtOAc (100:0 to 50:50), then DCM:MeOH (91:9)) to provide the title compound as a yellow solid (1.50 g, 69%).
[00433] 1H RMN (400 MHz, DMSO-d6) δ: 11,20 (s, 1 H), 8,38 (s, 1 H), 8,02 (s, 1 H), 7,96 (s, 1 H), 7,70 (s, 1 H), 3,85 (s, 3 H), 2,40 (s, 3H). Preparação 74 4-Cloro-3-metil-6-(1-metil-1H-pirazol-4-il)-pirazolo[1,5-a]pirazina [00433] 1H NMR (400 MHz, DMSO-d6) δ: 11.20 (s, 1 H), 8.38 (s, 1 H), 8.02 (s, 1 H), 7.96 (s , 1 H), 7.70 (s, 1 H), 3.85 (s, 3 H), 2.40 (s, 3H). Preparation 74 4-Chloro-3-methyl-6-(1-methyl-1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyrazine
[00434] A uma suspensão de 3-metil-6-(1-metil-1H-pirazol-4-il)- pirazolo[1,5-a]pirazin-4-ol (Preparação 73, 1,40 g, 6,11 mmol) em MeCN (60,0 mL) foi adicionado POCl3 (4,68 g, 30,5 mmol). A mistura de reação foi aquecida a cerca de 80 °C durante cerca de 16 hrs. Depois de resfriar, a mistura foi vertida em água (200 mL) a cerca de 25 °C. A mistura foi ajustada a cerca de pH 9 pela adição de NaHCO3 aq. saturado (200 mL), em seguida extraída com EtOAc (5 x 100 mL). Os extratos de EtOAc combinados foram secados (Na2SO4) e concentrados. O resíduo foi purificado por cromatografia, em seguida também purificado por HPLC para proporcionar o composto título como um sólido branco (163 mg, 11 %).[00434] To a suspension of 3-methyl-6-(1-methyl-1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyrazin-4-ol (Preparation 73, 1.40 g, 6 .11 mmol) in MeCN (60.0 mL) POCl3 (4.68 g, 30.5 mmol) was added. The reaction mixture was heated to about 80°C for about 16 hrs. After cooling, the mixture was poured into water (200 mL) at about 25 °C. The mixture was adjusted to about pH 9 by adding aq. saturated (200 mL), then extracted with EtOAc (5 x 100 mL). The combined EtOAc extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography, then further purified by HPLC to provide the title compound as a white solid (163 mg, 11%).
[00435] 1H RMN (400 MHz, CDCl3) δ: 8,37 (s, 1 H), 7,89 (s, 1 H), 7,85 (s, 1 H), 7,80 (s, 1 H), 3,96 (s, 3 H), 2,57 (s, 3 H).[00435] 1H NMR (400 MHz, CDCl3) δ: 8.37 (s, 1 H), 7.89 (s, 1 H), 7.85 (s, 1 H), 7.80 (s, 1 H), 3.96 (s, 3 H), 2.57 (s, 3 H).
[00436] LCMS m/z = 247,7 [MH]+ (35Cl isótopo) Exemplo 25 (1r,3r)-3-(Cianometil)-3-(4-(3-metil-6-(1-metil-1H-pirazol-4- il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)ciclobutano-1- carbonitrila [00436] LCMS m/z = 247.7 [MH]+ (35Cl isotope) Example 25 (1r,3r)-3-(Cyanomethyl)-3-(4-(3-methyl-6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile
[00437] A uma solução de 4-cloro-3-metil-6-(1-metil-1H-pirazol-4-il)- pirazolo[1,5-a]pirazina (Preparação 74, 98 mg, 0,40 mmol) e (1r,3r)-3- (cianometil)-3-(4-(4,4,5,5-tetrametil-1,3,2-dioxaborolan-2-il)-1H-pirazol- 1-il)ciclobutano-1-carbonitrila (Preparação 91, 247 mg, 0,79 mmol) em 1,4-dioxano (9 mL) foi adicionado K3PO4 aq. a 2 M (0,59 mL) a cerca de 25 °C, e a mistura foi purgada com nitrogênio durante cerca de 2 min antes de XPhos Pd G2 (62,3 mg, 0,079 mmol) ter sido adicionado. A mistura foi purgada com nitrogênio durante cerca de 3 min, em seguida aquecida a cerca de 80 °C durante cerca de 16 hrs. A mistura foi filtrada e concentrada. O resíduo foi purificado por cromatografia, em seguida também purificado por HPLC para proporcionar o composto título como um sólido amarelo leve (56 mg, 36 %).[00437] To a solution of 4-chloro-3-methyl-6-(1-methyl-1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyrazine (Preparation 74, 98 mg, 0.40 mmol) and (1r,3r)-3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol- 1- il)cyclobutane-1-carbonitrile (Preparation 91, 247 mg, 0.79 mmol) in 1,4-dioxane (9 mL) aq. K3PO4 was added. to 2 M (0.59 mL) at about 25 °C, and the mixture was purged with nitrogen for about 2 min before XPhos Pd G2 (62.3 mg, 0.079 mmol) was added. The mixture was purged with nitrogen for about 3 min, then heated to about 80 °C for about 16 hrs. The mixture was filtered and concentrated. The residue was purified by chromatography, then further purified by HPLC to provide the title compound as a light yellow solid (56 mg, 36%).
[00438] 1H RMN (400 MHz, DMSO-d6): δ: 8,98 (s, 1 H), 8,94 (s, 1 H), 8,60 (s, 1 H), 8,27 (s, 1 H), 8,22 (s, 1 H), 8,10 (s, 1 H), 7,98 (s, 1 H), 3,90 (s, 3 H), 3,52 - 3,57 (m, 3 H), 3,19 - 3,26 (m, 2 H), 2,91 - 2,97 (m, 2 H), 3,06 (s, 3 H).[00438] 1H NMR (400 MHz, DMSO-d6): δ: 8.98 (s, 1 H), 8.94 (s, 1 H), 8.60 (s, 1 H), 8.27 ( s, 1 H), 8.22 (s, 1 H), 8.10 (s, 1 H), 7.98 (s, 1 H), 3.90 (s, 3 H), 3.52 - 3.57 (m, 3 H), 3.19 - 3.26 (m, 2 H), 2.91 - 2.97 (m, 2 H), 3.06 (s, 3 H).
[00439] LCMS m/z = 398,0 [MH]+ Preparação 75 (1r,3r)-3-(4-(6-Cloropirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)-3- (cianometil)ciclobutano-1-carbonitrila [00439] LCMS m/z = 398.0 [MH]+ Preparation 75 (1r,3r)-3-(4-(6-Chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol- 1-yl)-3-(cyanomethyl)cyclobutane-1-carbonitrile
[00440] Uma mistura de 4,6-dicloropirazolo[1,5-a]pirazina (Preparação 4, 350 mg, 1,86 mmol), (1r,3r)-3-(cianometil)-3-(4-(4,4,5,5- tetrametil-1,3,2-dioxaborolan-2-il)-1H-pirazol-1-il)ciclobutano-1- carbonitrila, (Preparação 91, trans isômero, 581 mg, 1,86 mmol), e K3PO4 aq. a 2 M (2,79 mL) em 1,4-dioxano (10 mL) foi purgada com argônio durante cerca de 5 min, depois dos quais bis(tri-t- butilfosfina)paládio (0) (48,0 mg, 0,093 mmol) foi adicionado. A mistura foi mantida a cerca de 25 °C durante cerca de 2 hrs, em seguida filtrada. O precipitado foi lavado com Et2O e secado. O filtrado foi concentrado, triturado com Et2O, filtrado, lavado com Et2O e secado. Os dois precipitados foram combinados para proporcionar o composto título como um sólido branco (605 mg, 96 %).[00440] A mixture of 4,6-dichloropyrazolo[1,5-a]pyrazine (Preparation 4, 350 mg, 1.86 mmol), (1r,3r)-3-(cyanomethyl)-3-(4-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, (Preparation 91, trans isomer, 581 mg, 1.86 mmol), and K3PO4 aq. at 2 M (2.79 mL) in 1,4-dioxane (10 mL) was purged with argon for about 5 min, after which bis(tri-t-butylphosphine)palladium (0) (48.0 mg, 0.093 mmol) was added. The mixture was kept at about 25°C for about 2 hrs, then filtered. The precipitate was washed with Et2O and dried. The filtrate was concentrated, triturated with Et2O, filtered, washed with Et2O and dried. The two precipitates were combined to provide the title compound as a white solid (605 mg, 96%).
[00441] 1H RMN (400 MHz, DMSO-d6) δ: 9,05 (d, 1 H), 8,93 (s, 1 H), 8,46 (s, 1 H), 8,32 (d, 1 H), 7,61 (d, 1 H), 3,55 - 3,62 (m, 1 H), 3,54 (s, 2 H), 3,24 - 3,32 (m, 2 H), 2,89 - 3,00 (m, 2 H).[00441] 1H NMR (400 MHz, DMSO-d6) δ: 9.05 (d, 1 H), 8.93 (s, 1 H), 8.46 (s, 1 H), 8.32 (d , 1 H), 7.61 (d, 1 H), 3.55 - 3.62 (m, 1 H), 3.54 (s, 2 H), 3.24 - 3.32 (m, 2 H), 2.89 - 3.00 (m, 2 H).
[00442] LCMS m/z = 338,2 [MH]+ Exemplo 26 (1r,3r)-3-(Cianometil)-3-(4-(6-(5-metil-1H-pirazol-3-il)pirazolo[1,5- a]pirazin-4-il)-1H-pirazol-1-il)ciclobutano-1-carbonitrila [00442] LCMS m/z = 338.2 [MH]+ Example 26 (1r,3r)-3-(Cyanomethyl)-3-(4-(6-(5-methyl-1H-pyrazol-3-yl) pyrazolo[1,5- a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile
[00443] Uma mistura de (1r,3r)-3-(4-(6-cloropirazolo[1,5-a]pirazin-4- il)-1H-pirazol-1-il)-3-(cianometil)ciclobutano-1-carbonitrila (Preparação 75, 85 mg, 0,25 mmol), 3-metil-1-(tetra-hidro-2H-piran-2-il)-5-(4,4,5,5- tetrametil-1,3,2-dioxaborolan-2-il)-1H-pirazol (Preparação 93, 73 mg, 0,25 mmol) e K3PO4 aq. a 2 M (1,0 mL) em 1,4-dioxano (3,0 mL) foi purgada com argônio durante cerca de 2 min, depois dos quais XPhos Pd G2 (39,6 mg, 0,050 mmol) foi adicionado. A mistura foi aquecida a cerca de 45 °C durante cerca de 45 min antes de ser resfriada e con- centrada. O resíduo foi purificado por cromatografia para proporcionar (1r,3r)-3-(cianometil)-3-(4-(6-(5-metil-1-(tetra-hidro-2H-piran-2-il)-1H- pirazol-3-il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)ciclobutano-1- carbonitrila (26 mg, 22 %), o qual foi usado diretamente na Parte 2.[00443] A mixture of (1r,3r)-3-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)cyclobutane -1-carbonitrile (Preparation 75.85 mg, 0.25 mmol), 3-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 93, 73 mg, 0.25 mmol) and aq. 2 M (1.0 mL) in 1,4-dioxane (3.0 mL) was purged with argon for about 2 min, after which XPhos Pd G2 (39.6 mg, 0.050 mmol) was added. The mixture was heated to about 45°C for about 45 min before being cooled and concentrated. The residue was purified by chromatography to provide (1r,3r)-3-(cyanomethyl)-3-(4-(6-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H - pyrazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile (26 mg, 22 %), which was used directly in Part two.
[00444] LCMS m/z = 384,3 [MH-THP]+[00444] LCMS m/z = 384.3 [MH-THP]+
[00445] TFA (1 mL) foi adicionado a uma solução de (1r,3r)-3- (cianometil)-3-(4-(6-(5-metil-1-(tetra-hidro-2H-piran-2-il)-1H-pirazol-3- il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)ciclobutano-1-carbonitrila (26 mg, 0,055 mmol) em DCM (2 mL). A mistura de reação foi aquecida a cerca de 50 °C durante cerca de 1 hr. A mistura foi concentrada, e o resíduo foi concentrado duas vezes com tolueno (5 mL cada time). O resíduo foi em seguida purificado por cromatografia para proporcionar um sólido, o qual também foi triturado com éter para proporcionar o composto título (8 mg, 38 %).[00445] TFA (1 mL) was added to a solution of (1r,3r)-3-(cyanomethyl)-3-(4-(6-(5-methyl-1-(tetrahydro-2H-pyran- 2-yl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile (26 mg, 0.055 mmol) in DCM (2 mL). The reaction mixture was heated to about 50°C for about 1 hr. The mixture was concentrated, and the residue was concentrated twice with toluene (5 mL each time). The residue was then purified by chromatography to provide a solid, which was also triturated with ether to provide the title compound (8 mg, 38%).
[00446] 1H RMN (400 MHz, CD3CN) δ: 8,87 (s, 1 H), 8,66 (s, 1 H), 8,48 (s, 1 H), 8,15 (d, 1 H), 7,23 (s, 1 H), 6,73 (s, 1 H), 3,46 (dd, 1 H), 3,36 (s, 2 H), 3,32 - 3,41 (m, 2 H), 2,98 (dd, 2 H), 2,37 (s, 3 H).[00446] 1H NMR (400 MHz, CD3CN) δ: 8.87 (s, 1 H), 8.66 (s, 1 H), 8.48 (s, 1 H), 8.15 (d, 1 H), 7.23 (s, 1 H), 6.73 (s, 1 H), 3.46 (dd, 1 H), 3.36 (s, 2 H), 3.32 - 3.41 (m, 2 H), 2.98 (dd, 2 H), 2.37 (s, 3 H).
[00447] LCMS m/z = 384,4 [MH]+ Exemplo 27 2-((1s,3r)-1-(4-(6-(5-(Hidroximetil)-1H-pirazol-3-il)pirazolo[1,5- a]pirazin-4-il)-1H-pirazol-1-il)-3-metoxiciclobutil)acetonitrila [00447] LCMS m/z = 384.4 [MH]+ Example 27 2-((1s,3r)-1-(4-(6-(5-(Hydroxymethyl)-1H-pyrazol-3-yl)pyrazole [1,5- a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile
[00448] Uma solução de 2-((1s,3r)-1-(4-(6-cloropirazolo[1,5- a]pirazin-4-il)-1H-pirazol-1-il)-3-metoxiciclobutil)acetonitrila (Prepara- ção 82, 100 mg, 0,29 mmol), e (3-(tributilestanil)-1H-pirazol-5- il)metanol (Preparação 32, 113 mg, 0,29 mmol) em 1,4-dioxano (2 mL) foi purgada com argônio durante 5 min, seguido pela adição de XPhos Pd G2 (45,9 mg, 0,058 mmol). A mistura foi aquecida a cerca de 80 °C durante cerca de 18 hrs. O precipitado resultante foi filtrado, lavado com 1,4-dioxano e Et2O e secado para proporcionar o composto título como um sólido branco (62 mg, 53 %).[00448] A solution of 2-((1s,3r)-1-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl )acetonitrile (Preparation 82, 100 mg, 0.29 mmol), and (3-(tributylstanyl)-1H-pyrazol-5-yl)methanol (Preparation 32, 113 mg, 0.29 mmol) in 1.4 -dioxane (2 mL) was purged with argon for 5 min, followed by the addition of XPhos Pd G2 (45.9 mg, 0.058 mmol). The mixture was heated to about 80°C for about 18 hrs. The resulting precipitate was filtered, washed with 1,4-dioxane and Et2O and dried to provide the title compound as a white solid (62 mg, 53%).
[00449] 1H RMN (400 MHz, CD3CN) δ: 8,86 (s, 1 H), 8,58 (s, 1 H), 8,44 (s, 1 H), 8,13 (d, 1 H), 7,21 (d, 1 H), 6,85 (s, 1 H), 4,65 (d, 2 H), 4,05 (quin, 1 H), 3,27 (s, 3 H), 3,21 (s, 2 H), 2,90 - 2,99 (m, 2 H), 2,67 - 2,76 (m, 2 H).[00449] 1H NMR (400 MHz, CD3CN) δ: 8.86 (s, 1 H), 8.58 (s, 1 H), 8.44 (s, 1 H), 8.13 (d, 1 H), 7.21 (d, 1 H), 6.85 (s, 1 H), 4.65 (d, 2 H), 4.05 (quin, 1 H), 3.27 (s, 3 H), 3.21 (s, 2 H), 2.90 - 2.99 (m, 2 H), 2.67 - 2.76 (m, 2 H).
[00450] LCMS m/z = 405,3 [MH]+ Exemplo 28 2-((1r,3s)-1-(4-(6-(5-(Hidroximetil)-1H-pirazol-3-il)pirazolo[1,5- a]pirazin-4-il)-1H-pirazol-1-il)-3-metoxiciclobutil)acetonitrila [00450] LCMS m/z = 405.3 [MH]+ Example 28 2-((1r,3s)-1-(4-(6-(5-(Hydroxymethyl)-1H-pyrazol-3-yl)pyrazole [1,5- a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile
[00451] Uma solução de 2-((1r,3s)-1-(4-(6-cloropirazolo[1,5- a]pirazin-4-il)-1H-pirazol-1-il)-3-metoxiciclobutil)acetonitrila (Prepara-ção 39; 1000 mg, 2,92 mmol) e (3-(tributilestanil)-1H-pirazol-5- il)metanol (Preparação 32, 1130 mg, 2,92 mmol) em 1,4-dioxano (2 mL) foi purgada com argônio durante 5 min, seguido pela adição de XPhos Pd G2 (45,9 mg, 0,058 mmol). A mistura foi aquecida a cerca de 80 °C durante cerca de 18 hrs. O precipitado foi filtrado e em seguida purificado por cromatografia para proporcionar um sólido esbranquiçado. O sólido foi aquecido em EtOH em ebulição suficiente até que te- nha sido completamente dissolvido, e em seguida agitado durante cerca de 18 hrs a cerca de 20 °C. O precipitado foi filtrado e secado sob vácuo para proporcionar o composto título como um sólido cristalino (507 mg, 43 %).[00451] A solution of 2-((1r,3s)-1-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl )acetonitrile (Preparation 39; 1000 mg, 2.92 mmol) and (3-(tributylstanyl)-1H-pyrazol-5-yl)methanol (Preparation 32, 1130 mg, 2.92 mmol) in 1.4- dioxane (2 mL) was purged with argon for 5 min, followed by the addition of XPhos Pd G2 (45.9 mg, 0.058 mmol). The mixture was heated to about 80°C for about 18 hrs. The precipitate was filtered and then purified by chromatography to provide an off-white solid. The solid was heated in sufficiently boiling EtOH until it was completely dissolved, and then stirred for about 18 hrs at about 20°C. The precipitate was filtered and dried under vacuum to provide the title compound as a crystalline solid (507 mg, 43%).
