ES2609040T3 - Aminopirimidinas como inhibidores de Syk - Google Patents
Aminopirimidinas como inhibidores de Syk Download PDFInfo
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- ES2609040T3 ES2609040T3 ES10801736.9T ES10801736T ES2609040T3 ES 2609040 T3 ES2609040 T3 ES 2609040T3 ES 10801736 T ES10801736 T ES 10801736T ES 2609040 T3 ES2609040 T3 ES 2609040T3
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- free base
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Abstract
Un compuesto de formula (I) o una sal farmaceuticamente aceptable del mismo:**Fórmula** en la que p es de 0 a 4; q es 0, 1 o 2; Cy se selecciona entre cicloalquilo C4-7, oxetanilo, pirrolidinilo, piperidinilo y azepanilo; R1 se selecciona entre H, alquilo C1-4, haloalquilo C1-4, cicloalquilo C3-6 y Oalquilo C1-4; R4 se selecciona entre H, alquilo C1-4 y cicloalquilo C3-4; Ry(a) es aminometilo, OH, OCH3, OCH2CH2OH, F, CN, CO2Ra(a), CONRb(a)Rc(a), NRa(a)Ra(a), NHC(O)alquilo C1-3 (opcionalmente sustituido con OH), NHC(O)NH2, NHSO2NH2, NHSO2alquilo C1-3 o NHSO2haloalquilo C1-3; Rz(a) se selecciona entre (A) alquilo C1-4 opcionalmente sustituido con uno a tres grupos seleccionados independientemente entre OH, NH2, CN, CO2Ra(a) y CONH2, (B) fluoroalquilo C1-3, (C) halogeno, (D) CN, (E) COalquilo C1-4 (opcionalmente sustituido con uno o dos grupos seleccionados independientemente entre ORa(a), CN, CO2Ra(a), CONRa(a)Ra(a) y NRa(a)Ra(a)), (F) CO-fenilo (opcionalmente sustituido con uno o dos grupos seleccionados independientemente entre etinilo, CO2Ra(a), CN, F y OH), (G) CO-cicloalquilo C3-6 (opcionalmente sustituido con OH o CO2Ra(a)), (H) alquil C0-3-CO2Ra(a), (I) -C(O)NRb(a)Rc(a), (J) -ORa(a), (K) -OC(O)Ra(a), (L) -NRb(a)Rc(a), (M) -NHC(O)alquilo C1-4 (opcionalmente sustituido con uno a tres OH o un CONRa(a)Ra(a)), (N) -NHSO2alquilo C1-3, (O) -NHSO2NH2, (P) oxo, (Q) 1,3,4-oxadiazol-2(3H)-ona, (R) 1,2,4-oxadiazol-5(4H)-ona, (S) SO2NH2, (T) SO2alquilo C1-3, (U) SO2haloalquilo C1-3 y (V) SO2Ph; Ra(a) es H o alquilo C1-4; Rb(a) y Rc(a) se seleccionan independientemente entre (A) H, (B) cicloalquilo C3-6 opcionalmente sustituido con OH, (C) heteroarilo seleccionado entre imidazolilo, piridilo e indolilo, (D) tetrahidrofuranilo, (E) bencilo, (F) fenilo opcionalmente sustituido con uno o dos grupos seleccionados independientemente entre (CH2)0-2OH y F, (G1) alquilo C1-4 y (G2) haloalquilo C1-4, en donde (G1) y (G2) estan cada uno opcionalmente sustituido con uno a tres grupos seleccionados independientemente entre (i) OH, (ii) cicloalquilo C3-6 opcionalmente sustituido con uno o dos grupos seleccionados independientemente entre alquilo C1-4, CONH2, CO2H y CH2OH, (iii) CONH2, (iv) SO2NH2, (v) SO2alquilo C1-4, (vi) heterociclilo monociclico de 4 a 7 miembros opcionalmente sustituido con uno o dos grupos seleccionados independientemente entre oxo, (CH2)0-2OH y alquilo C1-4, (vii) un heteroarilo de 5 o 6 miembros opcionalmente sustituido con uno o dos grupos seleccionados independientemente entre carboxi, (CH2)0-2OH y alquilo C1-4, (viii) CN, (ix) Oalquilo C1-4, (x) CO2H, (xi) NRa(a)C(O)alquilo C1-4, (xii) fenilo opcionalmente sustituido con uno o dos grupos seleccionados independientemente entre (CH2)0-2OH, SO2NH2, CF3, F y Cl, (xiii) 1-pirrolidinilo opcionalmente sustituido con oxo, (xiv) 1-imidazolidinilo opcionalmente sustituido con oxo, (xv) 1-piperidinilo opcionalmente sustituido con oxo y (xvi) 4-morfolinilo; o Rb(a) y Rc(a) junto con el atomo de nitrogeno al que estan unidos forman un heterociclo de 6 o 7 miembros que tiene de 0 a 1 heteroatomo adicional seleccionado entre N, O y S, en donde dicho heterociclo esta opcionalmente sustituido con uno o dos grupos seleccionados independientemente entre oxo, CN, (CH2)0-2OH, acetilo, bencilo, SO2alquilo C1-4, CONH2, metoximetilo, carboximetilo, CO2Ra(a) y alquilo C1-4.
Description
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55
65
1-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2-il]ciclopropanocarboxamida; 4-{[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2-il]carbonil}piperazin-2-ona; 2-{[2-({3-metil-5-[2-(1,1,1-trifluoro-2-hidroxipropan-2-il)-1,3-tiazol-5-il]fenil}amino)-pirimidin-4-il]oxi}acetamida; 1-(5-{3-[(4-metoxipirimidin-2-il)amino]-5-metilfenil}-1,3-tiazol-2-il)ciclobutanol; 1-(5-{3-metil-5-[(4-metilpirimidin-2-il)amino]fenil}-1,3-tiazol-2-il)ciclobutanol; 1-{5-[3-metil-5-(pirimidin-2-ilamino)fenil]-1,3-tiazol-2-il}ciclobutanol; 1-(5-{3-[(4-ciclobutilpirimidin-2-il)amino]-5-metilfenil}-1,3-tiazol-2-il)ciclobutanol; 1-(5-{3-[(4-ciclopentilpirimidin-2-il)amino]-5-metilfenil}-1,3-tiazol-2-il)ciclobutanol; 1-(5-{3-[(4-ciclohexilpirimidin-2-il)amino]-5-metilfenil}-1,3-tiazol-2-il)ciclobutanol; 1-(5-{3-[(4-etoxipirimidin-2-il)amino]-5-metilfenil}-1,3-tiazol-2-il)ciclobutanol; 1-(5-{3-[(4-etoxipirimidin-2-il)amino]-5-metilfenil}-1,3-tiazol-2-il)ciclobutanol; 1-[5-(3-metil-5-{[4-(1-metiletoxi)pirimidin-2-il]amino}fenil)-1,3-tiazol-2-il]-ciclobutanol; cis-4-(aminometil)-1-(5-{3-metil-5-[(4-metilpirimidin-2-il)amino]fenil}-1,3-tiazol-2-il)ciclohexanol; trans-4-(aminometil)-1-(5-{3-metil-5-[(4-metilpirimidin-2-il)amino]fenil}-1,3-tiazol-2-il)ciclohexanol; 4-(aminometil)-1-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2-il]ciclohexanol; 4-(2-aminoetil)-1-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2-il]ciclohexanol; trans-4-(hidroximetil)-1-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]aminofenil)-1,3-tiazol-2-il]ciclohexanol; 