ES2587533T3 - Derivados de purina y su uso en el tratamiento de enfermedades - Google Patents

Derivados de purina y su uso en el tratamiento de enfermedades Download PDF

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Publication number
ES2587533T3
ES2587533T3 ES12798854.1T ES12798854T ES2587533T3 ES 2587533 T3 ES2587533 T3 ES 2587533T3 ES 12798854 T ES12798854 T ES 12798854T ES 2587533 T3 ES2587533 T3 ES 2587533T3
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Prior art keywords
morpholin
methyl
indole
purine
fluoro
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Inventor
Emmanuelle Briard
Pascal Furet
Andreas Lerchner
Peter Meier
Branko Radetich
David Andrew Sandham
Yanyi Zhu
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Novartis AG
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Novartis AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Un compuesto de fórmula (I), o una sal farmacéuticamente aceptable del mismo,**Fórmula** en donde R1 se selecciona del grupo que consiste de**Fórmula** en donde R18 en cada ocurrencia representa independientemente fluoro o metilo; m representa 0, 1, 2 o 3; R19 y R20 representan independientemente hidrógeno o fluoro; R21 representa fluoro; R22 en cada ocurrencia representa independientemente fluoro, metoxi, hidroximetilo o metoxicarbonilo; q representa 0, 1 o 2 y r representa 0, 1, 2 o 3 con la condición de que q + r no es 0; R2, R3, R4, R5, R6, R7, R8 y R9 representan independientemente hidrógeno, C1-3 alquilo o fluoro-C1-3 alquilo; o R3 y R6 juntos forman un puente de metileno; o R3 y R8 juntos forman un puente de etileno; o R5 y R6 juntos forman un puente de etileno; n y p representan independientemente 0, 1 o 2; R10, R11, R12, R13, R14, R15, R16 y R17 en cada ocurrencia representan independientemente hidrógeno, C1-3 alquilo, fluoro-C1-3 alquilo o hidroxi-C1-3 alquilo; o R11 y R16 juntos forman un puente de etileno; o R13 y R14 juntos forman un puente de etileno; o R14 y R15, junto con el átomo de carbono al que están unidos, están enlazados para formar un anillo tetrahidropiranilo; y Y representa O, CHR23, CR24R25 o NR26, en donde R23 representa hidroxilo o fluoro-C1-3 alquilo; o R23 y R13, junto con los átomos de carbono a los que están unidos, están enlazados para formar un anillo de de tetrahidrofuranilo fusionado; R24 y R25 representan independientemente hidrógeno o halógeno; o R24 y R25, junto con el átomo de carbono al que están unidos, están enlazados para formar un anillo tetrahidropiranilo; y R26 representa C1-3 alquilo u oxetanilo; y un compuesto, o una sal farmacéuticamente aceptable del mismo, seleccionado de la siguiente lista de compuestos: 8-(1H-Indol-4-il)-6-(3-metil-morfolin-4-il)-2-[1,4]oxazepan-4-il-9H-purina; 