[00452] 1H RMN (400 MHz, CD3CN) δ: 11,48 (br. s.), 8,89 (s), 8,65 (s), 8,46 (s), 8,15 (d), 7,23 (s), 6,87 (s), 4,67 (d), 4,08 (quin), 3,31 (s), 3,30 (s), 3,15 - 3,25 (m), 2,53 (dd).[00452] 1H NMR (400 MHz, CD3CN) δ: 11.48 (br. s.), 8.89 (s), 8.65 (s), 8.46 (s), 8.15 (d) , 7.23 (s), 6.87 (s), 4.67 (d), 4.08 (quin), 3.31 (s), 3.30 (s), 3.15 - 3.25 (m), 2.53 (dd).
[00453] LCMS m/z = 405,3 [MH]+ Preparação 76 Etil 5-(tributilestanil)isoxazol-3-carboxilato [00453] LCMS m/z = 405.3 [MH]+ Preparation 76 Ethyl 5-(tributylstanyl)isoxazole-3-carboxylate
[00454] TEA (0,69 mL, 4,95 mmol) foi adicionado gota a gota a uma solução gelada de etil 2-cloro-2-(hidroxiimino)acetato (500 mg, 3,30 mmol) e etiniltributilestanano (1040 mg, 3,30 mmol) em Et2O (10 mL). A mistura de reação foi aquecida a cerca de 20 °C e mantida durante cerca de 18 hrs. A mistura foi concentrada, e o resíduo foi purificado por cromatografia para proporcionar o composto título como um óleo incolor (810 mg, 57 %).[00454] TEA (0.69 mL, 4.95 mmol) was added dropwise to an ice-cold solution of ethyl 2-chloro-2-(hydroxyimino)acetate (500 mg, 3.30 mmol) and ethinyltributylstannan (1040 mg , 3.30 mmol) in Et2O (10 mL). The reaction mixture was heated to about 20°C and held for about 18 hrs. The mixture was concentrated, and the residue was purified by chromatography to provide the title compound as a colorless oil (810 mg, 57%).
[00455] 1H RMN (400 MHz, CDCl3) δ: 6,80 (s, 1 H), 6,77 - 6,84 (m, 1 H), 4,45 (q, 2 H), 1,51 - 1,63 (m, 6 H), 1,43 (t, 3 H), 1,34 (dq, 6 H), 1,15 - 1,26 (m, 6 H), 0,90 (t, 9 H).[00455] 1H NMR (400 MHz, CDCl3) δ: 6.80 (s, 1 H), 6.77 - 6.84 (m, 1 H), 4.45 (q, 2 H), 1.51 - 1.63 (m, 6 H), 1.43 (t, 3 H), 1.34 (dq, 6 H), 1.15 - 1.26 (m, 6 H), 0.90 (t , 9 H).
[00456] LCMS m/z = 454,2 [MNa]+ (isótopo 120Sn) Preparação 77 Etil 5-(4-(1-((1r,3r)-3-ciano-1-(cianometil)ciclobutil)-1H-pirazol-4- il)pirazolo[1,5-a]pirazin-6-il)isoxazol-3-carboxilato [00456] LCMS m/z = 454.2 [MNa]+ (isotope 120Sn) Preparation 77 Ethyl 5-(4-(1-((1r,3r)-3-cyano-1-(cyanomethyl)cyclobutyl)-1H -pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)isoxazol-3-carboxylate
[00457] Uma solução de (1r,3r)-3-(4-(6-cloropirazolo[1,5-a]pirazin-4- il)-1H-pirazol-1-il)-3-(cianometil)ciclobutano-1-carbonitrila (Preparação 75, 110 mg, 0,33 mmol) e etil 5-(tributilestanil)isoxazol-3-carboxilato (Preparação 76, 140 mg, 0,33 mmol) em 1,4-dioxano (3 mL) foi purgada com argônio durante cerca de 5 min, seguido pela adição de XPhos Pd G2 (51,2 mg, 0,065 mmol). A mistura foi aquecida a cerca de 100 °C durante cerca de 5 hrs. A mistura foi concentrada, e o resíduo foi purificado por cromatografia para proporcionar o composto título como um sólido amarelo leve (66 mg, 45 %).[00457] A solution of (1r,3r)-3-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)cyclobutane -1-carbonitrile (Preparation 75, 110 mg, 0.33 mmol) and ethyl 5-(tributylstanyl)isoxazole-3-carboxylate (Preparation 76, 140 mg, 0.33 mmol) in 1,4-dioxane (3 mL) was purged with argon for about 5 min, followed by the addition of XPhos Pd G2 (51.2 mg, 0.065 mmol). The mixture was heated to about 100°C for about 5 hrs. The mixture was concentrated, and the residue was purified by chromatography to provide the title compound as a light yellow solid (66 mg, 45%).
[00458] 1H RMN (400 MHz, DMSO-d6) δ: 9,44 (s, 1 H), 9,02 (s, 1 H), 8,60 (s, 1 H), 8,42 (d, 1 H), 7,65 (d, 1 H), 7,62 (s, 1 H), 4,44 (q, 2 H), 3,54 - 3,63 (m, 1 H), 3,53 (s, 2 H), 3,26 - 3,36 (m, 2 H), 2,90 - 2,98 (m, 2 H), 1,37 (t, 3 H).[00458] 1H NMR (400 MHz, DMSO-d6) δ: 9.44 (s, 1 H), 9.02 (s, 1 H), 8.60 (s, 1 H), 8.42 (d , 1 H), 7.65 (d, 1 H), 7.62 (s, 1 H), 4.44 (q, 2 H), 3.54 - 3.63 (m, 1 H), 3 .53 (s, 2 H), 3.26 - 3.36 (m, 2 H), 2.90 - 2.98 (m, 2 H), 1.37 (t, 3 H).
[00459] LCMS m/z = 443,3 [MH]+ Exemplo 29 5-(4-(1-((1r,3r)-3-Ciano-1-(cianometil)ciclobutil)-1H-pirazol-4- il)pirazolo[1,5-a]pirazin-6-il)isoxazol-3-carboxamida [00459] LCMS m/z = 443.3 [MH]+ Example 29 5-(4-(1-((1r,3r)-3-Cyano-1-(cyanomethyl)cyclobutyl)-1H-pyrazol-4- il)pyrazolo[1,5-a]pyrazin-6-yl)isoxazol-3-carboxamide
[00460] Uma solução de etil 5-(4-(1-((1r,3r)-3-ciano-1- (cianometil)ciclobutil)-1H-pirazol-4-il)pirazolo[1,5-a]pirazin-6-il)isoxazol- 3-carboxilato (Preparação 77, 54 mg, 0,12 mmol) em metanol (3 mL) foi tratada com uma solução a 7 M de gás amônia em metanol (2 mL, 14 mmol). O vaso de reação foi bem vedado, e a mistura foi aquecida a cerca de 95 °C durante cerca de 18 hrs. Depois de resfriar, o precipitado foi filtrado, lavado com EtOAc seguido por Et2O, e secado para proporcionar o composto título como um sólido branco (45 mg, 89 %).[00460] A solution of ethyl 5-(4-(1-((1r,3r)-3-cyano-1-(cyanomethyl)cyclobutyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a] pyrazin-6-yl)isoxazole-3-carboxylate (Preparation 77, 54 mg, 0.12 mmol) in methanol (3 mL) was treated with a 7 M solution of ammonia gas in methanol (2 mL, 14 mmol). The reaction vessel was tightly sealed, and the mixture was heated to about 95 °C for about 18 hrs. After cooling, the precipitate was filtered, washed with EtOAc followed by Et2O, and dried to provide the title compound as a white solid (45 mg, 89%).
[00461] 1H RMN (400 MHz, DMSO-d6) δ: 9,36 (s, 1 H), 9,01 (s, 1 H), 8,58 (s, 1 H), 8,41 (d, 1 H), 8,21 (br. s, 1 H), 7,91 (br. s, 1 H), 7,64 (d, 1 H), 7,50 (s, 1 H), 3,55 - 3,62 (m, 1 H), 3,53 (s, 2 H), 3,26 - 3,35 (m, 2 H), 2,90 - 2,98 (m, 2 H).[00461] 1H NMR (400 MHz, DMSO-d6) δ: 9.36 (s, 1 H), 9.01 (s, 1 H), 8.58 (s, 1 H), 8.41 (d , 1 H), 8.21 (br. s, 1 H), 7.91 (br. s, 1 H), 7.64 (d, 1 H), 7.50 (s, 1 H), 3 .55 - 3.62 (m, 1 H), 3.53 (s, 2 H), 3.26 - 3.35 (m, 2 H), 2.90 - 2.98 (m, 2 H) .
[00462] LCMS m/z = 414,3 [MH]+ Preparação 78 2-((1r,3s)-1-(4-(6-(5-(DiBoc)-amino-1-(tetra-hidro-2H-piran-2-il)- pirazol-3-il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)-3- metoxiciclobutil)acetonitrila [00462] LCMS m/z = 414.3 [MH]+ Preparation 78 2-((1r,3s)-1-(4-(6-(5-(DiBoc)-amino-1-(tetrahydro- 2H-pyran-2-yl)-pyrazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile
[00463] Uma mistura de 3-bromo-1-(tetra-hidro-2H-piran-2-il)-5-(diBo c)-amino-1H-pirazol (Preparação 43, 233 mg, 0,52 mmol), KOAc (162 mg, 1,57 mmol), e bis(pinacolato)diboro (199 mg, 0,78 mmol) em 1,4- dioxano (4 mL) foi purgada com argônio durante cerca de 5 min, depois dos quais XPhos Pd G2 (82,1 mg, 0,10 mmol) foi adicionado. A mistura foi aquecida a cerca de 65 °C durante cerca de 3,5 hrs. Depois de resfriar a cerca de 20 °C, 2-((1r,3s)-1-(4-(6-cloropirazolo[1,5-a]pirazin-4-il)-1H- pirazol-1-il)-3-metoxiciclo-butil)aceto-nitrila (Preparação 39, 125 mg, 0,36 mmol), K3PO4 aq. a 2 M (0,783 mL) e XPhos Pd G2 (82,1 mg, 0,10 mmol) foram adicionados. A mistura foi novamente purgada com argônio, em seguida aquecida a cerca de 80 °C durante cerca de 1 hr. Depois de resfriar, a mistura foi diluída com EtOAc e as fases foram separadas. A fase aquosa foi extraída duas vezes com EtOAc e os extratos de EtOAc combinados foram concentrados. O resíduo foi purificado por cromato- grafia para proporcionar o composto título como um óleo claro (220 mg, 62 %).[00463] A mixture of 3-bromo-1-(tetrahydro-2H-pyran-2-yl)-5-(diBo c)-amino-1H-pyrazole (Preparation 43, 233 mg, 0.52 mmol) , KOAc (162 mg, 1.57 mmol), and bis(pinacolato)diboron (199 mg, 0.78 mmol) in 1,4-dioxane (4 mL) was purged with argon for about 5 min, after which XPhos Pd G2 (82.1 mg, 0.10 mmol) was added. The mixture was heated to about 65°C for about 3.5 hrs. After cooling to about 20 °C, 2-((1r,3s)-1-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl) -3-methoxycyclobutyl)aceto-nitrile (Preparation 39, 125 mg, 0.36 mmol), aq. at 2 M (0.783 mL) and XPhos Pd G2 (82.1 mg, 0.10 mmol) were added. The mixture was purged again with argon, then heated to about 80 °C for about 1 hr. After cooling, the mixture was diluted with EtOAc and the phases were separated. The aqueous phase was extracted twice with EtOAc and the combined EtOAc extracts were concentrated. The residue was purified by chromatography to provide the title compound as a clear oil (220 mg, 62%).
[00464] 1H RMN (400 MHz, CDCl3) δ: 9,08 (s, 1 H), 8,39 (s, 1 H), 8,33 (s, 1 H), 8,09 (d, 1 H), 6,97 (d, 1 H), 6,90 (s, 1 H), 5,26 (dd, 1 H), 4,03 - 4,11 (m, 2 H), 3,64 (t, 1 H), 3,34 (s, 3 H), 3,25 (s, 2 H), 3,11 - 3,19 (m, 2 H), 2,55 - 2,63 (m, 2 H), 2,21 (m, 1 H), 1,93 (dd, 1 H), 1,59 - 1,84 (m, 4 H), 1,45 (s, 18 H).[00464] 1H NMR (400 MHz, CDCl3) δ: 9.08 (s, 1 H), 8.39 (s, 1 H), 8.33 (s, 1 H), 8.09 (d, 1 H), 6.97 (d, 1 H), 6.90 (s, 1 H), 5.26 (dd, 1 H), 4.03 - 4.11 (m, 2 H), 3.64 (t, 1 H), 3.34 (s, 3 H), 3.25 (s, 2 H), 3.11 - 3.19 (m, 2 H), 2.55 - 2.63 (m , 2 H), 2.21 (m, 1 H), 1.93 (dd, 1 H), 1.59 - 1.84 (m, 4 H), 1.45 (s, 18 H).
[00465] LCMS m/z = 674,5 [MH]+ Exemplo 30 2-((1r,3s)-1-(4-(6-(3-Amino-1H-pirazol-5-il)pirazolo[1,5-a]pirazin-4- il)-1H-pirazol-1-il)-3-metoxiciclobutil)acetonitrila [00465] LCMS m/z = 674.5 [MH]+ Example 30 2-((1r,3s)-1-(4-(6-(3-Amino-1H-pyrazol-5-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile
[00466] TFA (3 mL) foi adicionado a uma solução de 2-((1r,3s)-1-(4- (6-(5-(diBoc)-amino-1-(tetra-hidro-2H-piran-2-il)-pirazol-3- il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)-3- metoxiciclobutil)acetonitrila (Preparação 78, 220 mg, 0,33 mmol) em DCM (2 mL) a cerca de 20 °C. Depois de cerca de 1 hr nesta tempera-tura, a mistura foi concentrada, e o resíduo foi dissolvido em DCM e NaHCO3 aq. saturado, assegurando que o pH seja básico. O DCM foi separado, e a fase aquosa foi extraída duas vezes com DCM. Os ex-tratos de DCM combinados foram secados (Na2SO4), concentrados, e o resíduo foi purificado por cromatografia seguido por HPLC para pro-porcionar o composto título como um sólido branco (17 mg, 13 %).[00466] TFA (3 mL) was added to a solution of 2-((1r,3s)-1-(4-(6-(5-(diBoc)-amino-1-(tetrahydro-2H-pyran -2-yl)-pyrazol-3- yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile (Preparation 78, 220 mg, 0. 33 mmol) in DCM (2 mL) at about 20 °C. After about 1 hr at this temperature, the mixture was concentrated, and the residue was dissolved in DCM and aq. saturated, ensuring that the pH is basic. The DCM was separated, and the aqueous phase was extracted twice with DCM. The combined DCM extracts were dried (Na2SO4), concentrated, and the residue was purified by chromatography followed by HPLC to provide the title compound as a white solid (17 mg, 13%).
[00467] 1H RMN (400 MHz, CD3OD) δ: 8,89 (s, 1 H), 8,84 (s, 1 H), 8,54 (s, 1 H), 8,17 - 8,18 (m, 1 H), 7,34 (s, 1 H), 6,22 (s, 1 H), 4,09 - 4,12 (m, 1 H), 3,39 (s, 3 H), 3,22 - 3,27 (m, 2 H), 2,56 - 2,60 (m, 2 H).[00467] 1H NMR (400 MHz, CD3OD) δ: 8.89 (s, 1 H), 8.84 (s, 1 H), 8.54 (s, 1 H), 8.17 - 8.18 (m, 1 H), 7.34 (s, 1 H), 6.22 (s, 1 H), 4.09 - 4.12 (m, 1 H), 3.39 (s, 3 H) , 3.22 - 3.27 (m, 2 H), 2.56 - 2.60 (m, 2 H).
[00468] LCMS m/z = 390,3 [MH]+ Preparação 79 (4-Bromo-1-metil-1H-pirazol-3-il)metanol [00468] LCMS m/z = 390.3 [MH]+ Preparation 79 (4-Bromo-1-methyl-1H-pyrazol-3-yl)methanol
[00469] Boro-hidreto de sódio (3,4 g, 90 mmol) foi adicionado a uma solução de etil 4-bromo-1-metil-1H-pirazol-3-carboxilato (4,2 g, 18 mmol) em EtOH anidroso (150 mL) a cerca de 5 °C. A mistura foi em seguida aquecida a cerca de 50 °C durante cerca de 16 h, depois dos quais EtOAc (100 mL) e água (100 mL) foram adicionados. O EtOAc foi separado, secado (Na2SO4) e concentrado. O resíduo foi purificado por cromatografia para proporcionar o composto título como um sólido branco (1,05 g, 31 %).[00469] Sodium borohydride (3.4 g, 90 mmol) was added to a solution of ethyl 4-bromo-1-methyl-1H-pyrazol-3-carboxylate (4.2 g, 18 mmol) in EtOH anhydrous solution (150 mL) at about 5 °C. The mixture was then heated to about 50°C for about 16h, after which EtOAc (100ml) and water (100ml) were added. The EtOAc was separated, dried (Na2SO4) and concentrated. The residue was purified by chromatography to provide the title compound as a white solid (1.05 g, 31%).
[00470] 1H RMN (400 MHz, DMSO-d6) δ: 7,84 (s, 1 H), 5,01 (td, 1 H), 4,33 (d, 2 H), 3,77 (s, 3 H).[00470] 1H NMR (400 MHz, DMSO-d6) δ: 7.84 (s, 1 H), 5.01 (td, 1 H), 4.33 (d, 2 H), 3.77 (s , 3 H).
[00471] LCMS m/z = 192,7 [MH]+(isótopo 81Br) Preparação 80 4-Bromo-1-metil-3-(((tetra-hidro-2H-piran-2-il)óxi)metil)-1H-pirazol [00471] LCMS m/z = 192.7 [MH]+(isotope 81Br) Preparation 80 4-Bromo-1-methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl) -1H-pyrazole
[00472] A uma solução de (4-bromo-1-metil-1H-pirazol-3-il)metanol (Preparação 79, 1,00 mg, 5,23 mmol) em THF (30 mL) foram adicio-nados DHP (1,32 g, 15,7 mmol) e PTSA (19,9 mg, 0,10 mmol). A solução foi aquecida a cerca de 50 °C durante cerca de 16 hrs. A mistura foi concentrada, e o resíduo foi purificado por cromatografia para pro-porcionar o composto título como um óleo incolor (1,02 g, 71 %).[00472] To a solution of (4-bromo-1-methyl-1H-pyrazol-3-yl)methanol (Preparation 79, 1.00 mg, 5.23 mmol) in THF (30 mL) was added DHP (1.32 g, 15.7 mmol) and PTSA (19.9 mg, 0.10 mmol). The solution was heated to about 50°C for about 16 hrs. The mixture was concentrated, and the residue was purified by chromatography to provide the title compound as a colorless oil (1.02 g, 71%).