4-(hidroximetil)-1-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2-il]ciclohexanol; cis-4-(hidroximetil)-1-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2-il]ciclohexanol; 4-(hidroximetil)-1-(5-{3-metil-5-[(4-metilpirimidin-2-il)amino]fenil}-1,3-tiazol-2-il)ciclohexanol; ácido 1-amino-4-hidroxi-4-(5-{3-metil-5-[(4-metilpirimidin-2-il)amino]fenil}-1,3-tiazol-2-il)ciclohexanocarboxílico; ácido cis-[3-hidroxi-1-metil-3-(5-{3-metil-5-[(4-metilpirimidin-2-il)amino]fenil}-1,3-tiazol-2-il)ciclohexil]acético; ácido trans-[3-hidroxi-1-metil-3-(5-{3-metil-5-[(4-metilpirimidin-2-il)amino]fenil}-1,3-tiazol-2-il)ciclohexil]acético; ácido {cis-4-hidroxi-4-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2-il]ciclohexil}acético; ácido {trans-4-hidroxi-4-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2-il]ciclohexil}acético; 3-hidroxi-3-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2-il]ciclohexanocarboxilato de etilo; ácido (1R)-{(3S)-3-hidroxi-1-metil-3-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2il]ciclohexil}acético; ácido (1R)-{(3R)-3-hidroxi-1-metil-3-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2il]ciclohexil}acético; 4-hidroxi-4-(5-{3-metil-5-[(4-metilpirimidin-2-il)amino]fenil}-1,3-tiazol-2-il)-2-fenilciclohexanocarboxilato de etilo; ácido 3-{4-hidroxi-4-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2-il]ciclohexil}-2,2dimetilpropanoico; 4-(dimetilamino)-1-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenol)-1,3-tiazol-2-il]ciclohexanol; 5-hidroxi-5-(5-{3-metil-5-[(4-metilpirimidin-2-il)amino]fenil}-1,3-tiazol-2-il)azepan-2-ona; ácido 5-{4-hidroxi-4-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2-il]piperidin-1-il}-5oxopentanoico; 2-metil 4-hidroxi-4-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2-il]piperidin-1,2-dicarboxilato de 1-tercbutilo; 4-hidroxi-4-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2-il]-2-(trifluorometil)piperidin-1carboxilato de tercbutilo; 4-hidroxi-2,3-dimetil-4-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2il]ciclohexanocarboxilato de etilo; (1S,4R)-3,3-dimetil-1-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenol)-1,3-tiazol-2-il]ciclohexano-1,4-diol; (1R,4S)-3,3-dimetil-1-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenol)-1,3-tiazol-2-il]ciclohexano-1,4-diol; 3-hidroxi-2,2-dimetil-3-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenol)-1,3-tiazol-2-il]ciclohexanona; cis-2,2-dimetil-1-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2-il]ciclohexano-1,3-diol; trans2,2-dimetil-1-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenol)-1,3-tiazol-2-il]ciclohexano-1,3-diol; (5S)-5-hidroxi-5-[5-(3-metil-5-{[4-(1-metiletil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2-il]azepan-2-ona; (5R)-5-hidroxi-5-[5-(3-metil-5-{[4-(1-metiletil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2-il]azepan-2-ona; cis-4-hidroxi-4-[5-(3-metil-5-{[4-(1-metiletil)pirimidin-2-il]amino}fenol)-1,3-tiazol-2-il]ciclohexanocarboxilato de tercbutilo; cis-4-hidroxi-4-[5-(3-metil-5-{[4-(1-metiletoxi)pirimidin-2-il]amino}fenil)-1,3-tiazol-2-il]ciclohexanocarboxilato de tercbutilo; ácido [cis-4-hidroxi-4-(5-{3-metil-5-[(4-metilpirimidin-2-il)amino]fenil}-1,3-tiazol-2-il)ciclohexil]acético; ácido [trans-4-hidroxi-4-(5-{3-metil-5-[(4-metilpirimidin-2-il)amino]fenil}-1,3-tiazol-2-il)ciclohexil]acético; ácido {4-hidroxi-4-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2-il]ciclohexil}acético; ácido (4-{4-hidroxi-4-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2-il]ciclohexil}fenil)acético; ácido 3-{4-hidroxi-4-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2-il]ciclohexil}propanoico; ácido cis3{4-hidroxi-4-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2il]ciclohexil}propanoico; ácido trans-3-{4-hidroxi-4-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2il]ciclohexil}propanoico; 3-{4-hidroxi-4-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2-il]ciclohexil}propanoato de etilo; ácido (1S,4R)-4-hidroxi-4-(5-{3-[(4-metoxipirimidin-2-il)amino]-5-metilfenil}-1,3-tiazol-2-il)-2,2dimetilciclohexanocarboxílico;
8
- 4B-11
- CF3 H +++ 395,0 Base Libre
- 4B-12
- CF3 CH3 +++ 409,1 Base Libre
- 4B-57
- CF3 CH3 +++ 535 Base Libre
TABLA 4C
- Ej.
- R1* X R3/R4 Actividad de rhSYK [M+H] + Obs. Forma(s)
- R2 = H
- 4C-1
- CF3 CH2CH2 H/H +++ 435,1 Base libre
- R2 = CH3
- 4C-2
- CH3 CH2 H/CH2NH2 (cis) +++ 410,2 Sal TFA
- 4C-3
- CH3 CH2 H/CH2NH2 (trans) +++ 410,2 Sal TFA
- 4C-4
- CF3 CH2 H/CH2NH2 +++, +++ 464,2 Base Libre Sal TFA
- 4C-5
- CF3 CH2 H/CH2CH2NH2 +++ 478,2 Sal TFA
- 4C-6
- CF3 CH2 H/CH2OH (trans) +++ 465,2 Base Libre
- 4C-7
- CF3 CH2 H/CH2OH +++ 465,2 Base Libre
- 4C-8
- CF3 CH2 H/CH2OH (cis) +++ 465,2 Base Libre
- 4C-9
- CH3 CH2 H/CH2OH +++ 411,2 Base Libre
- 4C-10
- CH3 CH2 NH2/CO2H +++ 440,0 Sal TFA
- 4C-11
- CH3 CH2 CH3/CH2CO2H (isómero 1) +++ 453,1 Sal TFA
- 4C-12
- CH3 CH2 CH3/CH2CO2H (isómero 2) +++ 453,1 Sal TFA
- 4C-14
- CF3 CH2 H/CH2CO2H (cis) +++ 493,1 Base Libre
- 4C-15
- CF3 CH2 H/CH2CO2H (trans) +++ 493,1 Base Libre
- 4C-17
- CH3 CH(iPr) H/CO2CH3 +++ 481,1 Base Libre
- 4C-21
- CF3 CH(CO2Et) H/H ++ 507,1, 507,2 Base Libre
- 4C-22
- CF3 C(CH3) (CH2CO2H) H/H (1R, 3S) +++ 507,1 Sal TFA
- 4C-23
- CF3 C(CH3) (CH2CO2H) H/H (1R, 3R) +++ 507,1 Sal TFA
- 4C-25
- CF3 CH(iPr) H/CO2CH3 ++ 535,0 Base Libre
- 4C-26
- CF3 CH2 H/CH2C(CH3)2CO2H +++ 535,2 Sal TFA
- 4C-33
- CF3 CH2 H/N(CH3)2 +++ 478 Sal formiato
- * R1 está en la posición 4 del anillo de pirimidina, a menos que se indique otra cosa.
TABLA 4D
49
- Ej.