8-(1H-Indol-4-il)-6-(3-metil-morfolin-4-il)-2-(3-propil-morfolin-4-il)-9H-purina; 8-[8-(1H-Indol-4-il)-6-(3-metil-morfolin-4-il)-9H-purin-2-il]-8-aza-biciclo[3.2.1]octan-3-ol; 8-[8-(1H-Indol-4-il)-6-(3-metil-morfolin-4-il)-9H-purin-2-il]-8-aza-biciclo[3.2.1]octan-3-ol; 2-(3-Etil-morfolin-4-il)-8-(1H-indol-4-il)-6-(3-metil-morfolin-4-il)-9H-purina; 8-(1H-Indol-4-il)-6-(3-metil-morfolin-4-il)-2-(4-metil-piperazin-1-il)-9H-purina; 8-(1H-Indol-4-il)-6-(3-metil-morfolin-4-il)-2-(6-oxa-2-aza-espiro[3.5]non-2-il)-9H-purina; 8-(1H-Indol-4-il)-6-(3-metil-morfolin-4-il)-2-(4-oxetan-3-il-piperazin-1-il)-9H-purina; 8-(1H-Indol-4-il)-6-(3-metil-morfolin-4-il)-2-(tetrahidro-furo[3,4-c]pirrol-5-il)-9H-purina; 2-(Hexahidro-furo[3,4-c]piridin-5-il)-8-(1H-indol-4-il)-6-(3-metil-morfolin-4-il)-9H-purina; 8-(1H-Indol-4-il)-2-(3-isopropil-morfolin-4-il)-6-(3-metil-morfolin-4-il)-9H-purina; 8-(1H-Indol-4-il)-6-(3-metil-morfolin-4-il)-2-(4-trifluorometil-piperidin-1-il)-9H-purina; 2-(2,6-Dimetil-morfolin-4-il)-8-(1H-indol-4-il)-6-(3-metil-morfolin-4-il)-9H-purina; 8-(1H-Indol-4-il)-6-(3-metil-morfolin-4-il)-2-(7-oxa-1-aza-espiro[3.5]non-1-il)-9H-purina; {4-[8-(1H-Indol-4-il)-6-(3-metil-morfolin-4-il)-9H-purin-2-il]-morfolin-2-il}-metanol; y {4-[8-(1H-Indol-4-il)-6-(3-metil-morfolin-4-il)-9H-purin-2-il]-morfolin-2-il}-metanol.

Description

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Ejemplo Número
Prueba 1: ensayo de enlazamiento a mTOR IC50 (nM) Prueba 2: ensayo celular de T389 IC50 (nM) Prueba 3: Autofagia EC50 (nM)
3
164 76 422
4
2122 1550 2155
5
21 122 n.d.
6
66 1185 423
7
184 997 1317
8
1027 806 n.m.
9
860 n.d. n.d.
10
343 135 1439
11
385 190 1524
12
194 534 674
13
143 618 935
14
76 250 855
15
60 194 752
16
308 259 n.m.
17
112 224 663
18
91 249 n.m.
19
296 471 727
20
484 319 n.m.
21
122 179 n.d.
22
1510 1040 1682
23
78 104 n.m.
24
369 229 302
25
380 1930 n.d.
26
67 318 n.d.
27
2412 1191 4743
28
754 272 2371
29
1314 498 3606
30
364 1137 1457
31
28 71 145
32
533 1120 >6000
n.d. = no determinado; n.m. = no medible
Como se indica por los resultados de la prueba descritos aquí anteriormente, los compuestos de la presente invención pueden ser útiles para el tratamiento de enfermedades, condiciones y trastornos modulados por la inhibición de la enzima mTOR; en consecuencia, los compuestos de la presente invención (incluyendo las
5 composiciones y procesos utilizados en la misma) se pueden usar en la fabricación de un medicamento para las aplicaciones terapéuticas descritas aquí. Por lo tanto, otra realización de la presente invención es una composición farmacéutica que comprende un compuesto de la presente invención, o una sal farmacéuticamente aceptable del mismo, y un excipiente, diluyente o vehículo farmacéuticamente aceptable.