[00473] 1H RMN (400 MHz, CDCl3) δ: 7,36 (s, 1 H), 4,80 (t, 1 H), 4,73 (d, 1 H), 4,45 (d, 1 H), 3,95 - 4,03 (m, 1 H), 3,87 (s, 3 H), 3,53 - 3,64 (m, 1 H), 1,78 - 1,93 (m, 1 H), 1,60 - 1,77 (m, 3 H), 1,45 - 1,60 (m, 2 H).[00473] 1H NMR (400 MHz, CDCl3) δ: 7.36 (s, 1 H), 4.80 (t, 1 H), 4.73 (d, 1 H), 4.45 (d, 1 H), 3.95 - 4.03 (m, 1 H), 3.87 (s, 3 H), 3.53 - 3.64 (m, 1 H), 1.78 - 1.93 (m , 1 H), 1.60 - 1.77 (m, 3 H), 1.45 - 1.60 (m, 2 H).
[00474] LCMS m/z = 174,6 [MH-THP]+ Preparação 81 1-Metil-3-(((tetra-hidro-2H-piran-2-il)óxi)metil)-4-(4,4,5,5-tetrametil- 1,3,2-dioxaborolan-2-il)-1H-pirazol [00474] LCMS m/z = 174.6 [MH-THP]+ Preparation 81 1-Methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
[00475] A uma solução de 4-bromo-1-metil-3-(((tetra-hidro-2H-piran- 2-il)óxi)metil)-1H-pirazol (Preparação 80, 330 mg, 1,20 mmol) em DMF (12 mL) foram adicionados bis(pinacolato)diboro (457 mg, 1,8 mmol) e KOAc (353 mg, 3,6 mmol). A mistura foi purgada com nitrogênio durante cerca de 2 min, depois dos quais Pd(dppf)Cl2 (87,8 mg, 0,12 mmol) foi adicionado. A mistura foi aquecida a cerca de 90 °C durante cerca de 16 hrs. A mistura resfriada foi filtrada através de uma almofada de Celite®, e o filtro foi lavado com metanol (15 mL). O filtrado foi concentrado para proporcionar o composto título impuro como goma escura (1,17 g), a qual foi usada na próxima etapa do Exemplo 31 sem outra purificação.[00475] To a solution of 4-bromo-1-methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazole (Preparation 80, 330 mg, 1.20 mmol) in DMF (12 mL) bis(pinacolato)diboron (457 mg, 1.8 mmol) and KOAc (353 mg, 3.6 mmol) were added. The mixture was purged with nitrogen for about 2 min, after which Pd(dppf)Cl2 (87.8 mg, 0.12 mmol) was added. The mixture was heated to about 90°C for about 16 hrs. The cooled mixture was filtered through a pad of Celite®, and the filter was washed with methanol (15 mL). The filtrate was concentrated to provide the crude title compound as dark gum (1.17 g), which was used in the next step of Example 31 without further purification.
[00476] 1H RMN (400 MHz, CDCl3) δ: 7,61 (s, 1 H), 4,75 - 4,77 (m, 1 H), 4,50 - 4,57 (m, 2 H), 4,03 - 4,10 (m, 1 H), 3,91 - 3,98 (m, 1 H), 3,89 (s, 3 H), 1,81 - 1,90 (m, 1 H), 1,61 - 1,76 (m, 3 H), 1,49 - 1,56 (m, 2 H), 1,30 (s, 12 H).[00476] 1H NMR (400 MHz, CDCl3) δ: 7.61 (s, 1 H), 4.75 - 4.77 (m, 1 H), 4.50 - 4.57 (m, 2 H) , 4.03 - 4.10 (m, 1 H), 3.91 - 3.98 (m, 1 H), 3.89 (s, 3 H), 1.81 - 1.90 (m, 1 H), 1.61 - 1.76 (m, 3 H), 1.49 - 1.56 (m, 2 H), 1.30 (s, 12 H).
[00477] LCMS m/z = 239,1 [MH-THP]+ Exemplo 31 2-((1r,3s)-1-(4-(6-(3-(Hidroximetil)-1-metil-1H-pirazol-4- il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)-3- metoxiciclobutil)acetonitrila [00477] LCMS m/z = 239.1 [MH-THP]+ Example 31 2-((1r,3s)-1-(4-(6-(3-(Hydroxymethyl)-1-methyl-1H-pyrazole -4- yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile
[00478] Uma mistura de 2-((1r,3s)-1-(4-(6-cloropirazolo[1,5- a]pirazin-4-il)-1H-pirazol-1-il)-3-metóxi-ciclobutil)acetonitrila (Prepara-ção 39, 80 mg, 0,23 mmol), 1-metil-3-(((tetra-hidro-2H-piran-2- il)óxi)metil)-4-(4,4,5,5-tetrametil-1,3,2-dioxaborolan-2-il)-1H-pirazol (Preparação 81, 376 mg, 1,17 mmol), e K3PO4 aq. a 2 M (0,35 mL) em 1,4-dioxano (2,5 mL) foi tratada com XPhos Pd G2 (18,4 mg, 0,023 mmol), e a mistura foi purgada com nitrogênio. A mistura foi aquecida a cerca de 60 °C durante cerca de 20 hrs. A mistura foi concentrada, e o resíduo foi purificado por cromatografia para proporcionar o composto título como uma goma amarela. Esta amostra foi combinada com o produto de uma reação equivalente conduzida usando 2-((1r,3s)-1-(4- (6-cloropirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)-3- metoxiciclobutil)acetonitrila (Preparação 39, 120 mg, 0,35 mmol), 1- metil-3-(((tetra-hidro-2H-piran-2-il)óxi)metil)-4-(4,4,5,5-tetrametil-1,3,2- dioxaborolan-2-il)-1H-pirazol (Preparação 81, 564 mg, 1,75 mmol), K3PO4 aq. a 2 M (0,525 mL), e XPhos Pd G2 (13,8 mg, 0,023 mmol) em 1,4-dioxano (3,5 mL) para proporcionar 2-((1r,3s)-3-metóxi-1-(4-(6- (1-metil-3-(((tetra-hidro-2H-piran-2-il)óxi)metil)-1H-pirazol-4- il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)ciclobutil)acetonitrila em um rendimento total de 150 mg (51 %), o qual foi usado na Parte 2 sem outra purificação.[00478] A mixture of 2-((1r,3s)-1-(4-(6-chloropyrazolo[1,5- a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxy -cyclobutyl)acetonitrile (Preparation 39, 80 mg, 0.23 mmol), 1-methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 81, 376 mg, 1.17 mmol), and aq. 2 M (0.35 mL) in 1,4-dioxane (2.5 mL) was treated with XPhos Pd G2 (18.4 mg, 0.023 mmol), and the mixture was purged with nitrogen. The mixture was heated to about 60°C for about 20 hrs. The mixture was concentrated, and the residue was purified by chromatography to provide the title compound as a yellow gum. This sample was combined with the product of an equivalent reaction conducted using 2-((1r,3s)-1-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazole-1 -yl)-3- methoxycyclobutyl)acetonitrile (Preparation 39, 120 mg, 0.35 mmol), 1-methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 81, 564 mg, 1.75 mmol), K3PO4 aq. at 2 M (0.525 mL), and XPhos Pd G2 (13.8 mg, 0.023 mmol) in 1,4-dioxane (3.5 mL) to provide 2-((1r,3s)-3-methoxy-1- (4-(6-(1-methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin -4-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrile in a total yield of 150 mg (51%), which was used in Part 2 without further purification.
[00479] TFA (1 mL) foi adicionado a uma solução resfriada com gelo de 2-((1r,3s)-3-metóxi-1-(4-(6-(1-metil-3-(((tetra-hidro-2H-piran-2- il)óxi)metil)-1H-pirazol-4-il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1- il)ciclobutil)acetonitrila (Parte 1, 150 mg, 0,30 mmol) em DCM (3 mL). A mistura foi agitada com resfriamento em gelo durante cerca de 2 hrs, em seguida concentrada. O resíduo foi purificado por HPLC para pro-porcionar o composto título como um sólido amarelo leve (53 mg, 38 %).[00479] TFA (1 mL) was added to an ice-cooled solution of 2-((1r,3s)-3-methoxy-1-(4-(6-(1-methyl-3-(((tetra- hydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrile ( Part 1, 150 mg, 0.30 mmol) in DCM (3 mL). The mixture was stirred with ice-cooling for about 2 hrs, then concentrated. The residue was purified by HPLC to provide the title compound as a light yellow solid (53 mg, 38%).
[00480] 1H RMN (400 MHz, CD3OD) δ: 8,87 (s, 1 H), 8,69 (s, 1 H), 8,40 (s, 1 H), 8,21 (s, 1 H), 8,13 (d, 1 H), 7,28 (d, 1 H), 4,83 (s, 2 H), 4,05 - 4,14 (m, 1 H), 3,96 (s, 3 H), 3,37 (s, 2 H), 3,34 (s, 3 H), 3,18 - 3,27 (m, 2 H), 2,53 - 2,62 (m, 2 H).[00480] 1H NMR (400 MHz, CD3OD) δ: 8.87 (s, 1 H), 8.69 (s, 1 H), 8.40 (s, 1 H), 8.21 (s, 1 H), 8.13 (d, 1 H), 7.28 (d, 1 H), 4.83 (s, 2 H), 4.05 - 4.14 (m, 1 H), 3.96 (s, 3 H), 3.37 (s, 2 H), 3.34 (s, 3 H), 3.18 - 3.27 (m, 2 H), 2.53 - 2.62 (m , 2 H).
[00481] LCMS m/z = 419,1 [MH]+ Preparação 82 2-((1s,3r)-1-(4-(6-Cloropirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)-3- metoxiciclobutil)acetonitrila [00481] LCMS m/z = 419.1 [MH]+ Preparation 82 2-((1s,3r)-1-(4-(6-Chloropyrazolo[1,5-a]pyrazin-4-yl)-1H -pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile
[00482] A uma solução de 2-((1s,3r)-1-(4-bromo-1H-pirazol-1-il)-3- metoxiciclobutil)acetonitrila (Preparação 37, cis isômero, 400 mg, 1,48 mmol) em tolueno (9 mL) foram adicionados bis(pinacolato)diboro (564 mg, 2,22 mmol) e KOAc (436 mg, 4,44 mmol). A mistura foi purgada com nitrogênio durante cerca de 3 min, depois dos quais Pd(dppf)Cl2 (108 mg, 0,15 mmol) foi adicionado. A mistura foi novamente purgada com nitrogênio durante cerca de 3 min, em seguida aquecida a cerca de 110 °C durante cerca de 16 hrs. A mistura resfriada foi concentrada, e o resíduo foi purificado por cromatografia para proporcionar 2- ((1s,3r)-3-metóxi-1-(4-(4,4,5,5-tetrametil-1,3,2-dioxaborolan-2-il)-1H- pirazol-1-il)ciclobutil)acetonitrila impuro como óleo amarelo leve (500 mg), o qual foi usado na Parte 2.[00482] To a solution of 2-((1s,3r)-1-(4-bromo-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile (Preparation 37, cis isomer, 400 mg, 1.48 mmol) in toluene (9 mL) bis(pinacolato)diboron (564 mg, 2.22 mmol) and KOAc (436 mg, 4.44 mmol) were added. The mixture was purged with nitrogen for about 3 min, after which Pd(dppf)Cl2 (108 mg, 0.15 mmol) was added. The mixture was purged again with nitrogen for about 3 min, then heated to about 110 °C for about 16 hrs. The cooled mixture was concentrated, and the residue was purified by chromatography to provide 2-((1s,3r)-3-methoxy-1-(4-(4,4,5,5-tetramethyl-1,3,2- impure dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrile as light yellow oil (500 mg), which was used in Part 2.
[00483] Uma solução de 2-((1s,3r)-3-metóxi-1-(4-(4,4,5,5-tetrametil- 1,3,2-dioxaborolan-2-il)-1H-pirazol-1-il)ciclobutil)acetonitrila (Parte 1, 470 mg, 1,48 mmol) e 4,6-dicloropirazolo[1,5-a]pirazina (Preparação 4, 279 mg, 1,48 mmol), e K2CO3 aq. a 2 M (2,22 mL) em 1,4-dioxano (10 mL) foi purgada com nitrogênio durante cerca de 2 min, depois dos quais Pd(dppf)Cl2 (108 mg, 0,15 mmol) foi adicionado. A mistura foi novamente purgada com nitrogênio durante cerca de 3 min, em seguida aquecida a cerca de 90 °C durante cerca de 16 hrs. A mistura resfriada foi concentrada, e o resíduo foi purificado por cromatografia para proporcionar o composto título como um sólido amarelo (130 mg, 26 %).[00483] A solution of 2-((1s,3r)-3-methoxy-1-(4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H- pyrazol-1-yl)cyclobutyl)acetonitrile (Part 1, 470 mg, 1.48 mmol) and 4,6-dichloropyrazolo[1,5-a]pyrazine (Preparation 4, 279 mg, 1.48 mmol), and K2CO3 aq. at 2 M (2.22 mL) in 1,4-dioxane (10 mL) was purged with nitrogen for about 2 min, after which Pd(dppf)Cl2 (108 mg, 0.15 mmol) was added. The mixture was purged again with nitrogen for about 3 min, then heated to about 90 °C for about 16 hrs. The cooled mixture was concentrated, and the residue was purified by chromatography to provide the title compound as a yellow solid (130 mg, 26%).
[00484] 1H RMN (400 MHz, CDCl3) δ: 8,40 (s, 1 H), 8,35 (s, 1 H), 8,27 (s, 1 H), 8,08 (d, 1 H), 7,00 (s, 1 H), 4,05 (quin, 1 H), 3,30 (s, 3 H), 3,10 (s, 2 H), 3,00 (m, 2 H), 2,75 (m, 2 H).[00484] 1H NMR (400 MHz, CDCl3) δ: 8.40 (s, 1 H), 8.35 (s, 1 H), 8.27 (s, 1 H), 8.08 (d, 1 H), 7.00 (s, 1 H), 4.05 (quin, 1 H), 3.30 (s, 3 H), 3.10 (s, 2 H), 3.00 (m, 2 H), 2.75 (m, 2 H).
[00485] LCMS m/z = 343,2 [MH]+ (35Cl isótopo) Preparação 83 Etil 5-(4-(1-((1s,3r)-1-(cianometil)-3-metoxiciclobutil)-1H-pirazol-4- il)pirazolo[1,5-a]pirazin-6-il)-1H-pirazol-3-carboxilato [00485] LCMS m/z = 343.2 [MH]+ (35Cl isotope) Preparation 83 Ethyl 5-(4-(1-((1s,3r)-1-(cyanomethyl)-3-methoxycyclobutyl)-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-3-carboxylate
[00486] Uma solução de 2-((1s,3r)-1-(4-(6-cloropirazolo[1,5- a]pirazin-4-il)-1H-pirazol-1-il)-3-metoxiciclobutil)acetonitrila (Prepara-ção 82, 120 mg, 0,35 mmol) e etil 5-(tributilestanil)-1H-pirazol-3- carboxilato (Preparação 31, 150 mg, 0,35 mmol) em 1,4-dioxano (5 mL) foi tratada com XPhos Pd G2 (13,8 mg, 0,017 mmol), e a mistura foi purgada com nitrogênio durante cerca de 2 min. A mistura foi aquecida a cerca de 110 °C durante cerca de 2 hrs. A mistura resfriada foi concentrada, e o resíduo foi purificado por cromatografia para propor-cionar o composto título como um sólido amarelo (180 mg).[00486] A solution of 2-((1s,3r)-1-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl )acetonitrile (Preparation 82, 120 mg, 0.35 mmol) and ethyl 5-(tributylstanyl)-1H-pyrazol-3-carboxylate (Preparation 31, 150 mg, 0.35 mmol) in 1,4-dioxane ( 5 mL) was treated with XPhos Pd G2 (13.8 mg, 0.017 mmol), and the mixture was purged with nitrogen for about 2 min. The mixture was heated to about 110°C for about 2 hrs. The cooled mixture was concentrated, and the residue was purified by chromatography to provide the title compound as a yellow solid (180 mg).
[00487] 1H RMN (400 MHz, CDCl3) δ: 9,05 (br. s., 1 H), 8,39 (s, 1 H), 8,32 (s, 1 H), 8,14 (s, 1 H), 7,65 (s, 1 H), 7,02 (s, 1 H), 6,88 (s, 1 H), 4,44 - 4,50 (m, 2 H), 4,08 (t, 1 H), 3,80 (s, 3 H), 3,13 (s, 2 H), 3,00 - 3,08 (m, 2 H), 2,75 - 2,83 (m, 2 H), 1,46 (t, 3 H).[00487] 1H NMR (400 MHz, CDCl3) δ: 9.05 (br. s., 1 H), 8.39 (s, 1 H), 8.32 (s, 1 H), 8.14 ( s, 1 H), 7.65 (s, 1 H), 7.02 (s, 1 H), 6.88 (s, 1 H), 4.44 - 4.50 (m, 2 H), 4.08 (t, 1 H), 3.80 (s, 3 H), 3.13 (s, 2 H), 3.00 - 3.08 (m, 2 H), 2.75 - 2, 83 (m, 2 H), 1.46 (t, 3 H).
[00488] LCMS m/z = 447,1 [MH]+ Exemplo 32 5-(4-(1-((1s,3r)-1-(Cianometil)-3-metoxiciclobutil)-1H-pirazol-4- il)pirazolo[1,5-a]pirazin-6-il)-1H-pirazol-3-carboxamida [00488] LCMS m/z = 447.1 [MH]+ Example 32 5-(4-(1-((1s,3r)-1-(Cyanomethyl)-3-methoxycyclobutyl)-1H-pyrazol-4-yl )pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-3-carboxamide
[00489] Uma solução de etil 5-(4-(1-((1s,3r)-1-(cianometil)-3- metoxiciclobutil)-1H-pirazol-4-il)pirazolo[1,5-a]pirazin-6-il)-1H-pirazol-3- carboxilato (Preparação 83, 100 mg, 0,22 mmol) em MeOH (2 mL) foi tratada com uma solução a 4 M de gás amônia em metanol (1 mL). O vaso de reação foi bem vedado, e a mistura foi aquecida a cerca de 60 °C durante cerca de 16 hrs. A mistura foi concentrada, e o resíduo foi purificado por HPLC para proporcionar o composto título (23 mg, 25 %).[00489] A solution of ethyl 5-(4-(1-((1s,3r)-1-(cyanomethyl)-3-methoxycyclobutyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin -6-yl)-1H-pyrazol-3-carboxylate (Preparation 83, 100 mg, 0.22 mmol) in MeOH (2 mL) was treated with a 4 M solution of ammonia gas in methanol (1 mL). The reaction vessel was tightly sealed, and the mixture was heated to about 60 °C for about 16 hrs. The mixture was concentrated, and the residue was purified by HPLC to provide the title compound (23 mg, 25%).
[00490] H RMN (400 MHz, DMSO-d6) δ: 13,79 (br. s., 1 H), 9,31 (br. s., 1 H), 9,00 (br. s., 1 H), 8,67 (br. s., 1 H), 8,28 (d, 1 H), 7,56 (br. s., 2 H), 7,39 (br. s., 1 H), 7,25 - 7,35 (m, 1 H), 4,08 (quin, 1 H), 3,44 (s, 2 H), 3,21 (s, 3 H), 2,79 - 2,90 (m, 2 H), 2,63 - 2,73 (m, 3 H).[00490] H NMR (400 MHz, DMSO-d6) δ: 13.79 (br. s., 1 H), 9.31 (br. s., 1 H), 9.00 (br. s., 1 H), 8.67 (br. s., 1 H), 8.28 (d, 1 H), 7.56 (br. s., 2 H), 7.39 (br. s., 1 H), 7.25 - 7.35 (m, 1 H), 4.08 (quin, 1 H), 3.44 (s, 2 H), 3.21 (s, 3 H), 2.79 - 2.90 (m, 2 H), 2.63 - 2.73 (m, 3 H).