- R1 R2 X R3 Actividad de rhSYK [M+H] + Obs. Forma(s)
- 4D-1
- CF3 H CH2 C(O)CH3 +++ 464,3 Base Libre
- 4D-4
- CF3 H CH2 CO2Et +++ 494,1 Base Libre
- 4D-5
- CF3 H CH2 iPr ++ 464,1 Base Libre
- 4D-6
- CF3 H CH2 C(O)Ph +++ 526,1 Base Libre
- 4D-7
- CH3 CH3 CH2C(O) (se formó la lactama) H +++ 410,2 Base Libre
- 4D-13
- CF3 CH3 CH2 C(O)(CH2)3CO2H +++ 550,1 Sal Formiato
- 4D-14
- CF3 CH3 CH(CO2CH3) CO2C(CH3)3 ++ 594,1 Base Libre
- 4D-15
- CF3 CH3 CH(CF3) CO2C(CH3)3 ++ 604,1 Base Libre
Ejemplo 6 (Referencia)
2,2,2-trifluoro-1-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2-il]etanol
Etapa 1: Se añadió lentamente el INTERMEDIO 4 (500 mg, 1,487 mmol) en THF (7,4 ml) a LDA (1,8 M, 2478 µl, 4,46 mmol) enfriado previamente a -78 ºC durante 5 min con agitación. La mezcla de reacción se dejó en
10 agitación durante 30 min y después se trató con trifluoroacetato de etilo (0,27 ml, 2,2 mmol). Después de 1 h, la reacción se interrumpió añadiendo 5 ml de una solución acuosa saturada de NH4Cl, y la mezcla se calentó a temperatura ambiente. La mezcla se extrajo con acetato de etilo, y se lavó con una solución saturada de NaHCO3. La capa orgánica se secó sobre Na2SO4 anhidro, se filtró, se concentró y se purificó por cromatografía ultrarrápida para dar 2,2,2-trifluoro-1-[5-(3-metil-5- {[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2-il]etano
15 1,1-diol (513 mg, 1,139 mmol, rendimiento del 77 %) en forma de un aceite incoloro. APCI: [M + H]+ m/z 451,0. Etapa 2: Se añadió borohidruro sódico (41,6 mg, 1,099 mmol) al producto de la Etapa 1 (450 mg, 0,999 mmol) en MeOH (3,3 ml) a 0 ºC. Después de agitar durante 3 h, la reacción se vertió en un embudo de decantación que contenía acetato de etilo y NaHCO3 acuoso saturado. Las capas se separaron y la capa orgánica se lavó con agua y salmuera, se secó sobre sulfato sódico anhidro y se concentró. El residuo se purificó por cromatografía
50
- 33A-14
- 4-CF3 CH3 CO2Me/NHC(O)CH3 +++ 550,1 Base Libre
- 33A-15
- 4-CF3 CH3 CO2H/NHC(O)CH3 +++ 536,1 Sal TFA
- 33A-16
- 4-CF3 CH3 H/CH2CO2H (trans) +++ 493 Sal formiato
- 33A-18
- 4-CF3 CH3 H/CH2CH2CO2H +++ 507,2 Base Libre
- 33A-19
- 4-CF3 CH3 H/CH2CH2CO2H (cis) +++ 507,2 Base Libre
- 33A-20
- 4-CF3 CH3 H/CH2CH2CO2H (trans) +++ 507,2 Base Libre
- 33A-21
- 4-CF3 CH3 H/CH2CH2CO2CH2C H3 +++ 535,2 Base Libre
- 33A-22
- 4-CF3 CI H/CO2H (trans) +++ 499,1 Base Libre
- 33A-23
- 4-CF3 H H/CO2H (trans) +++ 465,0 Base Libre
- 33A-24
- 4-CF3 H H/CO2H (cis) +++ 465,0 Base Libre
- 33A-25
- 4-CF3 H H/CO2Et (cis) +++ 493,1 Base Libre
- 33A-26
- 4-CF3 H H/CO2Et (trans) ++ 493,1 Base Libre
- 33A-27
- 4-CF3 H CH3/CO2H (trans) +++ 479,1 Base Libre
- 33A-28
- 4-CF3 H CH3/CO2H (cis) +++ 479,1 Base Libre
- 33A-29
- 4-iPr CH3 H/CO2C(CH3)3 (cis) ++ 509,2 Base Libre
- 33A-30
- 4-CH3 CH3 H/CO2H (cis) +++ 425,1 Base Libre
- 33A-31
- 4-CH3 CH3 H/CO2H (trans) +++ 425,1 Base Libre
- 33A-32
- 4-CH3 CH3 H/CH2CO2H (cis) +++ 439,1 Base Libre
- 33A-33
- 4-CH3 CH3 H/CH2CO2H (trans) +++ 439,0 Base Libre
- 33A-34
- 4-O-iPr CH3 H/CO2C(CH3)3 (cis) ++ 525,2 Base Libre
- 33A-35
- 4-OCH3 CH3 H/CO2H (cis) +++ 441,1 Base Libre
- 33A-36
- 4-OCH3 CH3 H/CO2H (trans) +++ 441,1 Base Libre
- 33A-37
- 4-OCH3 CH3 CH3/CO2H (cis) +++ 455,1 Base Libre
- 33A-38
- 4-OCH3 CH3 CH3/CO2H (trans) +++ 455,1 Base Libre
- Fórmula B; R5 = H
- 33A-54
- CF3 CH3 H/CO2H (trans) +++ 507 Base Libre
- 33A-59
- CF3 c-Pr H/CO2H (enantiómero 1) +++ 533,2 Base Libre
- 33A-60
- CF3 c-Pr H/CO2H (enantiómero 2) +++, +++ 533,2 Base Libre, Sal TFA
- 33A-61
- CF3 c-Pr H/CO2CH3 +++ 547,2 Base Libre
- 33A-62
- CF3 c-Pr H/CO2H +++ 533,2 Sal TFA
- 33A-65
- CF3 H H/CO2CH3 ++ 507,1 Base Libre
- 33A-66
- CF3 H H/CO2H (cis, enantiómero 1) +++ 493 Base Libre
- 33A-67
- CF3 H H/CO2H (cis, enantiómero 2) +++ 493 Base Libre
- 33A-68
- CH3 CH3 H/CO2H (cis) +++ 452,1 Base Libre
- 33A-69
- CH3 CH3 H/CO2CH3 (cis) +++ 467,2 Base Libre
- 33A-70
- c-Pr CH3 H/CO2CH3 +++ 493,2 Base Libre
- 33A-71
- c-Pr CH3 H/CO2H +++ 479,2 Base Libre
- 33A-72
- OCH3 CH3 H/CO2H (isómero 1) +++ 469,1 Base Libre
- 33A-73
- OCH3 CH3 H/CO2H (isómero 2) +++ 469,1 Base Libre
- Fórmula B; R5 = CH3
- 33A-75
- CF3 CH3 H/CO2H +++ 521 Base Libre
- 33A-76
- CF3 CH3 H/CO2H (isómero 1) +++ 521 Base Libre
- 33A-77
- CF3 CH3 H/CO2H (isómero 2) +++ 521 Base Libre
- 33A-78
- CF3 CH3 H/CO2H (isómero 3) +++ 521 Base Libre
TABLA 33B
60
- Ej.