Una formulación típica se prepara mezclando un compuesto de la presente invención y un vehículo, diluyente o 10 excipiente. Los vehículos, diluyentes y excipientes adecuados son bien conocidos por los expertos en la técnica e
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Ejemplo Número
Estructura y Nombre 1H RMN LC/MS
8
2,6-Bis-((S)-3-metil-morfolin-4-il)-8-piridin-2-il9H-purina 1H RMN (600 MHz, DMSOd6):12.99 (s, 1H), 8.62 (d, 1H), 8.12 (d, 1H), 7.89 (ddd, 1H), 7.40 (ddd, 1H), 6.0-4.5 (brs, 2H), 4.56 (dd, 1H), 4.19 (d, 1H), 4.0-3.0 (brs, 1H), 3.96 (dd, 1H), 3.89 (dd, 1H), 3.76 (d, 1H), 3.71-3.66 (m, 2H), 3.57 (dd, 1H), 3.53 (ddd, 1H), 3.41 (ddd, 1H), 3.09 (ddd, 1H), 1.30 (d, 3 H) 1.16 (d, 3 H) Método 1 Tiempo de Retención:1.04 min Masa (ES+): 396.4
9
2,6-Di-morfolin-4-il-8-piridin-2-il-9H-purina Método 2 Tiempo de Retención:4.38 min Masa (ES+): 367.95
10
2,6-Bis-((S)-3-metil-morfolin-4-il)-8-(1H-pirazol3-il)-9H-purina 1H RMN (400 MHz, DMSO-d6): 13.13 (s, 1H), 12.72 (s, 1H), 7.84 (dd, 1H), 6.75 (dd, 1H), 6.0-4.5 (brs, 2H), 4.6-4.47 (m, 1H), 4.16 (dd, 1H), 4.0-3.0 (brs, 1H), 3.96 (dd, 1H), 3.90 (dd, 1H), 3.76 (d, 1H), 3.73-3.64 (m, 2H), 3.59 (dd, 1H), 3.52 (dd, 1H), 3.43 (dd, 1H), 3.09 (dd, 1H), 1.29 (d,3H) 1.17 (d,3H) Método 1 Tiempo de Retención:0.81 min Masa (ES+): 385.3
11
2,6-Bis-((R)-3-metil-morfolin-4-il)-8-(1H-pirazol3-il)-9H-purina 1H RMN (600 MHz, DMSOd6):13.12 (s, 1H), 12.71 (s, 1H), 7.82 (d, 1 H), 6.74 (d, 1H), 6.04.5 (brs, 2H), 4.52 (d, 1H), 4.16 (d, 1H), 4.0-3.0 (brs, 1H), 3.95 (d, 1H), 3.88 (d, 1H), 3.74 (d, 1H), 3.71-3.63 (m, 2H), 3.57 (d, 1H), 3.51 (dd, 1H), 3.41 (dd, 1H), 3.08 (ddd, 1H), 1.27 (d, 3 H), 1.15 (d, 3 H) Método 1 Tiempo de Retención:0.81 min Masa (ES+): 385.3
38
Ejemplo Número
Estructura y Nombre 1H RMN LC/MS
1H RMN (600 MHz, DMSO-d6):
12.77 (br. s., 1 H), 11.28 (br. s.,
1H), 7.66 (d, 1 H), 7.46 -7.43 (m,
2 H), 7.25 (t, 1 H), 7.15 (t, 1 H),
5.6-5.4 (s, 1 H), 5.1-4.8 (m, 1H),
Método 1
4.49 (t, 1H), 4.27 (d, 1H), 3.98
(dd, 1H), 3.85 (dd, 1H), 3.79 (d,
Tiempo de
2H), 3.72 (d, 1H), 3.59 -3.48 (m,
Retención:1.17
2H), 3.45 -3.35 (m, 1H), 3.31 (br.