[00491] LCMS m/z = 440,1 [MNa]+ Preparação 84 2-(Tetra-hidro-2H-piran-2-il)-2H-1,2,3-triazol [00491] LCMS m/z = 440.1 [MNa]+ Preparation 84 2-(Tetrahydro-2H-pyran-2-yl)-2H-1,2,3-triazole
[00492] A uma mistura de 1H-1,2,3-triazol (15 g, 220 mmol) em DCM (724 mL) foram adicionados DHP (21,9 g, 261 mmol) e PTSA (0,374 g, 2,17 mmol). A mistura foi mantida a cerca de 25 °C durante cerca de 18 hrs, depois dos quais NaOH (96 mg, 2,39 mmol) foi adicionado. A mistura foi agitada a cerca de 25 °C durante cerca de 1 hr em seguida filtrada. O filtrado foi concentrado, e o resíduo foi purificado por cromatografia para proporcionar o composto título como um óleo incolor (18 g, 54 %).[00492] To a mixture of 1H-1,2,3-triazole (15 g, 220 mmol) in DCM (724 mL) were added DHP (21.9 g, 261 mmol) and PTSA (0.374 g, 2.17 mmol). The mixture was maintained at about 25°C for about 18 hrs, after which NaOH (96 mg, 2.39 mmol) was added. The mixture was stirred at about 25°C for about 1 hr then filtered. The filtrate was concentrated, and the residue was purified by chromatography to provide the title compound as a colorless oil (18 g, 54%).
[00493] 1H RMN (400 MHz, CDCl3) δ: 7,68 (s, 2 H), 5,74 (dd, 1 H), 4,00 - 4,08 (m, 1 H), 3,69 - 3,81 (m, 1 H), 2,36 - 2,51 (m, 1 H), 2,02 - 2,20 (m, 2 H), 1,61 - 1,81 (m, 3 H). Preparação 85 2-(Tetra-hidro-2H-piran-2-il)-4-(4,4,5,5-tetrametil-1,3,2- dioxaborolan-2-il)-2H-1,2,3-triazol [00493] 1H NMR (400 MHz, CDCl3) δ: 7.68 (s, 2 H), 5.74 (dd, 1 H), 4.00 - 4.08 (m, 1 H), 3.69 - 3.81 (m, 1 H), 2.36 - 2.51 (m, 1 H), 2.02 - 2.20 (m, 2 H), 1.61 - 1.81 (m, 3 H). Preparation 85 2-(Tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,2, 3-triazole
[00494] A uma solução de 4,4,5,5-tetrametil-1,3,2-dioxaborolano (24 g, 129 mmol) em pentano (200 mL) foram adicionados 4,4'-di-terc-butil- 2,2'-bipiridina (0,315 g, 1,18 mmol) e dímero de (1,5- ciclooctadieno)(metóxi)irídio(I) (234 mg, 0,35 mmol). A solução rapi-damente tornou-se uma cor vermelha e evolução de gás foi observada. Depois de cerca de 15 min, 2-(tetra-hidro-2H-piran-2-il)-2H-1,2,3- triazol (Preparação 84, 18 g, 117 mmol) foi adicionado. A mistura foi agitada a cerca de 25 °C durante cerca de 6 h. A mistura foi concentrada, e o resíduo foi purificado por cromatografia para proporcionar o composto título como um sólido incolor (26 g, 79 %).[00494] To a solution of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (24 g, 129 mmol) in pentane (200 mL) was added 4,4'-di-tert-butyl- 2,2'-bipyridine (0.315 g, 1.18 mmol) and (1,5-cycloctadiene)(methoxy)iridium(I) dimer (234 mg, 0.35 mmol). The solution quickly turned a red color and gas evolution was observed. After about 15 min, 2-(tetrahydro-2H-pyran-2-yl)-2H-1,2,3-triazole (Preparation 84, 18 g, 117 mmol) was added. The mixture was stirred at about 25°C for about 6 h. The mixture was concentrated, and the residue was purified by chromatography to provide the title compound as a colorless solid (26 g, 79%).
[00495] 1H RMN (400 MHz, CDCl3) δ: 7,99 (s, 1 H), 5,81 (dd, 1 H), 4,07 (d, 1 H), 3,67 - 3,78 (m, 1 H), 2,41 - 2,55 (m, 1 H), 2,02 - 2,16 (m, 2 H), 1,60 - 1,80 (m, 3 H), 1,37 (s, 12 H).[00495] 1H NMR (400 MHz, CDCl3) δ: 7.99 (s, 1 H), 5.81 (dd, 1 H), 4.07 (d, 1 H), 3.67 - 3.78 (m, 1 H), 2.41 - 2.55 (m, 1 H), 2.02 - 2.16 (m, 2 H), 1.60 - 1.80 (m, 3 H), 1 .37 (s, 12 H).
[00496] LCMS m/z = 113,9 [MH-C2H2N]+ Preparação 86 (1r,3r)-3-(Cianometil)-3-(4-(6-(2-(tetra-hidro-2H-piran-2-il)-2H-1,2,3- triazol-4-il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)ciclobutano-1- carbonitrila [00496] LCMS m/z = 113.9 [MH-C2H2N]+ Preparation 86 (1r,3r)-3-(Cyanomethyl)-3-(4-(6-(2-(tetrahydro-2H-pyran -2-yl)-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile
[00497] Uma mistura de (1r,3r)-3-(4-(6-cloropirazolo[1,5-a]pirazin-4- il)-1H-pirazol-1-il)-3-(cianometil)ciclobutano-1-carbonitrila (Preparação 75, 300 mg, 0,89 mmol), 2-(tetra-hidro-2H-piran-2-il)-4-(4,4,5,5- tetrametil-1,3,2-dioxaborolan-2-il)-2H-1,2,3-triazol (Preparação 85, 248 mg, 0,89 mmol), e K3PO4 aq. a 2 M (1 mL) em 1,4-dioxano (4 mL) foi purgada com argônio durante cerca de 5 min, depois dos quais XPhos Pd G2 (140 mg, 0,18 mmol) foi adicionado. A mistura foi aquecida a cerca de 50 °C durante cerca de 1 hr, em seguida resfriada e diluída com EtOAc. As fases foram separadas, e a fase aquosa foi extraída duas vezes com DCM. Os extratos de EtOAc e DCM combinados foram secados (Na2SO4) e concentrados. O resíduo foi purificado por cromatografia para proporcionar o composto título como uma goma clara (384 mg, 95 %).[00497] A mixture of (1r,3r)-3-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)cyclobutane -1-carbonitrile (Preparation 75, 300 mg, 0.89 mmol), 2-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)-2H-1,2,3-triazole (Preparation 85, 248 mg, 0.89 mmol), and aq. 2 M (1 mL) in 1,4-dioxane (4 mL) was purged with argon for about 5 min, after which XPhos Pd G2 (140 mg, 0.18 mmol) was added. The mixture was heated to about 50°C for about 1 hr, then cooled and diluted with EtOAc. The phases were separated, and the aqueous phase was extracted twice with DCM. The combined EtOAc and DCM extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography to provide the title compound as a clear gum (384 mg, 95%).
[00498] 1H RMN (400 MHz, CDCl3) δ: 9,02 (s, 1 H), 8,41 (s, 1 H), 8,35 (s, 1 H), 8,28 (s, 1 H), 8,13 (d, 1 H), 7,00 (d, 1 H), 5,81 (dd, 1 H), 4,06 - 4,12 (m, 1 H), 3,77 - 3,87 (m, 1 H), 3,35 - 3,47 (m, 3 H), 3,30 (s, 2 H), 2,95 - 3,04 (m, 2 H), 2,45 - 2,59 (m, 1 H), 2,12 - 2,24 (m, 2 H), 1,69 - 1,87 (m, 3 H).[00498] 1H NMR (400 MHz, CDCl3) δ: 9.02 (s, 1 H), 8.41 (s, 1 H), 8.35 (s, 1 H), 8.28 (s, 1 H), 8.13 (d, 1 H), 7.00 (d, 1 H), 5.81 (dd, 1 H), 4.06 - 4.12 (m, 1 H), 3.77 - 3.87 (m, 1 H), 3.35 - 3.47 (m, 3 H), 3.30 (s, 2 H), 2.95 - 3.04 (m, 2 H), 2 .45 - 2.59 (m, 1 H), 2.12 - 2.24 (m, 2 H), 1.69 - 1.87 (m, 3 H).
[00499] LCMS m/z = 455,3 [MH]+ Preparação 87 (1r,3r)-3-(4-(6-(2H-1,2,3-Triazol-4-il)pirazolo[1,5-a]pirazin-4-il)-1H- pirazol-1-il)-3-(cianometil)ciclobutano-1-carbonitrila [00499] LCMS m/z = 455.3 [MH]+ Preparation 87 (1r,3r)-3-(4-(6-(2H-1,2,3-Triazol-4-yl)pyrazolo[1, 5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)cyclobutane-1-carbonitrile
[00500] Uma suspensão de (1r,3r)-3-(cianometil)-3-(4-(6-(2-(tetra- hidro-2H-piran-2-il)-2H-1,2,3-triazol-4-il)pirazolo[1,5-a]pirazin-4-il)-1H- pirazol-1-il)ciclobutano-1-carbonitrila (Preparação 86, 384 mg, 0,84 mmol) em MeOH (5 mL) foi tratada com PTSA (16,1 mg, 0,084 mmol). A mistura foi aquecida a cerca de 60 °C durante cerca de 3,5 h. Os sólidos dissolvidos para formar uma solução homogênea, depois da qual um sólido branco precipitou. O aquecimento foi continuado durante cerca de mais 1 hr. A mistura foi resfriada a cerca de 0 °C durante cerca de 30 min e filtrada. O precipitado foi lavado com MeOH e secado sob vácuo para proporcionar o composto título como um sólido branco (204 mg, 65 %).[00500] A suspension of (1r,3r)-3-(cyanomethyl)-3-(4-(6-(2-(tetrahydro-2H-pyran-2-yl)-2H-1,2,3 -triazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile (Preparation 86, 384 mg, 0.84 mmol) in MeOH ( 5 mL) was treated with PTSA (16.1 mg, 0.084 mmol). The mixture was heated to about 60°C for about 3.5 h. The solids dissolved to form a homogeneous solution, after which a white solid precipitated. Heating was continued for approximately 1 more hr. The mixture was cooled to about 0°C for about 30 min and filtered. The precipitate was washed with MeOH and dried under vacuum to provide the title compound as a white solid (204 mg, 65%).
[00501] 1H RMN (400 MHz, DMSO-d6) δ: 9,05 (s, 1 H), 8,97 (s, 1 H), 8,72 (br. s., 1 H), 8,57 (s, 1 H), 8,46 (s, 1 H), 8,30 (s, 1 H), 7,56 (s, 1 H), 3,55 - 3,62 (m, 1 H), 3,53 (s, 2 H), 3,22 - 3,30 (m, 2 H), 2,89 - 3,00 (m, 2 H).[00501] 1H NMR (400 MHz, DMSO-d6) δ: 9.05 (s, 1 H), 8.97 (s, 1 H), 8.72 (br. s., 1 H), 8, 57 (s, 1 H), 8.46 (s, 1 H), 8.30 (s, 1 H), 7.56 (s, 1 H), 3.55 - 3.62 (m, 1 H ), 3.53 (s, 2 H), 3.22 - 3.30 (m, 2 H), 2.89 - 3.00 (m, 2 H).
[00502] LCMS m/z = 371,3 [MH]+ Exemplo 33 (1r,3r)-3-(Cianometil)-3-(4-(6-(1-metil-1H-1,2,3-triazol-4- il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)ciclobutano-1- carbonitrila [00502] LCMS m/z = 371.3 [MH]+ Example 33 (1r,3r)-3-(Cyanomethyl)-3-(4-(6-(1-methyl-1H-1,2,3- triazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile
[00503] A uma mistura de (1r,3r)-3-(4-(6-(2H-1,2,3-triazol-4- il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)-3-(cianometil)ciclobutano- 1-carbonitrila (Preparação 87, 100 mg, 0,27 mmol) e K2CO3 (75 mg, 0,54 mmol) em DMF (1 mL) foi adicionado iodometano (0,034 mL, 0,540 mmol). A mistura foi agitada durante cerca de 2 hrs a cerca de 25 °C. A mistura foi filtrada, e a massa filtrante foi lavada duas vezes com DCM. O filtrado foi concentrado, e o resíduo foi purificado por cromatografia seguido por HPLC para proporcionar o composto título como um sólido branco (40 mg, 39 %).[00503] A mixture of (1r,3r)-3-(4-(6-(2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl) -1H-pyrazol-1-yl)-3-(cyanomethyl)cyclobutane-1-carbonitrile (Preparation 87, 100 mg, 0.27 mmol) and K2CO3 (75 mg, 0.54 mmol) in DMF (1 mL) was Iodomethane (0.034 mL, 0.540 mmol) is added. The mixture was stirred for about 2 hrs at about 25°C. The mixture was filtered, and the filter cake was washed twice with DCM. The filtrate was concentrated, and the residue was purified by chromatography followed by HPLC to provide the title compound as a white solid (40 mg, 39%).
[00504] 1H RMN (400 MHz, CDCl3) δ: 9,19 (s, 1 H), 8,51 (s, 1 H), 8,33 (s, 1 H), 8,30 (s, 1 H), 8,15 (d, 1 H), 7,03 (s, 1 H), 4,22 (s, 3 H), 3,35 - 3,46 (m, 3 H), 3,30 (s, 2 H), 2,99 (d, 2 H).[00504] 1H NMR (400 MHz, CDCl3) δ: 9.19 (s, 1 H), 8.51 (s, 1 H), 8.33 (s, 1 H), 8.30 (s, 1 H), 8.15 (d, 1 H), 7.03 (s, 1 H), 4.22 (s, 3 H), 3.35 - 3.46 (m, 3 H), 3.30 (s, 2H), 2.99 (d, 2H).
[00505] LCMS m/z = 385,4 [MH]+ Exemplo 34 (1s,3s)-3-(Cianometil)-1-metil-3-(4-(6-(1-metil-1H-pirazol-4- il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)ciclobutano-1- carbonitrila e Exemplo 35 (1r,3r)-3-(Cianometil)-1-metil-3-(4-(6-(1-metil-1H-pirazol-4- il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)ciclobutano-1- carbonitrila [00505] LCMS m/z = 385.4 [MH]+ Example 34 (1s,3s)-3-(Cyanomethyl)-1-methyl-3-(4-(6-(1-methyl-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile and Example 35 (1r,3r)-3-(Cyanomethyl)-1-methyl-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin- 4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile
[00506] DBU (327 mg, 2,15 mmol) foi adicionado a uma solução de 6-(1-metil-1H-pirazol-4-il)-4-(1H-pirazol-4-il)pirazolo[1,5-a]pirazina (Preparação 53, 190 mg, 0,72 mmol) e 3-(cianometileno)-1- metilciclobutano-1-carbonitrila (Preparação 89, 142 mg, 1,07 mmol) em MeCN (15 mL), e a mistura foi agitada a cerca de 50 °C durante cerca de 4 hrs. A mistura foi concentrada, e o resíduo foi purificado por cromatografia para proporcionar um resíduo, o qual também foi purificado por TLC para proporcionar uma mistura da dois compostos título (200 mg, 70 %) como um sólido marrom. A mistura de isômeros foi separada por HPLC para proporcionar (1r,3r)-3-(cianometil)-1-metil-3-(4- (6-(1-metil-1H-pirazol-4-il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1- il)ciclobutano-1-carbonitrila como um sólido rosa leve (trans isômero, 24 mg 8 %)[00506] DBU (327 mg, 2.15 mmol) was added to a solution of 6-(1-methyl-1H-pyrazol-4-yl)-4-(1H-pyrazol-4-yl)pyrazolo[1, 5-a]pyrazine (Preparation 53, 190 mg, 0.72 mmol) and 3-(cyanomethylene)-1-methylcyclobutane-1-carbonitrile (Preparation 89, 142 mg, 1.07 mmol) in MeCN (15 mL), and the mixture was stirred at about 50°C for about 4 hrs. The mixture was concentrated, and the residue was purified by chromatography to provide a residue, which was also purified by TLC to provide a mixture of the two title compounds (200 mg, 70%) as a brown solid. The mixture of isomers was separated by HPLC to provide (1r,3r)-3-(cyanomethyl)-1-methyl-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile as a light pink solid (trans isomer, 24 mg 8%)
[00507] 1H RMN (400 MHz, CD3CN) δ: 8,36 (s, 1 H), 8,28 (s, 1 H), 8,26 - 8,31 (m, 1 H), 8,14 (s, 1 H), 7,86 (s, 1 H), 7,79 (d, 1 H), 7,73 (s, 1 H), 6,87 (d, 1 H), 3,66 (s, 3 H), 3,10 (s, 2 H), 2,80 - 2,92 (m, 4 H), 1,25 (s, 3 H).[00507] 1H NMR (400 MHz, CD3CN) δ: 8.36 (s, 1 H), 8.28 (s, 1 H), 8.26 - 8.31 (m, 1 H), 8.14 (s, 1 H), 7.86 (s, 1 H), 7.79 (d, 1 H), 7.73 (s, 1 H), 6.87 (d, 1 H), 3.66 (s, 3 H), 3.10 (s, 2 H), 2.80 - 2.92 (m, 4 H), 1.25 (s, 3 H).
[00508] LCMS m/z = 398,0 [MH]+ e 420,0 [MNa]+ e (1s,3s)-3- (cianometil)-1-metil-3-(4-(6-(1-metil-1H-pirazol-4-il)pirazolo[1,5- a]pirazin-4-il)-1H-pirazol-1-il)ciclobutano-1-carbonitril (cis isômero, 24 mg, 8 %).[00508] LCMS m/z = 398.0 [MH]+ and 420.0 [MNa]+ and (1s,3s)-3- (cyanomethyl)-1-methyl-3-(4-(6-(1 -methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitril (cis isomer, 24 mg, 8%).
[00509] 1H RMN (400 MHz, CD3CN) δ: 8,68 (s, 1 H), 8,63 (s, 1 H), 8,44 (s, 1 H), 8,14 (s, 1 H), 8,05 (d, 1 H), 8,00 (s, 1 H), 7,15 (d, 1 H), 3,92 (s, 3 H), 3,47 - 3,55 (m, 2 H), 3,19 (s, 2 H), 2,74 - 2,82 (m, 2 H), 1,63 (s, 3 H).[00509] 1H NMR (400 MHz, CD3CN) δ: 8.68 (s, 1 H), 8.63 (s, 1 H), 8.44 (s, 1 H), 8.14 (s, 1 H), 8.05 (d, 1 H), 8.00 (s, 1 H), 7.15 (d, 1 H), 3.92 (s, 3 H), 3.47 - 3.55 (m, 2 H), 3.19 (s, 2 H), 2.74 - 2.82 (m, 2 H), 1.63 (s, 3 H).