- X Y R3/R4 Actividad de rhSYK [M+H]+ Obs. Forma(s)
- R1 = CF3, R5 = H
- 33B-1
- Enlace Enlace H/CO2H +++ 451,0 Sal amonio
- 33B-3
- C(CH3)2 Enlace H/CO2H +++ 493 Base Libre
- 33B-4
- C(CH3)2 Enlace H/CO2H (isómero 2) +++ 493 Base Libre
- 33B-5
- C(CH3)2 Enlace H/CO2H (isómero 4) +++ 493 Base Libre
- 33B-6
- C(CH3)2 Enlace H/CO2H (isómero 1) +++ 493 Base Libre
- 33B-7
- C(CH3)2 Enlace H/CO2H (isómero 3) +++ 493 Base Libre
- 33B-8
- C(CH3)2 CH2CH2 H/CO2H +++ 521 Base Libre
- 33B-9
- C(CH3)2 CH2CH2 H/CO2H (isómero 1) +++ 521 Base Libre
- 33B-10
- C(CH3)2 CH2CH2 H/CO2H (isómero 2) +++ 521 Base Libre
- 33B-11
- C(CH3)2 CH2CH2 H/CO2H (isómero 3) +++ 521 Base Libre
- 33B-12
- C(CH3)2 CH2CH2 H/CO2H (isómero 4) +++ 521 Base Libre
- 33B-13
- CH(OCH3) CH2 H/CO2H +++ 509 Base Libre
- 33B-14
- CH(OCH3) CH2 H/CO2H (cis,cis) +++ 509 Base Libre
- 33B-18
- CH(CH3) CH2 H/CO2H (isómero 1) +++ 493,1 Base Libre
- 33B-19
- CH(CH3) CH2 H/CO2H (isómero 2) +++ 493,2 Sal TFA
- 33B-20
- CH(CH3) CH2 H/CO2H (isómero 3) +++, +++ 493,1 Base Libre, Sal TFA
- 33B-21
- CH(CO2H) CH2 H/H +++ 479,1 Base Libre
- 33B-24
- CH(iPr) CH2 H/CO2H +++ 521 Base Libre
- 33B-22
- CH(iPr) CH2 H/CO2H (enantiómero 1) +++ 521 Base Libre
- 33B-23
- CH(iPr) CH2 H/CO2H (enantiómero 2) +++ 521 Base Libre
- 33B-24
- CH2 enlace H/CO2H +++ 465,0 Sal amonio
- 33B-25
- CH2 enlace H/CH2CO2H (trans, enantiómero 1)) +++ 479 Base Libre
- 33B-26
- CH2 enlace H/CH2CO2H (cis, enantiómero 1) +++ 479 Base Libre
- 33B-27
- CH2 enlace H/CH2 CO2H (trans, enantiómero 2) +++ 479 Base Libre
- 33B-28
- CH2 enlace H/CH2CO2H (cis, enantiómero 2) +++ 479 Base Libre
- R1 = CH3, R5 = H
- 33B-32
- CH(CH3) CH2 H/CO2H (isómero 1) +++ 439,2 Base Libre
- 33B-33
- CH(CH3) CH2 H/CO2H (isómero 2) +++ 439,2 Base Libre
- 33B-34
- CH(iPr) CH2 H/CO2H +++ 467 Base Libre
- 33B-35
- CH(iPr) CH2 H/CO2H (isómero 1) +++ 467 Base Libre
- 33B-36
- CH(iPr) CH2 H/CO2H (isómero 2) +++ 467 Base Libre
- 33B-37
- CH(Ph) CH2 H/CO2H +++ 501 Base Libre
- R1 = CF3, R5 = CH3
- 33B-38
- CH(CH3) CH2 H/CO2H (isómero 1) +++ 507 Sal TFA
- 33B-39
- CH(CH3) CH2 H/CO2H (isómero 2) +++ 507 Base Libre
- R1 = CF3, R5 = CH2CH3
- 33B-40
- CH(CH3) CH2 H/CO2H +++ 521 Sal TFA
- 33B-41
- CH(CH3) CH2 H/CO2H (isómero 1) +++ 521 Sal TFA
- 33B-42
- CH(CH3) CH2 H/CO2H (isómero 2) +++ 521 Sal TFA
Ejemplo 34 (Referencia)
4-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2-il]ciclohex-3-eno-1-carboxilato de etilo 61
Etapa 3: A 4-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2-il]ciclohexanocarboxilato de etilo (0,60 g, 0,12 mmol) en tetrahidrofurano (0,61 ml) se le añadió hidróxido potásico (1,2 ml, 1 M en metanol) y la 5 reacción se agitó durante una noche a temperatura ambiente. Tras la finalización, la reacción se diluyó con diclorometano y se lavó dos veces con ácido clorhídrico (2 M en agua). La capa orgánica se secó a presión reducida para dar cloruro de 2-({3-[2-(4-carboxiciclohexil)-1,3-tiazol-5-il]-5-metilfenil}amino)-4-(trifluorometil)pirimidin-1-io (0,060 g, rendimiento del 85 %). MS ESI: [M+H]+ m/z 463,1. 1H RMN (500 MHz, DMSO-d6) δ 10,25 (s, 1H), 8,83 (d, J = 5,2, 1H), 8,06 - 7,81 (m, 2H), 7,44 (s, 1H), 7,27 (d, J = 5,8, 1H), 7,14 (s, 1H), 2,30 (s, 3H), 2,14 -2,04 (m, 1H), 2,03
10 - 1,83 (m, 4H), 1,82-1,61 (m, 3H), 1,55 -1,33 (m, 2H). Actividad de rhSYK = +++
Los siguientes ejemplos se prepararon de una manera análoga a la descrita en los Ejemplos 34-36.
TABLA 36A
- Ejemplo
- R1 X R2/R2' o R2+R2' --- Actividad de rhSYK [M+H] + Obs. Forma(s)
- R3 = R3' = H
- 36A-2
- CH3 CHCO2Et H/H individual ++ 491,1 Base Libre
- 36A-4
- H CHCO2H (trans) H/H individual +++ 449,1 Base Libre
- 36A-5
- H CHCO2Me (trans) H/H individual ++ 463,1 Base Libre
- 36A-8
- CH3 CH2 =O individual +++ 433,1 Base Libre
- 36A-10
- CH3 CH2CH2 =O individual +++ 447,1 Base Libre
TABLA 36B
- Ejemplo
- R Actividad de rhSYK [M+H]+ Obs. Forma(s)
- 36B-1
-
imagen59 +++ 434,1 Base Libre
- 36B-3
- +++ 448,1 Base Libre
63
{[4-hidroxi-4-(5-{3-[(4-metoxipirimidin-2-il)amino]-5-metilfenil}-1,3-tiazol-2-il)piperidin-1-il]sulfonil}carbamato de metilo (7 mg, 0,013 mmol, 10 %). MS ESI: [M + H]+ m/z 535,1. 1H RMN (600 MHz, CD3OD): δ 8,09 (d, J = 6,0 Hz, 1H); 7,91 (s, 1H); 7,88 (s, 1H); 7,38 (s, 1H); 7,08 (s, 1H); 6,23 (d, J= 6,0 Hz, 1H); 3,98 (s, 3H); 3,73 (m, 3H); 3,34 (m, 2H); 3,19 (m, 2H); 2,35 (s, 3H); 2,25 (m, 2H); 1,90 (m, 2H). Actividad de rhSYk = +++
5 4-Cloro-4-(5-{3-[(4-metoxipirimidin-2-il)amino]-5-metilfenil}-1,3-tiazol-2-il)piperidin-1-sulfonamida (18 mg, 0,036 mmol, 28 %). MS ESI: [M + H]+ m/z 495,2. 1H RMN (500 MHz, CD3OD): δ 8,09 (d, J = 6,0 Hz, 1H); 7,89 (s, 2H); 7,38 (s, 1H); 7,09 (s, 1H); 6,24 (d, J = 6,0 Hz, 1H); 4,37 (m, 1H); 3,99 (s, 3H); 3,97 (m, 1H); 3,68 (m, 1H); 3,36 (m, 1H); 2,35 (s, 3H); 2,19 (m, 2H); 1,94 (m, 2H). Actividad de rhSYK = +++
10 Los siguientes ejemplos se prepararon de una manera análoga a la descrita en los Ejemplos 47-54 para urea N,Ndisustituida (Ejemplo 47), t-butil carbamato de sulfamoílo disustituido (Ejemplo 48), diamida sulfúrica N,N,N'trisustituida (Ejemplo 49), sulfonamida N,Ndisustituida o ácido sulfámico (Ejemplo 50), amida (Ejemplo 51), urea N,N,N'-trisustituida (Ejemplo 52), azetidina Nalquilada, pirrolidina, piperidina o azepano (Ejemplo 53), y carbamato de sulfamoílo N,N,N'-trisustituido (Ejemplo 54).