min
s., 1H), 3.10 (td, 1H), 1.75 -1.68
8-(1H-Indol-4-il)-6-((R)-3-metil-morfolin-4-il)-2
(m, 1H), 1.60 -1.53 (m, 1H), 1.37- Masa (ES+):
12
((R)-3-propil-morfolin-4-il)-9H-purina 1.20 (m, 5H), 0.89 (t, 3H) 462.3
13
8-[8-(1H-Indol-4-il)-6-((R)-3-metil-morfolin-4-il)9H-purin-2-il]-8-aza-biciclo[3.2.1]octan-3-ol 1H RMN (400 MHz, DMSO-d6): 12.93 (s, 1H), 11.28 (br. s., 1H), 7.67 (d, 1H), 7.56 -7.44 (m, 2H), 7.28 (br. s., 1H), 7.16 (t, 1H), 5.55.0 (m, 1H), 4.56 (br. s., 2H), 4.36 (d, 1H), 4.07 -3.95 (m, 3H), 3.84 -3.71 (m, 2H), 3.62-3.55 (m, 1H), 1.94 (d, 2H), 1.82 -1.66 (m, 4H), 1.66 -1.49 (m, 2H), 1.45 -1.31 (m, 3H) Método 1 Tiempo de Retención:0.85 min Masa (ES+): 460.4
14
8-[8-(1H-Indol-4-il)-6-((R)-3-metil-morfolin-4-il)9H-purin-2-il]-8-aza-biciclo[3.2.1]octan-3-ol 1H RMN (400 MHz, DMSO-d6): 12.87 (s, 1H), 11.28 (br. s., 1H), 7.66 (d, 1H), 7.50 -7.40 (m, 2H), 7.30-7.25 (m, 1H), 7.16 (t, 1H), 5.6-5.0 (m, 1H), 4.58-4.46 (m, 3H), 4.07 -3.94 (m, 2H), 3.88 (br. s., 1H), 3.85 -3.68 (m, 2H), 3.58 (t, 1H), 3.44-3.40 (m, 1H), 2.26 (d, 2H), 2.14-2.06 (d, 2H), 2.94 -1.79 (m, 2H), 1.65-1.57 (m, 2H), 1.36 (d, 3H) Método 1 Tiempo de Retención:0.86 min Masa (ES+): 460.3
39
Ejemplo Número
Estructura y Nombre 1H RMN LC/MS
15
2-((R)-3-Etil-morfolin-4-il)-8-(1H-indol-4-il)-6((R)-3-metil-morfolin-4-il)-9H-purina 1H RMN (600 MHz, DMSO-d6): 12.79 (s, 1H), 11.27 (br. s., 1H), 7.66 (d, 1H), 7.48 -7.42 (m, 2H), 7.25 (br. s., 1H), 7.14 (t, 1H), 5.74.7 (m, 2H), 4.37 (t, 1H), 4.27 (d, 1H), 3.99 (dd, 1H), 3.88-3.77 (m, 3H), 3.72 (d, 1H), 3.62 -3.47 (m, 2H), 3.42 (td, 2H), 3.12 -3.06 (m, 1H), 1.79 -1.72 (m, 1H), 1.63 -1.56 (m, 1H), 1.40 -1.29 (m, 3H), 0.87 (t, 3H) Método 1 Tiempo de Retención:1.07 min Masa (ES+): 448.3
16
8-(1H-Indol-4-il)-6-((R)-3-metil-morfolin-4-il)-2(4-metil-piperazin-1-il)-9H-purina 1H RMN (600 MHz, DMSO-d6) 12.81 (s, 1H), 11.28 (br. s., 1H), 7.65 (d, 1H), 7.53 -7.43 (m, 2H), 7.25 (t, 1H), 7.15 (t, 1H), 5.6-5.0 (m, 2H), 3.99 (dd, 1H), 3.82 -3.76 (m, 1H), 3.75 -3.65 (m, 3H), 3.583.53 (m, 1H), 3.49-3.46 (m, 1H), 3.40 (t, 1H), 3.34-3.29 (m, 1H), 2.39 -2.27 (m, 4H), 2.26 -2.10 (m, 3H), 1.34 (d, 3H) Método 1 Tiempo de Retención:0.69 min Masa (ES+): 433.3
17