[00510] LCMS m/z = 398,0 [MH]+ e 419,9 [MNa]+ Preparação 88 1-Metil-3-oxociclobutano-1-carbonitrila [00510] LCMS m/z = 398.0 [MH]+ and 419.9 [MNa]+ Preparation 88 1-Methyl-3-oxocyclobutane-1-carbonitrile
[00511] A uma solução de diisopropilamina (1,30 g, 12,9 mmol) em THF (30 mL) foi adicionado n-BuLi a 2,5 M (5,15 mL) a cerca de 0 °C. A solução foi agitada durante cerca de 30 min a cerca de 0 °C antes de ser resfriada a cerca de -78 °C. 3-Metilenociclobutano-1-carbonitrila (1,00 g, 10,74 mmol) foi adicionado, e a solução foi agitada durante cerca de 1 h a cerca de -78 °C. Iodometano (1,98 g, 14,0 mmol) foi adicionado à solução a cerca de -78 °C, em seguida a mistura foi permitida aquecer a cerca de 20 °C e foi mantida nesta temperatura durante cerca de 0,5 hrs. NH4Cl aq. saturado (30 mL) foi adicionado, e a mistura foi extraída com EtOAc (3 x 30 mL). Os extratos de EtOAc combinados foram concentrados para proporcionar 1-metil-3- metilenociclobutano-1-carbonitrila como um óleo amarelo pálido (1,1 g, 96 %).[00511] To a solution of diisopropylamine (1.30 g, 12.9 mmol) in THF (30 mL) was added 2.5 M n-BuLi (5.15 mL) at about 0 °C. The solution was stirred for about 30 min at about 0°C before being cooled to about -78°C. 3-Methylenecyclobutane-1-carbonitrile (1.00 g, 10.74 mmol) was added, and the solution was stirred for about 1 h at about -78 °C. Iodomethane (1.98 g, 14.0 mmol) was added to the solution at about -78°C, then the mixture was allowed to warm to about 20°C and was maintained at this temperature for about 0.5 hrs. aq. NH4Cl. saturated solution (30 mL) was added, and the mixture was extracted with EtOAc (3 x 30 mL). The combined EtOAc extracts were concentrated to provide 1-methyl-3-methylenecyclobutane-1-carbonitrile as a pale yellow oil (1.1 g, 96%).
[00512] 1H RMN (400 MHz, CDCl3) δ: 4,90 - 4,98 (m, 2 H), 3,23 - 3,35 (m, 2 H), 2,64 - 2,75 (m, 2 H), 1,55 (s, 3 H).[00512] 1H NMR (400 MHz, CDCl3) δ: 4.90 - 4.98 (m, 2 H), 3.23 - 3.35 (m, 2 H), 2.64 - 2.75 (m , 2 H), 1.55 (s, 3 H).
[00513] A uma mistura de 1-metil-3-metilenociclobutano-1- carbonitrila (1,10 g, 10,3 mmol) e hidrato de RuCl3 (50,9 mg, 0,23 mmol) em uma mistura de DCM (20 mL), MeCN (20 mL) e água (40 mL) foi adicionado NaIO4 (8,78 g, 41,1 mmol) em pequenas porções a cerca de 5 °C. A mistura foi em seguida agitada a cerca de 25 °C durante cerca de 17 hrs. A fase aquosa foi separada e extraída com DCM (2 x 50 mL). Os extratos de DCM foram combinados com a fase de DCM - MeCN e secados (Na2SO4), em seguida filtrados através de cerca de 10 g de sílica gel. A sílica gel foi lavada com DCM (50 mL). O filtrado foi concentrado para proporcionar o composto título como um óleo marrom (0,80 g, 71 %).[00513] A mixture of 1-methyl-3-methylenecyclobutane-1-carbonitrile (1.10 g, 10.3 mmol) and RuCl3 hydrate (50.9 mg, 0.23 mmol) in a mixture of DCM ( 20 mL), MeCN (20 mL) and water (40 mL) were added NaIO4 (8.78 g, 41.1 mmol) in small portions at about 5 °C. The mixture was then stirred at about 25°C for about 17 hrs. The aqueous phase was separated and extracted with DCM (2 x 50 mL). The DCM extracts were combined with the DCM - MeCN phase and dried (Na2SO4), then filtered through about 10 g of silica gel. The silica gel was washed with DCM (50 mL). The filtrate was concentrated to provide the title compound as a brown oil (0.80 g, 71%).
[00514] 1H RMN (400 MHz, CDCl3) δ: 3,71 (m, 2 H), 3,14 (m, 2 H), 1,71 (s, 3 H). Preparação 89 3-(Cianometileno)-1-metilciclobutano-1-carbonitrila [00514] 1H NMR (400 MHz, CDCl3) δ: 3.71 (m, 2 H), 3.14 (m, 2 H), 1.71 (s, 3 H). Preparation 89 3-(Cyanomethylene)-1-methylcyclobutane-1-carbonitrile
[00515] Uma mistura de 1-metil-3-oxociclobutano-1-carbonitrila (Preparação 88, 0,80 g, 7,0 mmol), (EtO)2P(O)CH2CN (1,43 g, 8,06 mmol), LiBr (0,955 g, 11,0 mmol) e TEA (1,48 g, 14,7 mmol) em THF (20 mL) foi agitada a cerca de 25 °C durante cerca de 16 hrs. Água (30 mL) foi adicionada, e a mistura foi extraída com EtOAc (3 x 50 mL). Os extratos de EtOAc combinados foram secados (Na2SO4) e concentradas. O resíduo foi purificado por cromatografia para proporcionar o composto título como um óleo incolor (0,65 g, 70 %).[00515] A mixture of 1-methyl-3-oxocyclobutane-1-carbonitrile (Preparation 88, 0.80 g, 7.0 mmol), (EtO)2P(O)CH2CN (1.43 g, 8.06 mmol ), LiBr (0.955 g, 11.0 mmol) and TEA (1.48 g, 14.7 mmol) in THF (20 mL) was stirred at about 25 °C for about 16 hrs. Water (30 mL) was added, and the mixture was extracted with EtOAc (3 x 50 mL). The combined EtOAc extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography to provide the title compound as a colorless oil (0.65 g, 70%).
[00516] 1H RMN (400 MHz, CDCl3) δ: 5,34 (m, 1 H), 3,47 (m, 2 H), 2,98 (m, 2 H), 1,60 (s, 3 H).[00516] 1H NMR (400 MHz, CDCl3) δ: 5.34 (m, 1 H), 3.47 (m, 2 H), 2.98 (m, 2 H), 1.60 (s, 3 H).
[00517] GCMS m/z = 131 [M-H]+ Preparação 90 2-(3-Metoxiciclobutilideno)acetonitrila [00517] GCMS m/z = 131 [MH]+ Preparation 90 2-(3-Methoxycyclobutylidene)acetonitrile
[00518] Doze reações idênticas foram realizadas em paralelo como segue:[00518] Twelve identical reactions were carried out in parallel as follows:
[00519] Para cada reação, um tubo vedado de 100 mL foi carregado com metoxieteno (37 g, 637 mmol), DIPEA (9,88 g, 76,4 mmol), e cloreto de acetila (5 g, 60 mmol) a cerca de -30 °C. A mistura foi em seguida aquecida a cerca de 70 °C durante cerca de 5 hrs. As doze reações fo-ram combinadas e lavadas com HCl aq. a 1 M (2 x 100 mL), NaHCO3 aq. saturado (2 x 100 mL), secadas (Na2SO4) e concentradas para pro-porcionar uma espécie crua de 3-metoxiciclobutan-1-ona como um óleo preto (27 g, 37 %). Este material foi cerca de 50 % puro como julgado por 1H RMN e foi usado sem outra purificação na Parte 2.[00519] For each reaction, a 100 mL sealed tube was charged with methoxyethene (37 g, 637 mmol), DIPEA (9.88 g, 76.4 mmol), and acetyl chloride (5 g, 60 mmol) at around -30°C. The mixture was then heated to about 70°C for about 5 hrs. The twelve reactions were combined and washed with aq. HCl. at 1 M (2 x 100 mL), aq. saturated (2 x 100 mL), dried (Na2SO4) and concentrated to provide a crude species of 3-methoxycyclobutan-1-one as a black oil (27 g, 37%). This material was about 50% pure as judged by 1H NMR and was used without further purification in Part 2.
[00520] Duas reações idênticas foram realizadas em paralelo.[00520] Two identical reactions were carried out in parallel.
[00521] A uma mistura de LiBr (13,4 g, 154 mmol) e TEA (39 mL, 280 mmol) em THF (200 mL) foi adicionado (EtO)2P(O)CH2CN (26 g, 147 mmol) a cerca de 0 °C. A agitação foi continuada a cerca de 25 °C durante cerca de 2 hrs. A esta mistura foi adicionado uma solução de 3-metoxiciclobutan-1-ona cru preparado na Parte 1 (13 g, cerca de 70 mmol) em THF (40 mL) a cerca de 0 °C. A mistura foi em seguida agi-tada a cerca de 25 °C durante cerca de 16 hrs. As duas misturas de reação foram combinadas e concentradas. O resíduo foi purificado por cromatografia para proporcionar o composto título como um óleo amarelo leve (9,2 g, 56 %).[00521] To a mixture of LiBr (13.4 g, 154 mmol) and TEA (39 mL, 280 mmol) in THF (200 mL) was added (EtO)2P(O)CH2CN (26 g, 147 mmol) to around 0°C. Stirring was continued at about 25°C for about 2 hrs. To this mixture was added a solution of crude 3-methoxycyclobutan-1-one prepared in Part 1 (13 g, about 70 mmol) in THF (40 mL) at about 0°C. The mixture was then stirred at about 25°C for about 16 hrs. The two reaction mixtures were combined and concentrated. The residue was purified by chromatography to provide the title compound as a light yellow oil (9.2 g, 56%).
[00522] 1H RMN (400 MHz, CDCl3) δ: 5,25 (m, 1 H), 4,05 (m, 1 H), 3,30 (s, 3 H), 3,25 (m,1 H), 3,10 (m, 1 H), 2,85 (m, 2 H).[00522] 1H NMR (400 MHz, CDCl3) δ: 5.25 (m, 1 H), 4.05 (m, 1 H), 3.30 (s, 3 H), 3.25 (m,1 H), 3.10 (m, 1 H), 2.85 (m, 2 H).
[00523] LCMS m/z = 124,08 [MH]+ Preparação 91 (1r,3r)-3-(Cianometil)-3-(4-(4,4,5,5-tetrametil-1,3,2-dioxaborolan-2- il)-1H-pirazol-1-il)ciclobutano-1-carbonitrila (trans isômero) e (1s,3s)-3-(cianometil)-3-(4-(4,4,5,5-tetrametil-1,3,2-dioxaborolan-2- il)-1H-pirazol-1-il)ciclobutano-1-carbonitrila (cis isômero) [00523] LCMS m/z = 124.08 [MH]+ Preparation 91 (1r,3r)-3-(Cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile (trans isomer) and (1s,3s)-3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl) cyclobutane-1-carbonitrile (cis isomer)
[00524] A uma solução de 4-(4,4,5,5,-tetrametil-1,3,2-dioxaborolan- 2-il)-1H-pirazol (1,3 kg, 6,67 mol) em MeCN (43 L) foram adicionados 3-cianometileno)ciclobutano-1-carbonitrila (Preparação 27, 953 g, 8 mol) e DBU (3,06 kg, 20,1 mol) a cerca de 20 °C. A agitação foi continuada a cerca de 20 °C durante cerca de 16 hrs. A mistura foi vertida em KH2PO4 aq. A 1 M (10 L) e extraída com EtOAc (5 x 5 L). Os extratos de EtOAc combinados foram concentrados, e o resíduo foi purificado por cromatografia para proporcionar (1r,3r)-3-(cianometil)-3-(4- (4,4,5,5-tetrametil-1,3,2-dioxaborolan-2-il)-1H-pirazol-1-il)ciclobutano- 1-carbonitrila como um sólido branco (trans isômero, 610 g, 30 %)[00524] To a solution of 4-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.3 kg, 6.67 mol) in MeCN (43 L) 3-cyanomethylene)cyclobutane-1-carbonitrile (Preparation 27, 953 g, 8 mol) and DBU (3.06 kg, 20.1 mol) were added at about 20 °C. Stirring was continued at about 20°C for about 16 hrs. The mixture was poured into aq. At 1 M (10 L) and extracted with EtOAc (5 x 5 L). The combined EtOAc extracts were concentrated, and the residue was purified by chromatography to provide (1r,3r)-3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutane- 1-carbonitrile as a white solid (trans isomer, 610 g, 30%)
[00525] ponto de fusão 137 - 140 °C[00525] melting point 137 - 140 °C
[00526] 1H RMN (400 MHz, CDCl3) δ: 7,90 (s, 1 H), 7,88 (s, 1 H), 3,21 - 3,28 (m, 3 H), 3,19 (s, 2 H), 2,86 - 2,94 (m, 2 H), 1,33 (s, 12 H).[00526] 1H NMR (400 MHz, CDCl3) δ: 7.90 (s, 1 H), 7.88 (s, 1 H), 3.21 - 3.28 (m, 3 H), 3.19 (s, 2 H), 2.86 - 2.94 (m, 2 H), 1.33 (s, 12 H).
[00527] 13C RMN (101MHz, CD3OD) δ: 147,54, 136,49, 122,49, 117,11, 84,96, 61,93, 37,52, 30,47, 25,28, 25,18, 17,21.[00527] 13C NMR (101MHz, CD3OD) δ: 147.54, 136.49, 122.49, 117.11, 84.96, 61.93, 37.52, 30.47, 25.28, 25, 18, 17,21.
[00528] LCMS m/z = 313,1 [MH]+ e (1s,3s)-3-(cianometil)-3-(4- (4,4,5,5-tetrametil-1,3,2-dioxaborolan-2-il)-1H-pirazol-1-il)ciclobutano-1- carbonitrila como um sólido esbranquiçado (cis isômero, 250 g, 12 %).[00528] LCMS m/z = 313.1 [MH]+ e (1s,3s)-3-(cyanomethyl)-3-(4- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile as an off-white solid (cis isomer, 250 g, 12%).
[00529] ponto de fusão 95 - 98 °C[00529] melting point 95 - 98 °C
[00530] 1H RMN (400 MHz, CDCl3) δ: 7,86 (s, 2 H), 3,24 - 3,31 (m, 1 H), 3,13 - 3,21 (m, 2 H), 3,07 (s, 2 H), 2,96 - 3,04 (m, 2 H), 1,34 (s, 12 H).[00530] 1H NMR (400 MHz, CDCl3) δ: 7.86 (s, 2 H), 3.24 - 3.31 (m, 1 H), 3.13 - 3.21 (m, 2 H) , 3.07 (s, 2 H), 2.96 - 3.04 (m, 2 H), 1.34 (s, 12 H).
[00531] 13C RMN (101MHz, CD3OD) δ: 147,43, 135,94, 121,94, 117,37, 84,98, 75,96, 60,10, 37,95, 28,42, 25,29, 16,16.[00531] 13C NMR (101MHz, CD3OD) δ: 147.43, 135.94, 121.94, 117.37, 84.98, 75.96, 60.10, 37.95, 28.42, 25, 29, 16,16.
[00532] LCMS m/z = 313,1 [MH]+ Preparação 92 5-Metil-1-(tetra-hidro-2H-piran-2-il)-1H-pirazol e 3-Metil-1-(tetra-hidro-2H-piran-2-il)-1H-pirazol [00532] LCMS m/z = 313.1 [MH]+ Preparation 92 5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole and 3-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole
[00533] Uma mistura de 3-metilpirazol (1,00 g, 12,18 mmol), DHP (1,54 g, 18,3 mmol) e TFA (0,007 mL, 0,089 mmol) foi aquecida a cerca de 85 °C durante cerca de 4 hrs. A mistura foi resfriada a cerca de 20 °C e NaH (60 % em óleo, 20 mg, 0,5 mmol) foi adicionado. A agitação a cerca de 20 °C foi continuada durante cerca de 18 hrs. A mistura foi concentrada o resíduo foi purificado por cromatografia para proporcionar 5-metil-1-(tetra-hidro-2H-piran-2-il)-1H-pirazol como um óleo (400 mg, 20 %)[00533] A mixture of 3-methylpyrazole (1.00 g, 12.18 mmol), DHP (1.54 g, 18.3 mmol) and TFA (0.007 mL, 0.089 mmol) was heated to about 85 °C for about 4 hours. The mixture was cooled to about 20°C and NaH (60% in oil, 20 mg, 0.5 mmol) was added. Stirring at about 20°C was continued for about 18 hrs. The mixture was concentrated and the residue was purified by chromatography to provide 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole as an oil (400 mg, 20%)
[00534] 1H RMN (400 MHz, CDCl3) δ: 7,45 (d, 1 H), 6,05 (d, 1 H), 5,24 - 5,30 (m, 1 H), 4,00 - 4,08 (m, 1 H), 3,61 - 3,70 (m, 1 H), 2,41 - 2,55 (m, 1 H), 2,35 (s, 3 H), 2,08 - 2,18 (m, 1 H), 1,93 - 2,02 (m, 1 H), 1,65 - 1,77 (m, 2 H), 1,55 - 1,64 (m, 1 H).[00534] 1H NMR (400 MHz, CDCl3) δ: 7.45 (d, 1 H), 6.05 (d, 1 H), 5.24 - 5.30 (m, 1 H), 4.00 - 4.08 (m, 1 H), 3.61 - 3.70 (m, 1 H), 2.41 - 2.55 (m, 1 H), 2.35 (s, 3 H), 2 .08 - 2.18 (m, 1 H), 1.93 - 2.02 (m, 1 H), 1.65 - 1.77 (m, 2 H), 1.55 - 1.64 (m , 1 H).
[00535] GCMS m/z = 166,1 [M]+[00535] GCMS m/z = 166.1 [M]+
[00536] e 3-metil-1-(tetra-hidro-2H-piran-2-il)-1H-pirazol como um óleo (352 mg, 15 %).[00536] and 3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole as an oil (352 mg, 15%).
[00537] 1H RMN (400 MHz, CDCl3) δ: 7,48 (d, 1 H), 6,08 (d, 1 H), 5,29 (dd, 1 H), 4,08 (dt, 1 H), 3,64 - 3,74 (m, 1 H), 2,30 (s, 3 H), 2,07 - 2,18 (m, 1 H), 1,98 - 2,07 (m, 2 H), 1,64 - 1,77 (m, 3 H).[00537] 1H NMR (400 MHz, CDCl3) δ: 7.48 (d, 1 H), 6.08 (d, 1 H), 5.29 (dd, 1 H), 4.08 (dt, 1 H), 3.64 - 3.74 (m, 1 H), 2.30 (s, 3 H), 2.07 - 2.18 (m, 1 H), 1.98 - 2.07 (m , 2 H), 1.64 - 1.77 (m, 3 H).