15 TABLA 54A
- EJ.
- R1 R2 Actividad de rhSYK [M+H]+ Observado Forma(s)
- N = 1
- 54A-1
- CF3 -SO2-IPR +++ 542,1 Sal formiato
- 54A-2
- CF3 -SO2-CF3 +++ 568,1 Sal formiato
- 54A-4
- CF3 -C(O)ET +++ 492,1 Sal formiato
- 54A-5
- CF3 -C(O)CH2OH +++ 494,1 Sal formiato
- 54A-6
- CF3 -C(O)CH2CN +++ 503,1 Sal formiato
- 54A-7
- CF3 -C(O)CH2N(CH3)2 +++ 521,2 Sal formiato
- 54A-11
- CF3 -C(O)-C-PR +++ 504,1 Sal formiato
- 54A-12
- CF3 -C(O)NHC-HEX +++ 561,2 Sal formiato
- 54A-13
- CF3 -C(O)NH-IPR +++ 521,2 Sal formiato
- 54A-14
- CF3 -C(O)NH-NPR +++ 521,2 Sal formiato
- 54A-15
- CF3 -C(O)N(CH3)2 +++ 507,1 Base Libre
- 54A-16
- CF3 -SO2NH2 +++ 515,2 Base Libre
- 54A-19
- OCH3 -C(O)NH2 +++ 441,2 Base Libre
- 54A-20
- OCH3 H +++ 398,2 Base Libre
- 54A-21
- CF3 -C(O)CH(OH)CH3 (R) +++ 508,2 Sal formiato
- 54A-22
- CF3 -C(O)CH2CH2OH +++ 508,2 Base Libre
- 54A-23
- CF3 -C(O)CH2CH2CN +++ 517,2 Sal formiato
- 54A-24
- CF3 -CH2CF3 +++ 518,1 Base Libre
- 54A-25
- CF3 -C(O)CH2C(O)NH2 +++ 521,2 Sal formiato
- 54A-26
- CF3 -C(O)CH2C(O)2H +++ 522,1 Base Libre
- 54A-27
- CF3 -C(O)CH2CH(OH)CH3 +++ 522,2 Base Libre
- 54A-33
- CF3 -C(O)-(3-OH-CBU) +++ 534,2 Sal formiato
- 54A-34
- CF3 -C(O)-PH +++ 540,2 Sal formiato
- 54A-43
- CF3 -C(O)CH2-CO2ET +++ 550,2 Base Libre
- 54A-44
- CF3 -C(O)C(CH2OH)2CH3 +++ 552,2 Sal formiato
- 54A-54
- CF3 -C(O)-(1-CO2CH3)-CPR +++ 562,2 Base Libre
- 54A-55
- CF3 -C(O)-(4-C≡CH)PH +++ 564,2 Sal formiato
- 54A-56
- CF3 -C(O)-(4-CN)PH +++ 565,2 Sal formiato
- 54A-57
- CF3 -C(O)-(3-F, 4-OH)PH +++ 574,2 Sal formiato
- 54A-59
- CF3 -C(O)-(4-CO2CH3)PH +++ 604,2 Sal formiato
- 54A-61
- CF3 (CH2)3CH3 +++ 535,2 Base Libre
78 TABLA 54B
- 54A-70
- CF3 CH2CO2CH3 +++ 508,2 Base Libre
- 54A-71
- CF3 CH2CH2CO2CH3 +++ 522,2 Base Libre
- 54A-72
- CF3 CH(CH3)CO2CH3 +++ 522,2 Base Libre
- 54A-73
- CF3 (CH2)3CO2CH3 +++ 536,2 Base Libre
- N = 2
- 54A-74
- CF3 CH3 +++ 507,2 Base Libre
- 54A-75
- CF3 CH3 (Enantiómero 1) +++ 507,2 Base Libre
- 54A-76
- CF3 CH3 (Enantiómero 2) +++ 507,2 Base Libre
- 54A-78
- CF3 CH2CH2CH3 +++ 535,2 Base Libre
- 54A-79
- CF3 CH(CH3)2 +++ 535,2 Base Libre
- 54A-80
- CF3 CH2CO2ET +++ 579,2 Base Libre
- 54A-81
- CF3 (CH2)3CO2ET +++ 607,2 Sal TFA
- 54A-82
- CF3 CH2CH2F +++ 496,2 Sal TFA
- 54A-83
- CF3 CH2CO2H ++ 508,2 TFA SALT
- 54A-84
- CF3 CH2CH2CO2H +++ 522,2 Base Libre
- 54A-85
- CF3 CH2CF3 (Enantiómero 1) +++ 532,2 Base Libre
- 54A-86
- CF3 CH2CF3 (Enantiómero 2) +++ 532,2 Base Libre
- 54A-87
- CF3 CH2CF3 +++ 532,2 Sal TFA
- 54A-88
- CF3 CH2CH2CO2CH3 +++ 536,2 Sal formiato
- 54A-89
- CF3 CH2CO2C(CH3)3 +++ 564,2 Base Libre
- EJ.
- R1 R2 Actividad de rhSYK [M+H]+ Observado Forma(s)
- X = CH2
- 54B-2
- CF3 -C(O)NH2 (Enantiómero 1) +++ 465,1 Base Libre
- 54B-3
- CF3 -C(O)NH2 (Enantiómero 2) +++ 465,1 Base Libre
- 54B-4
- CF3 -C(O)O-TBU ++ 522,2 Base Libre
- 54B-5
- CF3 H +++ 422,2 Base Libre
- 54B-6
- CF3 -SO2NH2 +++ 501,1 Base Libre
- 54B-7
- CF3 -C(O)NH2 +++ 465,1 Base Libre
- 54B-10
- OCH3 -C(O)NH2 +++ 427,2 Base Libre
- 54B-11
- OCH3 H +++ 384,2 Base Libre
- 54B-12
- CH3 H +++ 368,2 Base Libre
- 54B-13
- CH3 -C(O)NH2 (racémico) +++ 411,2 Base Libre
- 54B-14
- CH3 -C(O)NH2 (enantiómero 1) +++ 411,2 Base Libre
- 54B-15
- CH3 -C(O)NH2 (enantiómero 2) +++ 411,2 Base Libre
- 54B-19
- CF3 CH2CH2OH +++ 466,1 Sal TFA
- 54B-20
- CF3 CH2C(O)NH2 +++ 479,1 Sal TFA
- 54B-21
- CF3 -C(O)CH2OH +++ 480,1 Sal TFA
- 54B-22
- CF3 -CH2CO2H +++ 480,2 Sal TFA
- 54B-24
- CF3 -CH2CO2CH3 +++ 494,2 Base Libre
- 54B-26
- CF3 -C(O)CH2C(O)NH2 +++ 507,2 Sal TFA
- 54B-28
- CF3 -C(O)CH(OH)CH2OH +++ 510,2 Sal TFA
- 54B-30
- CF3 -C(O)-(1-OH)-C-BU +++ 520,2 Sal TFA
- X = CHCO2H 54B-36) O CHCO2CH3 (54B-37)
- 54B-36
- CF3 CONH2 +++ 509,2 Sal TFA
- 54B-37
- CF3 CONH2 +++ 523,2 Base Libre
TABLA 54C
79 TABLA 54D
- EJ.