8-(1H-Indol-4-il)-6-((R)-3-metil-morfolin-4-il)-2(6-oxa-2-aza-espiro[3.5]non-2-il)-9H-purina 1H RMN (600 MHz, DMSO-d6): 12.95 (s, 1H), 11.28 (br. s., 1H), 7.63-7.60 (m, 1H), 7.46 -7.40 (m, 2H), 7.25 (t, 1H), 7.14 (t, 1 H), 5.65-4.85 (m, 2H), 4.00 -3.95 (m, 1H), 3.81 -3.75 (m, 1H), 3.73 -3.66 (m, 3H), 3.65 -3.59 (m, 4H), 3.57-3.44 (m, 3H), 3.42-3.38 (m, 1H), 1.83 -1. 68 (m, 2H), 1.55 -1.43 (m, 2H), 1.34 (d, 3H) Método 1 Tiempo de Retención:0.97 min Masa (ES+): 460.3
40
Ejemplo Número
Estructura y Nombre 1H RMN LC/MS
18
8-(1H-Indol-4-il)-6-((R)-3-metil-morfolin-4-il)-2(4-oxetan-3-il-piperazin-1-il)-9H-purina NMR (600 MHz, DMSO-d6): 12.83 (s, 1H), 11.28 (br. s., 1H), 7.64 (d, 1H), 7.50 -7.42 (m, 2H), 7.25 (br. s., 1H), 7.15 (t, 1H), 5.75-4.70 (m, 2H), 4.55 (t, 2H), 4.47 (t, 2H), 3.99 (dd, 1 H), 3.81 3.76 (m, 1H), 3.75 -3. 64 (m, 5 H), 3.62 -3. 51 (m, 1H), 3.46 -3.38 (m, 2H), 2.30 (t, 4H), 1.34 (d, 3H) Método 1 Tiempo de Retención:0.72 min Masa (ES+): 475.3
19
8-(1H-Indol-4-il)-6-((R)-3-metil-morfolin-4-il)-2(tetrahydro-furo[3,4-c]pirrol-5-il)-9H-purina 1H RMN (400 MHz, DMSO-d6): 12.89 (s, 1H), 11.28 (br. s., 1H), 7.68-7.64 (m, 1H), 7.48 -7.44 (m, 2H), 7.28 (t, 1H), 7.16 (t, 1H), 5.7-4.2 (m, 2H), 4.01 (dd, 1 H), 3.89 -3.79 (m, 3H), 3.77-3.66 (m, 3H), 3.62 -3.55 (m, 3H), 3.54 -3.42 (m, 2H), 3.32 (s, 1H), 3.02 2.91 (m, 2H), 1.37 (d, 3H) Método 1 Tiempo de Retención:0.88 min Masa (ES+): 446.3
20
2-(Hexahidro-furo[3,4-c]piridin-5-il)-8-(1Hindol-4-il)-6-((R)-3-metil-morfolin-4-il)-9Hpurina 1H RMN (400 MHz, DMSOd6):12.81 (s, 1H), 11.29 (br. s., 1H), 7.69-7.64 (m,1H), 7.49 -7.44 (m, 2H), 7.27 (br. s., 1H), 7.16 (t, 1H), 5.6-4.8 (m, 2H), 3.98 -3.90 (m, 1H), 3.84 -3.71 (m, 6H), 3.62 -3.54 (m, 2H), 3.48-3.39 (m, 3H), 3.33 -3.30 (m, 1H), 2.49 -2.33 (m, 2H), 1.77 (br. s., 1H), 1.52 (br. s., 1H), 1.36 (d, 3H) Método 1 Tiempo de Retención:0.95 min Masa (ES+): 460.3
41
Ejemplo Número
Estructura y Nombre 1H RMN LC/MS
21
8-(1H-Indol-4-il)-2-((R)-3-isopropil-morfolin-4-il)6-((R)-3-metil-morfolin-4-il)-9H-purina 1H RMN (600 MHz, DMSO-d6): 12.75 (s, 1H), 11.27 (br. s., 1H), 7.64 (d, 1H), 7.38 -7.45 (m, 2H), 7.24 (t, 1H), 7.14 (t, 1H), 5.2-4.7 (m, 2H), 4.45 (d, 1H), 4.29 (d, 1H), 3.98 -3.92 (m, 2H), 3.84 -3.78 (m, 2H), 3.74 -3.69 (m, 1H), 3.60-3.53 (m, 1H), 3.43 -3.35 (m, 2H), 3.32 -3.21 (m, 1H), 3.09 (td, 1H), 2.48 -2.30 (m, 1H), 1.34 (d, 3H), 1.00 (d, 3H), 0.77 (d, 3H) Método 1 Tiempo de Retención:1.12 min Masa (ES+): 462.3