[00538] GCMS m/z = 166,1 [M]+ Preparação 93 3-Metil-1-(tetra-hidro-2H-piran-2-il)-5-(4,4,5,5-tetrametil-1,3,2- dioxaborolan-2-il)-1H-pirazol [00538] GCMS m/z = 166.1 [M]+ Preparation 93 3-Methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazole
[00539] Uma solução a 2,5 M de n-BuLi em hexano (0,44 mL, 1,10 mmol) foi adicionada a uma solução de 3-metil-1-(tetra-hidro-2H-piran- 2-il)-1H-pirazol (Preparação 92, 200 mg, 1,10 mmol) em THF (2 mL) a cerca de -70 °C. A mistura foi agitada a esta temperatura durante cerca de 10 min antes de 2-isopropóxi-4,4,5,5-tetrametil-1,3,2- dioxaborolano (214 mg, 1,15 mmol) ter sido adicionado. A mistura foi mantida a cerca de -70 °C durante cerca de 1 hr a mais, em seguida aquecida a cerca de 20 °C e concentrada para proporcionar o composto título misturado com cerca de 65 % de 3-metil-1-(tetra-hidro-2H- piran-2-il)-1H-pirazol não reagido. Esta mistura foi usada sem outra purificação.[00539] A 2.5 M solution of n-BuLi in hexane (0.44 mL, 1.10 mmol) was added to a solution of 3-methyl-1-(tetrahydro-2H-pyran-2- il)-1H-pyrazole (Preparation 92, 200 mg, 1.10 mmol) in THF (2 mL) at about -70 °C. The mixture was stirred at this temperature for about 10 min before 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (214 mg, 1.15 mmol) was added. The mixture was held at about -70°C for about 1 hr longer, then heated to about 20°C and concentrated to provide the title compound mixed with about 65% 3-methyl-1-(tetra unreacted -hydro-2H-pyran-2-yl)-1H-pyrazole. This mixture was used without further purification.
[00540] 1H RMN (400 MHz, CDCl3) δ: 6,51 (s, 1 H), 5,76 (dd, 1 H), 4,01 - 4,12 (m, 1 H), 3,59 - 3,74 (m, 1 H), 2,37 - 2,51 (m, 2 H), 2,29 (s, 3 H), 1,97 - 2,18 (m, 1 H), 1,62 - 1,76 (m, 2 H), 1,47 - 1,62 (m, 1 H), 1,33 (s, 12 H).[00540] 1H NMR (400 MHz, CDCl3) δ: 6.51 (s, 1 H), 5.76 (dd, 1 H), 4.01 - 4.12 (m, 1 H), 3.59 - 3.74 (m, 1 H), 2.37 - 2.51 (m, 2 H), 2.29 (s, 3 H), 1.97 - 2.18 (m, 1 H), 1 .62 - 1.76 (m, 2 H), 1.47 - 1.62 (m, 1 H), 1.33 (s, 12 H).
[00541] GCMS m/z = 292,2 [M]+ Preparação 94 3-(Benzilóxi)-N-metóxi-N-metilciclobutanocarboxamida [00541] GCMS m/z = 292.2 [M]+ Preparation 94 3-(Benzyloxy)-N-methoxy-N-methylcyclobutanecarboxamide
[00542] A uma solução de ácido 3-(benzilóxi)ciclobutanocarboxílico (324 g, 1,57 mol) em DCM (1,5 L) foi adicionado CDI (280 g, 1,73 mol) em porções. A mistura foi aquecida em refluxo durante cerca de 2 hrs, depois das quais cloridrato de N,O-dimetil-hidroxilamina (183,7 g, 1,88 mol) e TEA (261 mL, 1,88 mol) foram adicionados. A mistura foi aquecida em refluxo durante cerca de 3 hrs a mais, em seguida agitada a cerca de 25 °C durante cerca de 16 hrs. O DCM foi lavado com K2CO3 aq. saturado, secado (K2CO3) e concentrado. O resíduo foi purificado por cromatografia para proporcionar o composto título (298 g, 76 %).[00542] To a solution of 3-(benzyloxy)cyclobutanecarboxylic acid (324 g, 1.57 mol) in DCM (1.5 L) was added CDI (280 g, 1.73 mol) in portions. The mixture was heated at reflux for about 2 hrs, after which N,O-dimethylhydroxylamine hydrochloride (183.7 g, 1.88 mol) and TEA (261 mL, 1.88 mol) were added. The mixture was heated at reflux for about 3 hrs further, then stirred at about 25°C for about 16 hrs. The DCM was washed with aq. saturated, dried (K2CO3) and concentrated. The residue was purified by chromatography to provide the title compound (298 g, 76%).
[00543] 1H RMN (400 MHz, DMSO-d6) δ: 7,24-7,38 (m, 5 H), 4,37 (s, 2 H), 4,06 - 4,15 (m, 1 H), 3,61 (s, 3 H), 3,09 (s, 3 H), 2,96 (s, 1 H), 2,30 - 2,40 (m, 2 H), 2,09 - 2,22 (m, 1 H), 1,95 - 2,07 (m, 1H). Preparação 95 1-[3-(Benzilóxi)ciclobutil]etanona [00543] 1H NMR (400 MHz, DMSO-d6) δ: 7.24-7.38 (m, 5 H), 4.37 (s, 2 H), 4.06 - 4.15 (m, 1 H), 3.61 (s, 3 H), 3.09 (s, 3 H), 2.96 (s, 1 H), 2.30 - 2.40 (m, 2 H), 2.09 - 2.22 (m, 1H), 1.95 - 2.07 (m, 1H). Preparation 95 1-[3-(Benzyloxy)cyclobutyl]ethanone
[00544] A uma solução de 3-(benzilóxi)-N-metóxi-N- metilciclobutanocarboxamida (Preparação 94, 298 g, 1,2 mol) em THF (1,5 L) foi adicionado gota a gota uma solução de brometo de metil- magnésio (1,3 mol) a cerca de -20 °C. Depois que a adição de brometo de metilmagnésio foi concluída, o banho de resfriamento foi removido, e a mistura foi permitida aquecer a cerca de 25 °C. Em seguida, HCl aq. A 0,5 M (2,5 L) foi adicionado, e a mistura foi extraída com Et2O (1 L + 500 mL). Os extratos de Et2O combinados foram lavados com água, secados (Na2SO4) e concentrados. O resíduo foi purificado por cromatografia para proporcionar o composto título (194 g, 79 %).[00544] To a solution of 3-(benzyloxy)-N-methoxy-N-methylcyclobutanecarboxamide (Preparation 94, 298 g, 1.2 mol) in THF (1.5 L) was added dropwise a solution of hydrogen bromide methyl magnesium (1.3 mol) at about -20°C. After the addition of methylmagnesium bromide was complete, the cooling bath was removed, and the mixture was allowed to warm to about 25 °C. Then aq. HCl. 0.5 M (2.5 L) was added, and the mixture was extracted with Et2O (1 L + 500 mL). The combined Et2O extracts were washed with water, dried (Na2SO4) and concentrated. The residue was purified by chromatography to provide the title compound (194 g, 79%).
[00545] 1H RMN (400 MHz, DMSO-d6) δ: 7,24 - 7,38 (m, 5 H), 4,35 (s, 2 H), 3,90 - 3,99 (m, 0,5 H), 3,16 - 3,24 (m, 0,5 H), 2,75 - 2,87 (m, 1 H), 2,31 - 2,40 (m, 2 H), 2,06 - 2,15 (m, 1 H), 2,04 (s, 1,5 H), 1,99 (s, 1,5 H), 1,87 - 1,97 (m, 1H). Preparação 96 1-[3-(Benzilóxi)ciclobutil]-3-(dimetilamino)prop-2-en-1-ona [00545] 1H NMR (400 MHz, DMSO-d6) δ: 7.24 - 7.38 (m, 5 H), 4.35 (s, 2 H), 3.90 - 3.99 (m, 0 .5 H), 3.16 - 3.24 (m, 0.5 H), 2.75 - 2.87 (m, 1 H), 2.31 - 2.40 (m, 2 H), 2 .06 - 2.15 (m, 1H), 2.04 (s, 1.5H), 1.99 (s, 1.5H), 1.87 - 1.97 (m, 1H). Preparation 96 1-[3-(Benzyloxy)cyclobutyl]-3-(dimethylamino)prop-2-en-1-one
[00546] A uma solução de 1-[3-(benzilóxi)ciclobutil]etanona (Prepa- ração 95,194 g, 0,95 mol) em DMF (500 mL) foi adicionado dimetilfor- mamida dimetil acetal (285 g, 2,4 mol). A mistura foi aquecida a cerca de 110 °C durante cerca de 12 hrs. A mistura foi concentrada para proporcionar o composto título (258 g), o qual foi usado sem purificação ou também caracterização. Preparação 97 5-[3-(Benzilóxi)ciclobutil]-1H-pirazol [00546] To a solution of 1-[3-(benzyloxy)cyclobutyl]ethanone (Preparation 95.194 g, 0.95 mol) in DMF (500 mL) was added dimethylformamide dimethyl acetal (285 g, 2.4 mole). The mixture was heated to about 110°C for about 12 hrs. The mixture was concentrated to provide the title compound (258 g), which was used without purification or further characterization. Preparation 97 5-[3-(Benzyloxy)cyclobutyl]-1H-pyrazole
[00547] A uma solução de 1-[3-(benzilóxi)ciclobutil]-3- (dimetilamino)prop-2-en-1-ona (Preparação 96, 110 g, 0,42 mol) em MeOH (500 mL) foi adicionado hidrato de hidrazina (30 g, 0,6 mol). A mistura foi aquecida em refluxo durante cerca de 12 hrs, em seguida concentrada. O resíduo foi purificado por cromatografia para proporcionar o composto título (79 g, 82 %), o qual foi usado sem purificação ou também caracterização. Preparação 98 3-(1H-Pirazol-5-il)ciclobutanol [00547] To a solution of 1-[3-(benzyloxy)cyclobutyl]-3-(dimethylamino)prop-2-en-1-one (Preparation 96, 110 g, 0.42 mol) in MeOH (500 mL) Hydrazine hydrate (30 g, 0.6 mol) was added. The mixture was heated at reflux for about 12 hrs, then concentrated. The residue was purified by chromatography to provide the title compound (79 g, 82%), which was used without purification or further characterization. Preparation 98 3-(1H-Pyrazol-5-yl)cyclobutanol
[00548] A uma solução de 5-[3-(benzilóxi)ciclobutil]-1H-pirazol (Preparação 97, 79 g, 0,35 mol) em metanol (800 mL) em um frasco de hidrogenação de 2 L foi adicionado paládio sobre carbono (Pd a 10 %, 16 g). A mistura foi pressurizada sob hidrogênio (2,81 kg/cm2 (40 psi)), e a mistura foi agitada a cerca de 60 °C durante cerca de 12 hrs. Paládio sobre carbono adicional (Pd a 10 %, 16 g) foi adicionado, e a hidrogenação foi continuada durante cerca de 10 hrs. A mistura foi fil- trada, e o filtrado foi concentrado. O resíduo foi purificado por croma- tografia para proporcionar o composto título (46 g, 96 %), o qual foi usado sem purificação ou também caracterização. Preparação 99 3-(1H-pirazol-5-il)ciclobutano-1-ona [00548] To a solution of 5-[3-(benzyloxy)cyclobutyl]-1H-pyrazole (Preparation 97.79 g, 0.35 mol) in methanol (800 mL) in a 2 L hydrogenation flask was added palladium on carbon (10% Pd, 16 g). The mixture was pressurized under hydrogen (2.81 kg/cm2 (40 psi)), and the mixture was stirred at about 60 °C for about 12 hrs. Additional palladium on carbon (10% Pd, 16 g) was added, and hydrogenation was continued for about 10 hrs. The mixture was filtered, and the filtrate was concentrated. The residue was purified by chromatography to provide the title compound (46 g, 96%), which was used without purification or characterization. Preparation 99 3-(1H-pyrazol-5-yl)cyclobutan-1-one
[00549] A uma solução de cloreto de oxalila (7,8 mL, 0,09 mol) em DCM (50 mL) a cerca de -78 °C foi adicionado gota a gota uma solução de DMSO (12,7 mL, 0,18 mol) em DCM (50 mL). A mistura foi agitada durante cerca de 30 min, em seguida 3-(1H-pirazol-5- il)ciclobutanol (Preparação 98, 13,7 g, 0,09 mol) foi adicionado gota a gota nesta temperatura. A mistura resultante foi mantida durante cerca de 30 min, depois dos quais TEA (25 mL, 0,18 mol) foi adicionado gota a gota. O banho de resfriamento foi removido, e a mistura foi permitida aquecer a cerca de 25 °C e foi mantida a essa temperatura durante cerca de 3 hrs. Em seguida, uma solução aquosa de K2CO3 (100 mL) foi adicionada. O DCM foi separado, e a fase aquosa foi extraída com DCM. Os extratos de DCM combinados foram lavados com água, secados (Na2SO4) e concentrados. O resíduo foi purificado por cromato- grafia para proporcionar o composto título (7,4 g, 55 %) como um sólido branco.[00549] To a solution of oxalyl chloride (7.8 mL, 0.09 mol) in DCM (50 mL) at about -78 °C was added dropwise a solution of DMSO (12.7 mL, 0 .18 mol) in DCM (50 mL). The mixture was stirred for about 30 min, then 3-(1H-pyrazol-5-yl)cyclobutanol (Preparation 98, 13.7 g, 0.09 mol) was added dropwise at this temperature. The resulting mixture was maintained for about 30 min, after which TEA (25 mL, 0.18 mol) was added dropwise. The cooling bath was removed, and the mixture was allowed to warm to about 25°C and was held at that temperature for about 3 hrs. Then, an aqueous solution of K2CO3 (100 mL) was added. The DCM was separated, and the aqueous phase was extracted with DCM. The combined DCM extracts were washed with water, dried (Na2SO4) and concentrated. The residue was purified by chromatography to provide the title compound (7.4 g, 55%) as a white solid.
[00550] 1H RMN (400 MHz, DMSO-d6) δ: 12,56 (s, 1 H), 7,61 (s, 1 H), 6,21 (d, 1 H), 3,46 - 3,68 (m, 1 H), 3,37 - 3,46 (m, 2 H), 3,15 - 3,25 (m, 2H).[00550] 1H NMR (400 MHz, DMSO-d6) δ: 12.56 (s, 1 H), 7.61 (s, 1 H), 6.21 (d, 1 H), 3.46 - 3 .68 (m, 1H), 3.37 - 3.46 (m, 2H), 3.15 - 3.25 (m, 2H).
[00551] LCMS m/z = 137,1 [MH]+ Preparação 100 2-((1r,3s)-1-(4-(6-cloropirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)-3- metoxiciclobutil)acetonitrila (trans isômero) [00551] LCMS m/z = 137.1 [MH]+ Preparation 100 2-((1r,3s)-1-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H -pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile (trans isomer)
[00552] A uma solução de 2-((1r,3s)-1-(4-bromo-1H-pirazol-1-il)-3- metoxiciclobutil)acetonitrila (Preparação 37, trans isômero, 3399 mg, 12,58 mmol) em 1,4-dioxano (33 mL) foram adicionados bis(pinacolato)diboro (3510 mg, 13,8 mmol) e KOAc (3700 mg, 37,7 mmol). A mistura foi purgada com argônio durante cerca de 5 min, depois dos quais XPhos Pd G2 (1980 mg, 2,52 mmol) foi adicionado. A mistura foi aquecida a cerca de 65 °C durante cerca de 4 hrs. A mistura resfriada foi concentrada, e o resíduo foi purificado por cromatogra- fia. O produto foi agitada com EtOAc (10 mL) a cerca de 25 °C, em seguida heptano (40 mL) foi adicionado e cristalização foi permitida ocorrer durante cerca de 30 min. O precipitado foi filtrado e secado para proporcionar 2-((1r,3s)-3-metóxi-1-(4-(4,4,5,5-tetrametil-1,3,2- dioxaborolan-2-il)-1H-pirazol-1-il)ciclobutil)acetonitrila como um sólido branco (1950 mg, 49 %).[00552] To a solution of 2-((1r,3s)-1-(4-bromo-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile (Preparation 37, trans isomer, 3399 mg, 12.58 mmol) in 1,4-dioxane (33 mL) bis(pinacolato)diboron (3510 mg, 13.8 mmol) and KOAc (3700 mg, 37.7 mmol) were added. The mixture was purged with argon for about 5 min, after which XPhos Pd G2 (1980 mg, 2.52 mmol) was added. The mixture was heated to about 65°C for about 4 hrs. The cooled mixture was concentrated, and the residue was purified by chromatography. The product was stirred with EtOAc (10 mL) at about 25 °C, then heptane (40 mL) was added and crystallization was allowed to occur for about 30 min. The precipitate was filtered and dried to yield 2-((1r,3s)-3-methoxy-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazol-1-yl)cyclobutyl)acetonitrile as a white solid (1950 mg, 49%).
[00553] 1H RMN (400 MHz, CDCl3) δ: 7,91 (s, 1 H), 7,87 (s, 1 H), 3,98 (tt, 1 H), 3,29 (s, 3 H), 3,17 (s, 2 H), 2,97 - 3,07 (m, 2 H), 2,44 - 2,53 (m, 2 H), 1,33 (s, 12 H).[00553] 1H NMR (400 MHz, CDCl3) δ: 7.91 (s, 1 H), 7.87 (s, 1 H), 3.98 (tt, 1 H), 3.29 (s, 3 H), 3.17 (s, 2 H), 2.97 - 3.07 (m, 2 H), 2.44 - 2.53 (m, 2 H), 1.33 (s, 12 H) .
[00554] LCMS m/z = 318,0 [MH]+[00554] LCMS m/z = 318.0 [MH]+
[00555] Uma solução de 2-((1r,3s)-3-metóxi-1-(4-(4,4,5,5-tetrametil- 1,3,2-dioxaborolan-2-il)-1H-pirazol-1-il)ciclobutil)acetonitrila (Parte 1, 1950 mg, 6,15 mmol) e 4,6-dicloropirazolo[1,5-a]pirazina (Preparação 4, 1160 mg, 6,15 mmol), e K3PO4 aq. a 2 M (9,22 mL) em 1,4-dioxano (25 mL) foi purgada com argônio durante cerca de 5 min, depois dos quais bis(tri-t-butilfosfina)paládio (0) (157 mg, 0,31 mmol) foi adicionado. A mistura foi agitada a cerca de 25 °C durante cerca de 2 hrs. A mistura resfriada foi diluída com EtOAc e as fases foram separadas. A fase aquosa foi extraída duas vezes com DCM. Os extratos de EtOAc e DCM combinados foram secados (Na2SO4) e concentrados. O resíduo foi dissolvido em DCM (20 mL) e aquecido a cerca de 40 °C até que tudo tenha sido dissolvido, em seguida heptano (10 mL) foi adicionado e a cristalização foi permitida ocorrer durante cerca de 30 min. O precipitado foi filtrado e secado para proporcionar o composto título como um sólido esbranquiçado (1120 mg, 53 %). O filtrado foi concentrado, e o resíduo foi purificado por cromatografia para proporcionar o composto título adicional (640 mg, 30 %).[00555] A solution of 2-((1r,3s)-3-methoxy-1-(4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H- pyrazol-1-yl)cyclobutyl)acetonitrile (Part 1, 1950 mg, 6.15 mmol) and 4,6-dichloropyrazolo[1,5-a]pyrazine (Preparation 4, 1160 mg, 6.15 mmol), and K3PO4 aq. 2 M (9.22 mL) in 1,4-dioxane (25 mL) was purged with argon for about 5 min, after which bis(tri-t-butylphosphine)palladium (0) (157 mg, 0. 31 mmol) was added. The mixture was stirred at about 25°C for about 2 hrs. The cooled mixture was diluted with EtOAc and the phases were separated. The aqueous phase was extracted twice with DCM. The combined EtOAc and DCM extracts were dried (Na2SO4) and concentrated. The residue was dissolved in DCM (20 mL) and heated to about 40 °C until everything was dissolved, then heptane (10 mL) was added and crystallization was allowed to occur for about 30 min. The precipitate was filtered and dried to provide the title compound as an off-white solid (1120 mg, 53%). The filtrate was concentrated, and the residue was purified by chromatography to provide the additional title compound (640 mg, 30%).