- R2 Actividad de rhSYK [M+H]+ Observado Forma(s)
- 54C-1
- H +++ 408,2 Base Libre
- 54C-2
- -C(O)NH2 +++ 451,1 Base Libre
- EJ.
- R1 R2 Actividad de rhSYK [M+H]+ Obs. Forma(s)
- 54D-1
- IPR H +++ 424,2 Base Libre
- 54D-2
- CF3 -C(O)CH3 +++ 492,2 Base Libre
- 54D-3
- IPR -(S)-C(O)CH(OH)CH3 +++ 496,2 Base Libre
- 54D-4
- IPR -C(O)CH(OH)CH3 +++ 496,2 Base Libre
- 54D-5
- CF3 -C(O)ET +++ 506,2 Base Libre
- 54D-6
- IPR -C(O)CH2C(O)NH2 +++ 509,2 Base Libre
- 54D-7
- IPR -C(O)CH2CO2H +++ 510,2 Base Libre
- 54D-8
- IPR -C(O)CH(OH)CH2OH +++ 512,2 Base Libre
- 54D-9
- CF3 -C(O)CH2CN +++ 517,2 Base Libre
- 54D-10
- CF3 -C(O)-CPR +++ 518,2 Base Libre
- 54D-12
- CF3 -C(O)CH2OCH3 +++ 522,2 Base Libre
- 54D-13
- CF3 -C(O)CH2CH2OH +++ 522,2 Sal formiato
- 54D-14
- CF3 -C(O)CH(OH)CH3 +++ 522,2 Sal formiato
- 54D-15
- IPR -C(O)CH2CH2C(O)NH2 +++ 523,2 Base Libre
- 54D-16
- CF3 -C(O)CH2CH2CN +++ 531,2 Base Libre
- 54D-20
- CF3 -C(O)CH2C(O)NH2 (enantiómero 1) +++ 535,2 Base Libre
- 54D-21
- CF3 -C(O)CH2C(O)NH2 (enantiómero 2) +++ 535,2 Base Libre
- 54D-22
- CF3 -C(O)CH2C(O)NH2 +++ 535,2 Base Libre
- 54D-23
- CF3 -C(O)CH2CH(OH)CH3 +++ 536,2 Sal formiato
- 54D-24
- CF3 -C(O)CH2CO2H +++ 536,2 Sal formiato
- 54D-25
- CF3 -C(O)CH2CO2H (Enantiómero 1) +++ 536,2 Base Libre
- 54D-26
- CF3 -C(O)CH2CO2H (Enantiómero 2) +++ 536,2 Base Libre
- 54D-27
- CF3 -C(O)CH(OH)CH2OH +++ 538,2 Sal formiato
- 54D-28
- CF3 -C(O)CH(OH)CH2OH (isómero 1) +++ 538,2 Sal formiato
- 54D-29
- CF3 -C(O)CH(OH)CH2OH (isómero 2) +++ 538,2 Sal formiato
- 54D-30
- IPR -C(O)CH2CO2ET +++ 538,2 Base Libre
- 54D-31
- IPR -C(O)C(CH2OH)2CH3 +++ 540,3 Sal TFA
- 54D-41
- CF3 -C(O)CH2CH2C(O)NH2 (enantiómero 1) +++ 549,2 Sal TFA
- 54D-42
- CF3 -C(O)CH2CH2C(O)NH2 (enantiómero 2) +++ 549,2 Sal TFA
80 TABLA 54E
- 54D-43
- CF3 -C(O)CH2CH2CO2H +++ 550,2 Sal TFA
- 54D-44
- CF3 -C(O)CH2C(CH3)2OH +++ 550,2 Sal formiato
- 54D-45
- CF3 -C(O)-PH +++ 554,2 Base Libre
- 54D-70
- CF3 -C(O)-(1-CO2H-CPR) +++ 562,2 Sal formiato
- 54D-71
- CF3 -C(O)-(2-CO2H-CPR) +++ 562,2 Sal formiato
- 54D-72
- CF3 -C(O)CH2CH2CO2CH3 +++ 564,2 Base Libre
- 54D-73
- CF3 -C(O)CH2CO2CH2CH3 +++ 564,2 Sal formiato
- 54D-74
- CF3 -C(O)CH2CO2CH2CH3 (enantiómero 1) +++ 564,2 Base Libre
- 54D-75
- CF3 -C(O)CH2CO2CH2CH3 (enantiómero 2) +++ 564,2 Base Libre
- 54D-77
- CF3 -C(O)CH(OH)C(CH3)2OH +++ 566,2 Sal formiato
- 54D-78
- CF3 -C(O)C(CH2OH)2CH3 +++ 566,2 Base Libre
- 54D-79
- CF3 -C(O)C(CH2OH)2CH3 (enantiómero 1) +++ 566,2 Sal TFA
- 54D-80
- CF3 -C(O)C(CH2OH)2CH3 (enantiómero 2) +++ 566,2 Sal TFA
- 54D-84
- CF3 -C(O)-(4-OH)PH +++ 570,2 Base Libre
- 54D-95
- CF3 -C(O)-(1-CO2CH3)-CPR +++ 576,2 Sal formiato
- 54D-98
- CF3 -C(O)CH2CH2C(O)N(CH3)2 +++ 577,2 Base Libre
- 54D-99
- CF3 -C(O)-(4-C≡CH)PH +++ 578,2 Base Libre
- 54D103
- CF3 -C(O)-(3-F, 4-OH)PH +++ 588,2 Base Libre
- 54D104
- CF3 -C(O)-(2-F, 5-OH)PH +++ 588,2 Base Libre
- 54D111
- CF3 -C(O)-(4-CO2CH3)-CHEX +++ 618,2 Base Libre
- 54D113
- IPR -C(O)CH2C(O)NH2 +++ 509,2 Sal TFA
- 54D115
- CF3 SO2NH2 +++ 529,1 Sal TFA
- 54D116
- CF3 SO2NH2 (Enantiómero 1) +++ 529,1 Base Libre
- 54D117
- CF3 SO2NH2 (Enantiómero 2) +++ 529,1 Base Libre
- 54D119
- CF3 C(O)NH2 (Enantiómero 1) +++ 493,1 Base Libre
- 54D120
- CF3 C(O)NH2 (Enantiómero 2) +++ 493,1 Base Libre
- 54D121
- CF3 C(O)CH2OH +++ 508,2 Base Libre
- 54D122
- CF3 C(O)CH2OH (Enantiómero 1) +++ 508,1 Base Libre
- 54D123
- CF3 C(O)CH2OH (Enantiómero 2) +++ 508,1 Base Libre
- Ej.