22
8-(1H-Indol-4-il)-6-((R)-3-metil-morfolin-4-il)-2(4-trifluorometil-piperidin-1-il)-9H-purina 1H RMN (600 MHz, DMSO-d6): 12.84 (br. s., 1H), 11.28 (br. s., 1H), 7.65 (d, 1H), 7.47-7.43 (m, 2H), 7.25 (br. s., 1H), 7.15 (t, 1H), 5.7-5.3 (m, 1H), 4.75 (d, 2H), 4.00 (d, 1H), 3.82 -3.77 (m, 1H), 3.76 -3.70 (m, 1H), 3.57 (t, 1H), 3.37 (br. s., 1H), 2.86 (t, 2H), 2.64-2. 56 (m, H), 1.83 (d, 2H), 1.43-1.36 (m, 3H), 1.34 (d, 3H) Método 1 Tiempo de Retención:1.24 min Masa (ES+): 486.3
23
2-((2S,6R)-2,6-Dimetil-morfolin-4-il)-8-(1Hindol-4-il)-6-((R)-3-metil-morfolin-4-il)-9H-purina 1H RMN (600 MHz, DMSO-d6): 12.83 (br. s., 1H), 11.28 (br. s., 1H), 7.65 (d,1H), 7.53-7.42 (m, 2H), 7.25 (br. s., 1H), 7.15 (t, 1H), 5.5-5.0 (m, 2H), 4.42 (d, 2H), 4.00 (d, 1H), 3.80 (d, 1H), 3.73 (d, 1H), 3.60 -3.52 (m, 3H), 3.3 (m, 1H), 2.48-2.43 (m, 2H), 1.35 (d, 3H), 1.15 (d, 6H) Método 1 Tiempo de Retención: 1.1 min Masa (ES+): 448.3
42
Ejemplo Número
Estructura y Nombre 1H RMN LC/MS
24
8-(1H-Indol-4-il)-6-((R)-3-metil-morfolin-4-il)-2(7-oxa-1-aza-espiro[3.5]non-1-il)-9H-purina 1H RMN (600 MHz, CHLOROFORM-d): 8.42 (br. s., 1H), 7.55 (d, 1H), 7.49 (d, 1H) 7.38 (br. s., 1H), 7.31 -7.26 (m, 2H), 4.17 -4.07 (m, 3H), 4.01 (dd, 3H), 3.88 (d, 2H), 3.77-3.64 (m, 3H), 3.43 (t, 3 H), 2.73 (br. s., 2 H), 2.25 (t, 2H), 1.76 (d, 2H), 1.51 (br. s., 3H) Método 1 Tiempo de Retención:0.92 min Masa (ES+): 460.3
25
{(S)-4-[8-(1H-Indol-4-il)-6-((R)-3-metil-morfolin4-il)-9H-purin-2-il]-morfolin-2-il} -metanol 1H RMN (600 MHz, DMSO-d6): 12.87 (s, 1H), 11.28 (br. s., 1H), 7.65 (d, 1H), 7.45 (d, 2H), 7.25 (br. s., 1H), 7.15 (t, 1H), 5.7-4.9 (m, 2H), 4.80 (t, 1H), 4.53 (d, 1H), 4.36 (d, 1H), 4.00 (d, 1H), 3.91 (d, 1H), 3.80 (d, 1H), 3.73 (d, 1H), 3.60 -3.46 (m, 3H), 3.44 3.36 (m, 3H), 2.90 (t, 1H), 2.58 -2.64 (m, 1H), 1.35 (d, 3H) Método 1 Tiempo de Retención:0.82 min Masa (ES+): 450.3
26