[00556] 1H RMN (500 MHz, CDCl3) δ: 8,39 (d, 1 H), 8,38 (s, 1 H), 8,28 (s, 1 H), 8,08 (d, 1 H), 7,03 (dd, 1 H), 4,03 - 4,10 (m, 1 H), 3,34 (s, 3 H), 3,25 (s, 2 H), 3,08 - 3,16 (m, 2 H), 2,53 - 2,60 (m, 2 H).[00556] 1H NMR (500 MHz, CDCl3) δ: 8.39 (d, 1 H), 8.38 (s, 1 H), 8.28 (s, 1 H), 8.08 (d, 1 H), 7.03 (dd, 1 H), 4.03 - 4.10 (m, 1 H), 3.34 (s, 3 H), 3.25 (s, 2 H), 3.08 - 3.16 (m, 2 H), 2.53 - 2.60 (m, 2 H).
[00557] LCMS m/z = 343,3 [MH]+ (isótopo 35Cl) Preparação 101 Etil 5-metil-1-(2-(1-metil-1H-pirazol-4-il)-2-oxoetil)-1H-pirazol-3- carboxilato [00557] LCMS m/z = 343.3 [MH]+ (isotope 35Cl) Preparation 101 Ethyl 5-methyl-1-(2-(1-methyl-1H-pyrazol-4-yl)-2-oxoethyl)- 1H-pyrazole-3-carboxylate
[00558] Etil 3-metil-1H-pirazol-5-carboxilato (92 mg, 0,6 mmol), 2- bromo-1-(1-metil-1H-pirazol-4-il)etan-1-ona (Preparação 6, 134 mg, 0,66mmol) e K2CO3 (104 mg, 0,75 mmol) foram combinados em MeCN ( 2 mL), e a suspensão foi agitada a cerca de 40 °C durante cerca de 16 hrs. Os sólidos foram filtrados, e o filtrado foi concentrado. O resíduo foi purificado por cromatografia para proporcionar o composto título como um óleo amarelo (125 mg, 5,5 %).[00558] Ethyl 3-methyl-1H-pyrazol-5-carboxylate (92 mg, 0.6 mmol), 2-bromo-1-(1-methyl-1H-pyrazol-4-yl)ethan-1-one ( Preparation 6, 134 mg, 0.66 mmol) and K2CO3 (104 mg, 0.75 mmol) were combined in MeCN (2 mL), and the suspension was stirred at about 40 °C for about 16 hrs. The solids were filtered, and the filtrate was concentrated. The residue was purified by chromatography to provide the title compound as a yellow oil (125 mg, 5.5%).
[00559] 1H RMN (400 MHz, CDCl3) δ: 7,86 (s, 2 H), 6,73 (s, 1 H), 5,65 (s, 2 H), 4,26 (q, 2 H), 3,95 (s, 3 H), 2,32 (s, 3 H), 1,31 (t, 3 H).[00559] 1H NMR (400 MHz, CDCl3) δ: 7.86 (s, 2 H), 6.73 (s, 1 H), 5.65 (s, 2 H), 4.26 (q, 2 H), 3.95 (s, 3 H), 2.32 (s, 3 H), 1.31 (t, 3 H).
[00560] LCMS m/z = 277,1 [MH]+ Preparação 102 2-Metil-6-(1-metil-1H-pirazol-4-il)pirazolo[1,5-a]pirazin-4-ol [00560] LCMS m/z = 277.1 [MH]+ Preparation 102 2-Methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-ol
[00561] A uma solução de etil 5-metil-1-(2-(1-metil-1H-pirazol-4-il)- 2-oxoetil)-1H-pirazol-3-carboxilato (Preparação 101, 125 mg, 0,45 mmol) em EtOH (5 mL) foi adicionado NH4OAc (105 mg, 1,06 mmol). A mistura foi aquecida sob irradiação de micro-ondas a cerca de 105 °C durante cerca de 4 hrs. A mistura foi concentrada, e o resíduo foi dis-solvido em EtOH e concentrado novamente para proporcionar o com-posto título (110 mg, 85 %).[00561] To a solution of ethyl 5-methyl-1-(2-(1-methyl-1H-pyrazol-4-yl)-2-oxoethyl)-1H-pyrazol-3-carboxylate (Preparation 101, 125 mg, 0.45 mmol) in EtOH (5 mL) was added NH4OAc (105 mg, 1.06 mmol). The mixture was heated under microwave irradiation at about 105°C for about 4 hrs. The mixture was concentrated, and the residue was dissolved in EtOH and concentrated again to provide the title compound (110 mg, 85%).
[00562] 1H RMN (400 MHz, DMSO-d6) δ: 8,25 (s, 1 H), 8,01 (s, 1 H), 7,97 (s, 1 H), 6,76 (s, 1 H), 3,87 (s, 3 H), 2,34 (s, 3 H).[00562] 1H NMR (400 MHz, DMSO-d6) δ: 8.25 (s, 1 H), 8.01 (s, 1 H), 7.97 (s, 1 H), 6.76 (s , 1 H), 3.87 (s, 3 H), 2.34 (s, 3 H).
[00563] LCMS m/z = 230,0 [MH]+ Preparação 103 4-Cloro-2-metil-6-(1-metil-1H-pirazol-4-il)pirazolo[1,5-a]pirazina [00563] LCMS m/z = 230.0 [MH]+ Preparation 103 4-Chloro-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine
[00564] 2-Metil-6-(1-metil-1H-pirazol-4-il)pirazolo[1,5-a]pirazin-4-ol (Preparação 102) foi suspenso em POCl3 e aquecido a cerca de 120 °C durante cerca de 6 hrs. A solução foi concentrada para proporcionar uma amostra impura do composto título, o qual foi usado na próxima etapa sem outra purificação.[00564] 2-Methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-ol (Preparation 102) was suspended in POCl3 and heated to about 120° C for about 6 hrs. The solution was concentrated to provide an impure sample of the title compound, which was used in the next step without further purification.
[00565] LCMS m/z = 248,0 [MH]+ (35Cl isótopo) Exemplo 36 (1r,3r)-3-(Cianometil)-3-(4-(2-metil-6-(1-metil-1H-pirazol-4-il) pira- zolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)ciclobutano-1-carbonitrila (trans isômero) [00565] LCMS m/z = 248.0 [MH]+ (35Cl isotope) Example 36 (1r,3r)-3-(Cyanomethyl)-3-(4-(2-methyl-6-(1-methyl- 1H-pyrazol-4-yl) pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile (trans isomer)
[00566] Uma mistura de 4-cloro-2-metil-6-(1-metil-1H-pirazol-4- il)pirazolo[1,5-a]pirazina cru (Preparação 103, 100 mg, 0,40 mmol), (1r,3r)-3-(cianometil)-3-(4-(4,4,5,5-tetrametil-1,3,2-dioxaborolan-2-il)- 1H-pirazol-1-il)ciclobutano-1-carbonitrila (Preparação 91, 132 mg, 0,42 mmol), Pd(dppf)Cl2 DCM(16,5 mg, 0,02 mmol) e K2CO3 (167 mg, 1,21 mmol) foi combinada em uma mistura de 1,4-dioxano (2,5 mL) e água (0,5 mL). A mistura foi purgada com nitrogênio durante cerca de 5 min, em seguida aquecida a cerca de 90 °C durante cerca de 3 hrs. A mistura foi concentrada, e o resíduo foi purificado por cromatografia e HPLC para proporcionar o composto título (5,6 mg, 3 % durante duas etapas).[00566] A mixture of raw 4-chloro-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (Preparation 103, 100 mg, 0.40 mmol ), (1r,3r)-3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazol-1-yl )cyclobutane-1-carbonitrile (Preparation 91, 132 mg, 0.42 mmol), Pd(dppf)Cl2 DCM(16.5 mg, 0.02 mmol) and K2CO3 (167 mg, 1.21 mmol) were combined into a mixture of 1,4-dioxane (2.5 mL) and water (0.5 mL). The mixture was purged with nitrogen for about 5 min, then heated to about 90 °C for about 3 hrs. The mixture was concentrated, and the residue was purified by chromatography and HPLC to provide the title compound (5.6 mg, 3% over two steps).
[00567] 1H RMN (400 MHz, CDCl3) δ: 8,37 (s, 1 H), 8,33 (s, 1 H), 8,30 (s, 1 H), 7,92 (s, 1 H), 7,90 (s, 1 H), 6,68 (s, 1 H), 3,99 (s, 3 H), 3,32 - 3,42 (m, 3 H), 3,27 (s, 2 H), 2,93 - 3,02 (m, 2 H), 2,56 (s, 3 H).[00567] 1H NMR (400 MHz, CDCl3) δ: 8.37 (s, 1 H), 8.33 (s, 1 H), 8.30 (s, 1 H), 7.92 (s, 1 H), 7.90 (s, 1 H), 6.68 (s, 1 H), 3.99 (s, 3 H), 3.32 - 3.42 (m, 3 H), 3.27 (s, 2 H), 2.93 - 3.02 (m, 2 H), 2.56 (s, 3 H).
[00568] LCMS m/z = 398,0 [MH]+ Preparação 104 3-((4-Metoxibenzil)óxi)-1-metil-1H-pirazol [00568] LCMS m/z = 398.0 [MH]+ Preparation 104 3-((4-Methoxybenzyl)oxy)-1-methyl-1H-pyrazole
[00569] A um frasco com fundo redondo de 100 mL foram adicionados 1-metil-1H-pirazol-3-ol (1,40 g, 14,3 mmol), DMF (30 mL), e K2CO3 (3,94 g, 28,5 mmol). Por fim, cloreto de 4-metoxibenzila (2,32 mL, 17,1 mmol) foi adicionado à mistura. A mistura foi aquecida a cerca de 60 °C durante cerca de 8 horas. A mistura foi em seguida diluída com água (80 mL) e extraída com EtOAc (60 mL x 3). Os extratos de EtOAc combinados foram lavados com salmoura (60 mL x 2), secados (Na2SO4) e concentrados. O resíduo foi purificado por cromatografia para proporcionar o composto título como um óleo incolor (2,6 g, 83 %).[00569] To a 100 mL round bottom flask were added 1-methyl-1H-pyrazol-3-ol (1.40 g, 14.3 mmol), DMF (30 mL), and K2CO3 (3.94 g , 28.5 mmol). Finally, 4-methoxybenzyl chloride (2.32 mL, 17.1 mmol) was added to the mixture. The mixture was heated at about 60°C for about 8 hours. The mixture was then diluted with water (80 mL) and extracted with EtOAc (60 mL x 3). The combined EtOAc extracts were washed with brine (60 mL x 2), dried (Na2SO4) and concentrated. The residue was purified by chromatography to provide the title compound as a colorless oil (2.6 g, 83%).
[00570] 1H RMN (400 MHz, CDCl3) δ: 7,38 (d, 2 H), 7,13 (d, 1 H), 6,91 (d, 2 H), 5,64 (d, 1 H), 5,11 (s, 2 H), 3,82 (s, 3 H), 3,76 (s, 3 H).[00570] 1H NMR (400 MHz, CDCl3) δ: 7.38 (d, 2 H), 7.13 (d, 1 H), 6.91 (d, 2 H), 5.64 (d, 1 H), 5.11 (s, 2 H), 3.82 (s, 3 H), 3.76 (s, 3 H).
[00571] LCMS m/z = 218,9 [MH]+ Preparação 105 4-Iodo-3-((4-metoxibenzil)óxi)-1-metil-1H-pirazol [00571] LCMS m/z = 218.9 [MH]+ Preparation 105 4-Iodo-3-((4-methoxybenzyl)oxy)-1-methyl-1H-pyrazole
[00572] A um frasco com fundo redondo de 100 mL foram adicionados 3-((4-metoxibenzil)óxi)-1-metil-1H-pirazol (Preparação 104,1,0 g, 4,58 mmol) e MeCN (20 mL), depois dos quais nitrato de amônio céri- co (1,51 g, 2,75 mmol) e iodo (698 mg, 2,75 mmol) foram adicionados à mistura. A mistura marrom foi agitada a cerca de 20 °C durante cerca de 1 h. A mistura foi extinguida com bissulfeto de sódio aquoso a 5 % (50 mL) e extraída com EtOAc (40 mL x 3). Os extratos de EtOAc combinados foram secados (Na2SO4) e concentrados. O resíduo foi purificado por cromatografia para proporcionar o composto título como um óleo verde (800 mg, 51 %).[00572] To a 100 mL round bottom flask were added 3-((4-methoxybenzyl)oxy)-1-methyl-1H-pyrazole (Preparation 104.1.0 g, 4.58 mmol) and MeCN (20 mL), after which ceric ammonium nitrate (1.51 g, 2.75 mmol) and iodine (698 mg, 2.75 mmol) were added to the mixture. The brown mixture was stirred at about 20°C for about 1 h. The mixture was quenched with 5% aqueous sodium disulfide (50 mL) and extracted with EtOAc (40 mL x 3). The combined EtOAc extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography to provide the title compound as a green oil (800 mg, 51%).
[00573] 1H RMN (400 MHz, CDCl3) δ: 7,40 (d, 2 H), 7,19 (s, 1 H), 6,91 (d, 2 H), 5,18 (s, 2 H), 3,82 (s, 3 H), 3,77 (s, 3 H). Preparação 106 3-((4-Metoxibenzil)óxi)-1-metil-4-(4,4,5,5-tetrametil-1,3,2- dioxaborolan-2-il)-1H-pirazol [00573] 1H NMR (400 MHz, CDCl3) δ: 7.40 (d, 2 H), 7.19 (s, 1 H), 6.91 (d, 2 H), 5.18 (s, 2 H), 3.82 (s, 3 H), 3.77 (s, 3 H). Preparation 106 3-((4-Methoxybenzyl)oxy)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
[00574] A um frasco com fundo redondo de 100 mL foram adicionados 4-iodo-3-((4-metoxibenzil)óxi)-1-metil-1H-pirazol (Preparação 105, 800 mg, 2,32 mmol) e THF (16 mL), seguido pela adição gota a gota de cloreto de isopropilmagnésio (1,3 M em THF, 2,15 mL, 2,79 mmol) à mistura a cerca de - 10 °C. A mistura foi agitada a uma temperatura entre cerca de - 18 °C e 10 °C durante cerca de 45 min. 2 - Isopropóxi- 4,4,5,5-tetrametil-1,3,2-dioxaborolano (649 mg, 3,49 mmol) foi adicionado à mistura a cerca de - 10 °C, e a mistura foi permitida aquecer a cerca de 15 °C durante cerca de 1,5 h. Cloreto de isopropilmagnésio adicional (1,3 M em THF, 0,72 mL, 0,93 mmol) e 2-isopropóxi-4,4,5,5- tetrametil-1,3,2-dioxaborolano (216 mg, 1,16 mmol) foram adicionados à mistura a cerca de - 15 °C. A mistura foi permitida aquecer a cerca de 15 °C durante cerca de 1 h. A mistura foi diluída com EtOAc (40 mL) e lavada com NH4Cl aquoso saturado (30 mL), salmoura (30 mL), secada (Na2SO4) e concentrada. O resíduo foi purificado por cromato- grafia para proporcionar o composto título como um sólido branco (600 mg, 75 %).[00574] To a 100 mL round bottom flask were added 4-iodo-3-((4-methoxybenzyl)oxy)-1-methyl-1H-pyrazole (Preparation 105, 800 mg, 2.32 mmol) and THF (16 mL), followed by the dropwise addition of isopropylmagnesium chloride (1.3 M in THF, 2.15 mL, 2.79 mmol) to the mixture at about -10 °C. The mixture was stirred at a temperature between about -18°C and 10°C for about 45 min. 2 - Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (649 mg, 3.49 mmol) was added to the mixture at about - 10 °C, and the mixture was allowed to warm to about 15 °C for approximately 1.5 h. Additional isopropylmagnesium chloride (1.3 M in THF, 0.72 mL, 0.93 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (216 mg, 1. 16 mmol) were added to the mixture at about -15°C. The mixture was allowed to heat to about 15°C for about 1 h. The mixture was diluted with EtOAc (40 mL) and washed with saturated aqueous NH4Cl (30 mL), brine (30 mL), dried (Na2SO4) and concentrated. The residue was purified by chromatography to provide the title compound as a white solid (600 mg, 75%).
[00575] 1H RMN (400 MHz, CDCl3) δ: 7,40 - 7,45 (m, 3 H), 6,88 (d, 2 H), 5,24 (s, 2 H), 3,81 (s, 3 H), 3,73 (s, 3 H), 1,31 (s, 12 H).[00575] 1H NMR (400 MHz, CDCl3) δ: 7.40 - 7.45 (m, 3 H), 6.88 (d, 2 H), 5.24 (s, 2 H), 3.81 (s, 3 H), 3.73 (s, 3 H), 1.31 (s, 12 H).
[00576] LCMS m/z = 345,1 [MH]+ Preparação 107 (1r,3r)-3-(Cianometil)-3-(4-(6-(3-((4-metoxibenzil)óxi)-1-metil-1H- pirazol-4-il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)ciclobutano-1- carbonitrila [00576] LCMS m/z = 345.1 [MH]+ Preparation 107 (1r,3r)-3-(Cyanomethyl)-3-(4-(6-(3-((4-methoxybenzyl)oxy)-1 -methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile
[00577] A um frasco com fundo redondo de 25 ml foram adicionados (1r,3r)-3-(4-(6-cloropirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)-3- (cianometil)ciclobutano-1-carbonitrila (Preparação 75, 300 mg, 0,88 mmol), 3-((4-metoxibenzil)óxi)-1-metil-4-(4,4,5,5-tetrametil-1,3,2- dioxaborolan-2-il)-1H-pirazol (Preparação 106, 367 mg, 1,07 mmol), dioxano (16 mL), XPhos Pd G2 (140 mg, 0,178 mmol) e K3PO4 aq. a 2 M (3,55 mL, 7,11 mmol). A mistura foi colocada sob nitrogênio, em seguida aquecida a cerca de 60 °C durante cerca de 4 h. A mistura foi diluída com água (70 mL) e extraída com EtOAc (50 mL x 3). Os extratos de EtOAc combinados foram secados (Na2SO4) e concentrados. O resíduo foi purificado por cromatografia para proporcionar o composto título como um sólido amarelo (450 mg, 98 %).[00577] To a 25 ml round bottom flask were added (1r,3r)-3-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl )-3-(cyanomethyl)cyclobutane-1-carbonitrile (Preparation 75, 300 mg, 0.88 mmol), 3-((4-methoxybenzyl)oxy)-1-methyl-4-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 106, 367 mg, 1.07 mmol), dioxane (16 mL), XPhos Pd G2 (140 mg, 0.178 mmol) and K3PO4 aq. at 2 M (3.55 mL, 7.11 mmol). The mixture was placed under nitrogen, then heated to about 60 °C for about 4 h. The mixture was diluted with water (70 mL) and extracted with EtOAc (50 mL x 3). The combined EtOAc extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography to provide the title compound as a yellow solid (450 mg, 98%).