- R Actividad de rhSYK [M+H]+ Observado Forma(s)
- 54E-1
- CH(OH)CH3 (2R; cis) +++ 522,2 Sal formiato
- 54E-2
- CH(OH)CH3 (2S; cis) +++ 522,2 Sal formiato
81
- 113A-4
- 4-CH3 CH3 H/CH3 (isómero 1) H +++ 439 Base Libre
- 113A-5
- 4-CH3 CH3 H/CH3 (isómero 2) H +++ 439 Base Libre
- 113A-6
- 4-CH3 CH3 H/CH3 (isómero 3) H +++ 439 Base Libre
- 113A-7
- 4-CH3 CH3 H/CH3 (isómero 4) H +++ 439 Base Libre
- 113A-8
- 4-CH3 CH3 H/CH3 (isómero 1) CH3 +++ 453 Base Libre
- 113A-9
- 4-CH3 CH3 H/CH3 (isómero 2) CH3 ++ 453 Base Libre
- 113A-10
- 4-CH3 CH3 H/CH3 (isómero 3) CH3 +++ 453 Base Libre
- 113A-11
- 4-CH3 CH3 H/CH3 (isómero 4) CH3 +++ 453 Base Libre
- 113A-12
- 4-CH3 CH3 H/CH3 (isómero 5) CH3 ++ 453 Base Libre
- 113A-13
- 4-CH3 CH3 H/CH3 (isómero 6) CH3 ++ 453 Base Libre
- 113A-14
- 4-Et CH3 H/CH3 (isómero 1) H +++ 453,1 Base Libre
- 113A-15
- 4-Et CH3 H/CH3 (isómero 2) H +++ 453,1 Base Libre
- 113A-16
- 4-OCH3 CH3 H/CH3 (1S,2R,4R) H +++ 455 Sal formiato
- 113A-17
- 4-OCH3 CH3 H/CH3 (1R,2S,4S) H +++ 455 Sal formiato
- 113A-20
- 4-cPr CH3 H/CH3 (1R,2S,4S) H +++ 465 Sal formiato
- 113A-21
- 4-cPr CH3 H/CH3 (1S,2R,4R) H +++ 465,1 Sal formiato
- 113A-22
- 4-cPr CH3 H/CH3 H +++ 465,2 Sal TFA
- 113A-23
- 4-CH3 cPr H/CH3 (isómero 1) H +++ 465,1 Base Libre
- 113A-24
- 4-CH3 cPr H/CH3 (isómero 2) H +++ 465,1 Base Libre
- 113A-25
- 4-iPr CH3 H/CH3 (1S,2R,4R) H +++ 467,2 Base Libre
- 113A-26
- 4-iPr CH3 H/CH3 (1R,2S,4S) H +++ 467,2 Base Libre
- 113A-31
- 4-Et CH3 H/CH3 (isómero 1) Et +++ 481,1 Base Libre
- 113A-32
- 4-Et CH3 H/CH3 (isómero 2) Et +++ 481,1 Base Libre
- 113A-35
- 4-O-iPr CH3 H/CH3 (1R,2S,4S) H +++ 483 Sal formiato
- 113A-45
- 4-CF3 CH3 H/CH3 Et ++ 535 Base Libre
- 113A-49
- 4-Et CH3 CH3/CH3 (1S, 4R) H +++ 467,1 Base Libre
- 113A-51
- 4-cPr CH3 CH3/CH3 (cis) H +++ 479 Base Libre
- 113A-52
- 4-iPr CH3 CH3/CH3 (cis) H +++ 481 Base Libre
- 113A-53
- 4-Et CH3 CH3/CH3 (1S, 4R) CH3 +++ 481,1 Base Libre
- 113A-54
- 4-OCH3 CH3 CH3/CH3 (1S, 4R) CH3 +++ 483,1 Base Libre
- 113A-55
- 4-OCH3 CH3 CH3/CH3 (1R, 4S) CH3 +++ 483,2 Base Libre
- 113A-56
- 4-cPr CH3 CH3/CH3 (cis) CH3 +++ 493 Base Libre
- 113A-64
- 4-CF3* CH3 CH3/CH3 (1S,4R) H +++ 508,0 Base Libre
- 113A-65
- 4-CF3* CH3 CH3/CH3 (1S,4R) CH3 +++ 522,1 Base Libre
- R4a/R4b = H/CH3
- 113A-66
- 4-CH3 CH3 H/CH3 (isómero 1) H +++ 453 Base Libre
- 113A-67
- 4-CH3 CH3 H/CH3 (isómero 2) H +++ 453 Base Libre
- 113A-68
- 4-CH3 CH3 H/CH3 (isómero 3) H +++ 453 Base Libre
- 113A-69
- 4-CH3 CH3 H/CH3 (isómero 4) H +++ 453 Base Libre
- 113A-70
- 4-CH3 CH3 H/CH3 (isómero 1) Et +++ 481 Base Libre
- 113A-71
- 4-CH3 CH3 H/CH3 (isómero 2) Et +++ 481 Base Libre
- 113A-72
- 4-CH3 CH3 H/CH3 (isómero 3) Et +++ 481 Base Libre
- 113A-73
- 4-CH3 CH3 H/CH3 (isómero 4) Et +++ 481 Base Libre
- 113A-74
- 4-CH3 CH3 H/CH3 (isómero 1) H +++ 507 Base Libre
- 113A-75
- 4-CH3 CH3 H/CH3 (isómero 2) H +++ 507 Base Libre
- 113A-76
- 4-CH3 CH3 H/CH3 (isómero 3) H +++ 507 Base Libre
- 113A-77
- 4-CF3 CH3 H/CH3 (isómero 1) Et +++ 535 Base Libre
- 113A-78
- 4-CF3 CH3 H/CH3 (isómero 2) Et +++ 535 Base Libre
- 113A-79
- 4-CF3 CH3 H/CH3 (isómero 3) Et +++ 535 Base Libre
- 113A-80
- 4-CH3 CH3 H/H H +++ 439 Base Libre
- 113A-81
- 4-CH3 CH3 H/H (isómero 1) H +++ 439 Base Libre
- 113A-82
- 4-CH3 CH3 H/H (isómero 2) H +++ 439 Base Libre
- 113A-83
- 4-CH3 CH3 H/H (isómero 3) H +++ 439 Sal TFA
- 113A-84
- 4-CH3 CH3 H/H (isómero 4) H +++ 439 Sal TFA
- 113A-85
- 4-CH3 CH3 H/H (isómero 5) H +++ 439 Sal TFA
- 113A-86
- 4-CH3 CH3 H/H (isómero 6) H +++ 439 Sal TFA
- 113A-87
- 4-CH3 CH3 H/H Et +++ 467 Base Libre
- 113A-88
- 4-CF3 CH3 H/H H +++ 493 Base Libre
- 113A-89
- 4-CF3 CH3 H/H Et +++ 521 Base Libre
- R4a/R4b = H/OH
- 113A-90
- 4-CH3 CH3 H/H (isómero 1) H +++ 441 Base Libre
- 113A-91
- 4-CH3 CH3 H/H (isómero 2) H +++ 441 Base Libre
- R4a/R4b = CH3/CH3
95 TABLA 113B
- 113A-92
- 4-CH3 CH3 H/H H +++ 453 Base Libre
- * deuterado en la posición 6 de pirimidina
- Ejemplo
- R1 R2a/R2b R3 Actividad de rhSYK [M+H]+ Obs. Forma(s)
- 113B-1
- CH3 2,5-di(CH3) H +++ 453 Base Libre
- 113B-2
- CH3 2,5-di(CH3) (isómero 1) H +++ 453 Base Libre
- 113B-3
- CH3 2,5-di(CH3) (isómero 2) H +++ 453 Base Libre
- 113B-4
- CH3 2,5-di(CH3) (isómero 3) H +++ 453 Base Libre
- 113B-5
- CH3 2,5-di(CH3) (isómero 4) H +++ 453 Base Libre
- 113B-6
- CH3 2,5-di(CH3) (isómero 5) H +++ 453 Base Libre
- 113B-7
- CH3 2,5-di(CH3) Et +++ 481 Base Libre
- 113B-8
- CH3 2,5-di(CH3) (isómero 1) Et +++ 481 Base Libre