{(R)-4-[8-(1H-Indol-4-il)-6-((R)-3-metil-morfolin4-il)-9H-purin-2-il]-morfolin-2-il} -metanol 1H RMN (600 MHz, DMSO-d6): 12.86 (s, 1H), 11.28 (br. s., 1H), 7.65 (d, 1H), 7.55 -7.43 (m, 2H), 7.27-7.23 (m, 1H), 7.15 (t, 1H), 5.7-5.0 (m, 2H), 4.81 (t, 1H), 4.52 (d, 1H), 4.42 -4.32 (m, 1H), 3.99 (d, 1H), 3.91 (d, 1H), 3.80 (d, 1H), 3.73 (d, 1H), 3.56 -3.38 (m, 6H), 2.93 -2.86 (m, 1H), 2.64 -2.58 (m, 1H), 1.33 (d, 3H) Método 1 Tiempo de Retención:0.83 min Masa (ES+): 450.3
43
Ejemplo Número
Estructura y Nombre 1H RMN LC/MS
27
5-[2,6-Bis-((S)-3-metil-morfolin-4-il)-9H-purin-8il]-piridin-2-ilamina 1H RMN (600 MHz, DMSOd6):12.72 (s, 1H), 8.58 (d, 1H), 7.97 (dd, 1H), 6.51 (d, 1H), 6.36 (s, 2H), 6.0-4.5 (brs, 2H), 4.52 (dd, 1H), 4.16 (dd, 1H), 4.0-3.0 (brs, 1H), 3.96 (dd, 1H), 3.90 (dd, 1H), 3.76 (d, 1H), 3.72-3.64 (m, 2H), 3.60 (dd, 1H), 3.52 (ddd, 1H), 3.44 (ddd, 1H), 3.09 (ddd, 1H), 1.29 (d,3H) 1.17 (d,3H) Método 1 Tiempo de Retención:0.73 min Masa (ES+): 411.3
28
5-[2,6-Bis-((R)-3-metil-morfolin-4-il)-9H-purin-8il]-piridin-2-ilamina 1H RMN (600 MHz, DMSOd6):12.72 (s, 1H), 8.58 (d, 1H), 7.97 (dd, 1H), 6.51 (d, 1H), 6.36 (s, 2H), 6.0-4.5 (brs, 2H), 4.52 (dd, 1H), 4.16 (dd, 1H), 4.0-3.0 (brs, 1H), 3.96 (dd, 1H), 3.90 (dd, 1H), 3.76 (d, 1H), 3.72-3.64 (m, 2H), 3.60 (dd, 1H), 3.52 (ddd, 1H), 3.44 (ddd, 1H), 3.09 (ddd,1H), 1.29 (d,3H) 1.17 (d,3H) Método 1 Tiempo de Retención:0.73 min Masa (ES+): 411.3
29
5-[2,6-Bis-((R)-3-metil-morfolin-4-il)-9H-purin-8il]-pirimidin-2-il-amina H NMR (600 MHz, DMSO-d6): 12.84 (s, 1 H), 8.80 (s, 2H), 7.08 (s, 2H), 6.0-4.5 (brs, 2H), 4.49 (dd, 1H), 4.14 (d, 1H), 4.0-3.0 (brs, 1H), 3.94 (dd, 1H), 3.88 (dd, 1H), 3.74 (d, 1H), 3.71-3.63 (m, 2H), 3.58 (dd, 1H), 3.50 (ddd, 1H), 3.42 (ddd, 1H), 3.07 (ddd, 1H), 1.27 (d,3H) 1.15 (d,3H) Método 1 Tiempo de Retención:0.78 min Masa (ES+): 412.3
30
8-[4-(1H-Imidazol-2-il)-fenil]-2,6-bis-((S)-3metil-morfolin-4-il)-9H-purina 1H RMN (600 MHz, DMSOd6):13.82 (brs, 1H), 13.11 (s, 1H), 8.17 (d, 2H), 8.05 (d, 2 H), 7.47 (s, 2H), 6.0-4.5 (brs, 2H), 4.55 (dd, 1H), 4.20 (d, 1H), 4.0-3.0 (brs, 1H), 3.99 (dd, 1H), 3.92 (dd, 1H), 3.79 (d, 1H), 3.74-3.66 (m, 2H), 3.61 (dd, 1H), 3.55 (ddd, 1H), 3.45 (ddd, 1H), 3.12 (ddd, 1H), 1.33 (d, 3 H), 1.19 (d,3H) Método 1 Tiempo de Retención:0.76 min Masa (ES+): 461.3
44

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