[00578] 1H RMN (400 MHz, DMSO-d6) δ: 8,92 (s, 1 H), 8,57 (s, 1 H), 8,52 (s, 1 H), 8,31 (s, 1 H), 8,16 (d, 1 H), 7,50 (d, 2 H), 7,45 (s, 1 H), 7,00 (d, 2 H), 5,29 (s, 2 H), 3,95 (s, 3 H), 3,82 (s, 3 H), 3,55 - 3,59 (m, 1 H), 3,52 (s, 2 H), 3,25 - 3,32 (m, 2 H), 2,94 (dd, 2 H).[00578] 1H NMR (400 MHz, DMSO-d6) δ: 8.92 (s, 1 H), 8.57 (s, 1 H), 8.52 (s, 1 H), 8.31 (s , 1 H), 8.16 (d, 1 H), 7.50 (d, 2 H), 7.45 (s, 1 H), 7.00 (d, 2 H), 5.29 (s , 2 H), 3.95 (s, 3 H), 3.82 (s, 3 H), 3.55 - 3.59 (m, 1 H), 3.52 (s, 2 H), 3 .25 - 3.32 (m, 2 H), 2.94 (dd, 2 H).
[00579] LCMS m/z = 542,1 [MNa]+ Exemplo 37 (1r,3r)-3-(Cianometil)-3-(4-(6-(1-metil-3-oxo-2,3-dihidro-1H-pirazol- 4-il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1-il)ciclobutano-1- carbonitrila (trans isômero) [00579] LCMS m/z = 542.1 [MNa]+ Example 37 (1r,3r)-3-(Cyanomethyl)-3-(4-(6-(1-methyl-3-oxo-2,3- dihydro-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile (trans isomer)
[00580] (1r,3r)-3-(Cianometil)-3-(4-(6-(3-((4-metoxibenzil)óxi)-1- metil-1H-pirazol-4-il)pirazolo[1,5-a]pirazin-4-il)-1H-pirazol-1- il)ciclobutano-1-carbonitrila (Preparação 107, 450 mg, 0,86 mmol) e TFA (13 mL) foram agitados a cerca de 10 °C durante cerca de 4 h. A mistura foi concentrada, e o resíduo foi diluído com DCM (40 mL) e MeOH (40 mL) e neutralizado com NaHCO3 sólido. A mistura foi filtrada. O filtrado foi concentrado, e o resíduo foi purificado por HPLC para proporcionar o composto título como um sólido amarelo (54 mg, 16 %).[00580] (1r,3r)-3-(Cyanomethyl)-3-(4-(6-(3-((4-methoxybenzyl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile (Preparation 107, 450 mg, 0.86 mmol) and TFA (13 mL) were stirred at about 10° C for about 4 h. The mixture was concentrated, and the residue was diluted with DCM (40 mL) and MeOH (40 mL) and neutralized with solid NaHCO3. The mixture was filtered. The filtrate was concentrated, and the residue was purified by HPLC to provide the title compound as a yellow solid (54 mg, 16%).
[00581] 1H RMN (400 MHz, DMSO-d6) δ: 10,76 (br. s., 1 H), 8,92 (s, 1 H), 8,71 (s, 1 H), 8,51 (s, 1 H), 8,18 (d, 1 H), 8,16 (s, 1 H), 7,45 (d, 1 H), 3,73 (s, 3 H), 3,55 - 3,62 (m, 1 H), 3,53 (s, 2 H), 3,25 - 3,33 (m, 2 H), 2,90 - 2,99 (m, 2 H).[00581] 1H NMR (400 MHz, DMSO-d6) δ: 10.76 (br. s., 1 H), 8.92 (s, 1 H), 8.71 (s, 1 H), 8, 51 (s, 1 H), 8.18 (d, 1 H), 8.16 (s, 1 H), 7.45 (d, 1 H), 3.73 (s, 3 H), 3, 55 - 3.62 (m, 1 H), 3.53 (s, 2 H), 3.25 - 3.33 (m, 2 H), 2.90 - 2.99 (m, 2 H).
[00582] LCMS m/z = 400,1 [MH]+[00582] LCMS m/z = 400.1 [MH]+
[00583] Os compostos da invenção foram avaliados por métodos in vitro para determinar a sua respectiva capacidade para inibir as JAK cinases (TYK2, JAK1, JAK2, JAK3).[00583] The compounds of the invention were evaluated by in vitro methods to determine their respective ability to inhibit JAK kinases (TYK2, JAK1, JAK2, JAK3).
[00584] A atividade inibidora de JAK humana foi determinada utilizando um ensaio microfluídico para monitorizar a fosforilação de um peptídeo sintético pelo domínio de cinase humana recombinante de cada um dos quatro membros da família JAK, JAK1, JAK2, JAK3 e TYK2. As misturas de reação continham 1 μM de um peptídeo sintético marcado com fluorescência, uma concentração inferior à Km aparente e 1 mM de ATP. Cada condição de ensaio foi otimizada para a concentração de enzima e tempo de incubação em temperatura ambiente para obter uma razão de conversão de 20% a 30% de produto peptídi- co fosforilado. As reações foram terminadas pela adição de tampão de interrupção contendo EDTA. Utilizando a tecnologia de deslocamento de mobilidade LabChip 3000 (Caliper Life Science), cada reação de ensaio foi amostrada para determinar o nível de fosforilação. Essa tecnologia é baseada em separação, permitindo a detecção direta de substratos e produtos marcados com fluorescência. As separações são controladas por uma combinação de pressão a vácuo e intensidade do campo elétrico otimizada para cada substrato peptídico.[00584] Human JAK inhibitory activity was determined using a microfluidic assay to monitor the phosphorylation of a synthetic peptide by the recombinant human kinase domain of each of the four members of the JAK family, JAK1, JAK2, JAK3 and TYK2. Reaction mixtures contained 1 μM of a fluorescently labeled synthetic peptide, a concentration lower than the apparent Km, and 1 mM ATP. Each assay condition was optimized for enzyme concentration and incubation time at room temperature to obtain a conversion ratio of 20% to 30% of phosphorylated peptide product. Reactions were terminated by addition of stop buffer containing EDTA. Using LabChip 3000 mobility shift technology (Caliper Life Science), each assay reaction was sampled to determine the level of phosphorylation. This technology is based on separation, allowing direct detection of fluorescently labeled substrates and products. Separations are controlled by a combination of vacuum pressure and electric field intensity optimized for each peptide substrate.
[00585] Os compostos foram adicionados a uma placa de 384 poços. As misturas de reação continham HEPES a 10 mM, pH 7,4, MgCl2 a 10 mM, BSA a 0,01%, Tween 20 a 0,0005%, ATP a 1 mM e substrato peptídico a 1 M. Os ensaios JAK1 e TYK2 continham 1 μM do pep- tídeo IRStide (5FAM-KKSRGDYMTMQID) e os ensaios JAK2 e JAK3 continham 1 μM do peptídeo JAKtide (FITC-KGGEEEEYFELVKK). Os ensaios foram iniciados pela adição de JAK1 20 nM, JAK2 1 nM, JAK 1 nM ou enzima TYK2 1 nM e foram incubados em temperatura ambiente durante três horas para JAK1, 60 minutos para JAK2, 75 minutos para JAK3 ou 135 minutos para TYK2 . As concentrações de enzimas e os tempos de incubação foram otimizados para cada nova preparação enzimática e foram modificados levemente ao longo do tempo para garantir 20% a 30% de fosforilação. Os ensaios foram interrompidos com 15 μl de HEPES 180 mM, pH 7,4, EDTA 20 mM e 0,2% de reagente de revestimento 3. As placas de ensaio foram colocadas em um instrumento Caliper Life Science LC3000, e cada poço foi amostrado usando condições de separação adequadas para medir o peptídeo não fosforilado e fosforilado.[00585] The compounds were added to a 384-well plate. Reaction mixtures contained 10 mM HEPES, pH 7.4, 10 mM MgCl2, 0.01% BSA, 0.0005% Tween 20, 1 mM ATP, and 1 M peptide substrate. TYK2 contained 1 μM of the IRStide peptide (5FAM-KKSRGDYMTMQID) and the JAK2 and JAK3 assays contained 1 μM of the JAKtide peptide (FITC-KGGEEEEYFELVKK). Assays were initiated by adding 20 nM JAK1, 1 nM JAK2, 1 nM JAK, or 1 nM TYK2 enzyme and were incubated at room temperature for three hours for JAK1, 60 minutes for JAK2, 75 minutes for JAK3, or 135 minutes for TYK2. Enzyme concentrations and incubation times were optimized for each new enzyme preparation and were modified slightly over time to ensure 20% to 30% phosphorylation. Assays were stopped with 15 μl of 180 mM HEPES, pH 7.4, 20 mM EDTA, and 0.2% coating reagent 3. Assay plates were placed in a Caliper Life Science LC3000 instrument, and each well was sampled. using suitable separation conditions to measure unphosphorylated and phosphorylated peptide.
[00586] Os dados foram coletados usando o software HTS Well Analyzer da Caliper Life Sciences. A saída de dados para análise de dados é o percentual do produto convertido calculado na altura do pico (Equação 1). Equação 1: % do produto convertido = 100* ((produto) / (produto + substrato))[00586] Data was collected using HTS Well Analyzer software from Caliper Life Sciences. The data output for data analysis is the percentage of converted product calculated at peak height (Equation 1). Equation 1: % of converted product = 100* ((product) / (product + substrate))
[00587] O efeito percentual em cada concentração de composto foi calculado com base no poço de controle positivo e negativo contido em cada placa de ensaio (Equação 2). Os poços de controle positivo continham uma concentração de saturação de um composto de controle que produziu um nível de fosforilação comparável ao antecedente (isto é, JAK1, JAK2, JAK3 ou TYK2 completamente inibidas). Os poços de controle negativo continham apenas DMSO (na mesma concentração dos poços do composto) que foi utilizado para definir a atividade de referência no ensaio (isto é, JAK1, JAK2, JAK3 ou TYK2 não inibidos). Equação 2: % efeito = 100 * ((poço de amostra / controle negativo) / (controle positivo - negativo controle))[00587] The percentage effect at each compound concentration was calculated based on the positive and negative control well contained in each assay plate (Equation 2). Positive control wells contained a saturating concentration of a control compound that produced a level of phosphorylation comparable to the background (i.e., JAK1, JAK2, JAK3, or TYK2 completely inhibited). The negative control wells contained only DMSO (at the same concentration as the compound wells) which was used to define the reference activity in the assay (i.e., uninhibited JAK1, JAK2, JAK3, or TYK2). Equation 2: % effect = 100 * ((sample well / negative control) / (positive control - negative control))
[00588] O efeito percentual foi traçado contra o composto de con-centração do composto. Uma curva sigmoide não restrita foi ajustada utilizando um modelo logístico de 4 parâmetros e a concentração do composto necessária para 50% de inibição (IC50) foi determinada (Equação 3). Equação 3: y = ((máx - min) / (1 + ((x/IC50)As))) + min[00588] The percentage effect was plotted against the compound's concentration compound. An unconstrained sigmoid curve was fitted using a 4-parameter logistic model and the compound concentration required for 50% inhibition (IC50) was determined (Equation 3). Equation 3: y = ((max - min) / (1 + ((x/IC50)As))) + min
[00589] Onde máx é a assíntota máxima (inibição completa), min é a assíntota mínima (sem inibição) e s é o fator de inclinação. Os valo- res de IC50 são relatados em nM para cada composto: TABELA I. Dados Caliper de JAK [00589] Where max is the maximum asymptote (complete inhibition), min is the minimum asymptote (no inhibition) and s is the slope factor. IC50 values are reported in nM for each compound: TABLE I. JAK Caliper Data
[00590] Os compostos selecionados toram avaliados quanto à sua capacidade para inibir a sinalização de IL-12 em um ensaio de citome- tria de fluxo de sangue total humano. Sinais de IL-12 através de TYK2 e JAK2.[00590] The selected compounds were evaluated for their ability to inhibit IL-12 signaling in a human whole blood flow cytometry assay. IL-12 signals through TYK2 and JAK2.
[00591] Os artigos de teste foram preparados como matérias-prima de 30 mM em DMSO. Uma série de diluições de 11 pontos de 2,5 foi criada em DMSO com uma concentração máxima de 10 mM. Diluição adicional foi feita adicionando 4 μL das soluções do artigo de teste acima em 96 μL de PBS com uma concentração de topo de 400 μM. Recolheu-se sangue total humano de doadores saudáveis por punção venosa em tubos de colheita Vacutainer contendo heparina de sódio (N.° de Catálogo 366480; Becton Dickinson, Franklin Lakes, NJ). O sangue foi aquecido a 37 °C antes do uso. Sangue total humano foi aliquotado (90 mL / poço) em placas de fundo em V de poço profundo de 96 poços, e tratadas com compostos a 11 concentrações diferentes (DMSO final a 0,2%) a 37 °C durante 60 minutos. Isto foi seguido por um desafio com IL-12 (5 mL / poço; final, 5 ng / mL) durante 15 minutos. As amostras foram tratadas com tampão 1X Lyse / Fix quente (700 mL / poço) para terminar a ativação e depois incubadas a 37 °C durante 20 minutos para lisar os glóbulos vermelhos. As placas foram centrifugadas a 300 x g durante 5 minutos, o sobrenadante foi aspirado e as células foram lavadas com 800 mL por poço de tampão de manchamento (PBS contendo 0,5% de soro bovino fetal e 0,01% de azida de sódio). Os péletes de células lavados foram ressuspensos com 350 mL / poço de metanol a 90% pré-arrefecido e incubados a 4 °C durante 30 minutos. As placas foram centrifugadas a 300 x g durante 5 minutos, o sobrenadante contendo 90% de metanol foi aspirado e as células foram lavadas com 800 ml / poço de tampão de mancha- mento. Os péletes de células foram ressuspensos em tampão de man- chamento contendo anti-pSTAT4-AlexaFluor647 (1 a 150 de diluição, 150 mL / poço) e incubados em temperatura ambiente no escuro durante a noite.[00591] Test articles were prepared as 30 mM raw materials in DMSO. An 11-point dilution series of 2.5 was created in DMSO with a maximum concentration of 10 mM. Further dilution was done by adding 4 μL of the above test article solutions into 96 μL of PBS with a top concentration of 400 μM. Human whole blood was collected from healthy donors by venipuncture into Vacutainer collection tubes containing sodium heparin (Catalog No. 366480; Becton Dickinson, Franklin Lakes, NJ). Blood was warmed to 37°C before use. Human whole blood was aliquoted (90 mL/well) into 96-well deep-well V-bottom plates, and treated with compounds at 11 different concentrations (0.2% final DMSO) at 37 °C for 60 minutes. This was followed by an IL-12 challenge (5 mL/well; final, 5 ng/mL) for 15 minutes. Samples were treated with warm 1X Lyse/Fix buffer (700 mL/well) to terminate activation and then incubated at 37 °C for 20 minutes to lyse red blood cells. The plates were centrifuged at 300 x g for 5 minutes, the supernatant was aspirated, and the cells were washed with 800 mL per well of staining buffer (PBS containing 0.5% fetal bovine serum and 0.01% sodium azide). . The washed cell pellets were resuspended with 350 ml/well of pre-chilled 90% methanol and incubated at 4°C for 30 minutes. The plates were centrifuged at 300 x g for 5 minutes, the supernatant containing 90% methanol was aspirated and the cells were washed with 800 ml/well of staining buffer. Cell pellets were resuspended in staining buffer containing anti-pSTAT4-AlexaFluor647 (1 to 150 dilution, 150 mL/well) and incubated at room temperature in the dark overnight.
[00592] As amostras foram transferidas para placas de 96 cavidades com fundo em U e a análise citométrica de fluxo foi realizada em um FACSCalibur ou LSRFortessa equipado com um carregador de placas HTS (BD Biosciences). A população de linfócitos foi fechada para análise de histograma de pSTAT4. A fluorescência de base foi definida utilizando células não estimuladas e uma porta foi colocada no pé do pico para incluir uma população com ~ 0,5% de entrada. A análise estatística do histograma foi realizada utilizando o software CellQuest™ Pro versão 5.2.1 (BD Biosciences) ou FACSDiva versão 6.2 (BD Biosciences). A unidade de fluorescência relativa (RFU), que mede o nível de fosfo STAT4, foi calculada multiplicando a percentagem de população positiva e a sua fluorescência média. Dados de 11 concentrações de compostos (singlicate em cada concentração) foram normalizados como uma porcentagem de controle com base na fórmula: % de controle = 100 x (A - B)/(C - B)[00592] Samples were transferred to 96-well U-bottom plates and flow cytometric analysis was performed on a FACSCalibur or LSRFortessa equipped with an HTS plate loader (BD Biosciences). The lymphocyte population was gated for pSTAT4 histogram analysis. Baseline fluorescence was defined using unstimulated cells and a gate was placed at the foot of the peak to include a population with ~0.5% input. Statistical analysis of the histogram was performed using CellQuest™ Pro version 5.2.1 (BD Biosciences) or FACSDiva version 6.2 (BD Biosciences) software. The relative fluorescence unit (RFU), which measures the level of phospho STAT4, was calculated by multiplying the percentage of positive population and its average fluorescence. Data from 11 compound concentrations (singlicate at each concentration) were normalized as a percentage of control based on the formula: % control = 100 x (A - B)/(C - B)
[00593] onde A é a RFU de poços contendo composto e IL-12, B é a RFU de poços sem IL-12 e composto (fluorescência mínima) e C é a RFU de poços contendo apenas IL-12 (fluorescência máxima). As curvas de inibição e os valores de IC50 foram determinados utilizando o software Prism versão 5 (GraphPad, La Jolla, CA). TABELA II. Dados de IL-12 no sangue total humano. [00593] where A is the RFU of wells containing compound and IL-12, B is the RFU of wells without IL-12 and compound (minimum fluorescence) and C is the RFU of wells containing only IL-12 (maximum fluorescence). Inhibition curves and IC50 values were determined using Prism version 5 software (GraphPad, La Jolla, CA). TABLE II. IL-12 data in human whole blood.
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