- 113B-9
- CH3 2,5-di(CH3) (isómero 2) Et +++ 481 Base Libre
- 113B-10
- CH3 2,5-di(CH3) (isómero 3) Et +++ 481 Base Libre
- 113B-11
- CH3 2,5-di(CH3) (isómero 4) Et ++ 481 Base Libre
- 113B-12
- CF3 2,5-di(CH3) H +++ 507 Base Libre
- 113B-13
- CF3 2,5-di(CH3) (isómero 1) H +++ 507 Base Libre
- 113B-14
- CF3 2,5-di(CH3) (isómero 2) H +++ 507 Base Libre
- 113B-15
- CF3 2,5-di(CH3) (isómero 3) H +++ 507 Base Libre
- 113B-16
- CF3 2,5-di(CH3) (isómero 4) H +++ 507 Base Libre
- 113B-17
- CF3 2,5-di(CH3) Et +++ 535 Base Libre
- 113B-18
- CF3 2,5-di(CH3) (isómero 1) Et +++ 535 Base Libre
- 113B-19
- CF3 2,5-di(CH3) (isómero 2) Et +++ 535 Base Libre
- 113B-20
- CF3 2,5-di(CH3) (isómero 3) Et ++ 535 Base Libre
- 113B-21
- CH3 2,6-di(CH3) H +++ 453 Base Libre
- 113B-22
- CH3 2,6-di(CH3) (trans,trans,trans) H +++ 453 Base Libre
- 113B-23
- CH3 2,6-di(CH3) iPr ++ 495 Base Libre
- 113B-24
- CF3 2,6-di(CH3) H +++ 507 Base Libre
- 113B-25
- CF3 2,6-di(CH3) (trans,trans,trans) H +++ 507 Base Libre
- 113B-26
- CF3 2,6-di(CH3) (isómero 1) iPr + 549 Base Libre
- 113B-27
- CF3 2,6-di(CH3) (isómero 2) iPr ++ 549 Base Libre
- 113B-28
- CH3 3,5-di(CH3) H +++ 453 Base Libre
- 113B-29
- CH3 3,5-di(CH3) Et +++ 481 Base Libre
- 113B-30
- CF3 3,5-di(CH3) H +++ 507 Base Libre
- 113B-31
- CF3 3,5-di(CH3) Et +++ 535 Base Libre
96 TABLA 113C
- n es 1 o 2 sustituyentes como se especifica en la Tabla.
- Ej.
- R1 R2 R3 X Actividad de rhSYK [M+H]+ Obs. Forma(s)
- 113C-2
- 4-cPr CH3 H C(O) +++ 436,2 Sal TFA
- 113C-3
- 4-CH(F)-CH3 CH3 H (enantiómero 1) C(O) +++ 442,1 Base Libre
- 113C-4
- 4-CH(F)-CH3 CH3 H (enantiómero 2) C(O) +++ 442,2 Base Libre
- 113C-7
- 4-CHF2 CH3 H C(O) +++ 446,1 Base Libre
- 113C-8
- 4-CF3 H H C(O) +++ 450,1 Sal TFA
- 113C-9
- 4-tBu CH3 H C(O) +++ 452,2 Base Libre
- 113C10
- 4-O-iPr CH3 H C(O) +++ 454,2 Base Libre
- 113C13
- 4-cPr CH3 H CH2 +++ 422,2 Base Libre
- 113C14
- 4-iPr CH3 H CH2 +++ 424,2 Base Libre
- 113C17
- 4-cPr CH3 BOC (enantiómero 1) CH2 +++ 522,3 Base Libre
- 113C18
- 4-cPr CH3 BOC (enantiómero 2) CH2 ++ 522,3 Base Libre
- 113C19
- 4-iPr CH3 BOC CH2 +++ 524,3 Base Libre
- 113C20
- 4-iPr CH3 BOC (enantiómero 1) CH2 ++ 524,3 Base Libre
- 113C21
- 4-iPr CH3 BOC (enantiómero 2) CH2 + 524,3 Base Libre
- Ej.
- Estructura Actividad de rhSYK [M+H]+ Obs. Forma(s)
- 113D-13
-
imagen87 +++ 443,1 Base Libre
97
TABLA 116A
- n es 1 o 2 sustituyentes como se especifica en la Tabla.
- Ej.
- R1 R2 X Actividad de rhSYK [M+H]+ Obs. Forma(s)
- 116A-3
- 4-iPr CO2H (cis) CH2 +++, +++ 453,2 Base Libre, Sal TFA
- 116A-6
- 4-tBu CO2H (cis) CH2 +++ 467,2 Sal TFA
- 116A-7
- 4-O-iPr CO2H (cis) CH2 +++ 469,2 Sal TFA
- 116A10
- 4-CH(F)CH3 CO2C(CH3)3 CH2 +++ 513,2 Base Libre
- 116A12
- 4-tBu CO2C(CH3)3 (cis) CH2 ++ 523,2 Base Libre
- 116A13
- 4-CF2CF3 CO2H (cis) CH2 +++ 529,1 Sal TFA
- 116A16
- 4-CF2CF3 CO2C(CH3)3 (cis) CH2 + 585,2 Sal TFA
- 116A18
- 4-CHF2 CO2H (isómero 1) CH(CH3) +++ 475,2 Base Libre
- 116A19
- 4-CHF2 CO2H (isómero 2) CH(CH3) +++ 475,2 Base Libre
- 116A20
- 4-tBu CO2H CH(CH3) +++ 481,2 Base Libre
- 116A21
- 4-O-iPr CO2H CH(CH3) +++, +++ 483,2 Base Libre, Sal formiato
- 116A30
- 4-CHF2 CO2H (1S, 4R) C(CH3)2 +++ 489,2 Base Libre
- 116A31
- 4-cBu CO2H (1S, 4R) C(CH3)2 +++ 493,2 Sal TFA
- 116A32
- 4-tBu CO2H (cis) C(CH3)2 +++ 495,2 Base Libre
- 116A33
- 4-O-iPr CO2H (1S,4R) C(CH3)2 +++ 497,2 Base Libre
- 116A37
- 4-CF3 CO2H (1S,4R) C(CH3)2 +++ 507,1 Sal TFA
- 116A39
- (R) 4-CH(F)CH3 CO2H (1S,4R) C(CH3)2 +++ 485,2 Base Libre
- 116A40
- (S) 4-CH(F)CH3 CO2H (1S,4R) C(CH3)2 +++ 485,2 Base Libre
99
Ejemplo 117
cis-4-hidroxi-1-metil-4-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2-il]ciclohexanocarboxamida
5
A una solución agitada de ácido cis-4-hidroxi-1-metil-4-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3tiazol-2-il]ciclohexanocarboxílico (442 mg, 0,90 mmol) en DMF (9,0 ml) se le añadieron cloruro de amonio (144 mg, 2,69 mmol), EDC (344 mg, 1,80 mmol), HOBt (243 mg, 1,80 mmol) y diisopropiletil amina (0,94 ml, 5,38 mmol). La 10 solución se dejó en agitación a temperatura ambiente durante 16 h. La reacción se diluyó con agua y se extrajo con EtOAc (3 x). Las capas orgánicas combinadas se lavaron con bicarbonato sódico acuoso saturado y salmuera, después se secaron (sulfato de magnesio), se filtraron y se concentraron. El residuo se purificó por cromatografía en columna para dar el compuesto del título en forma de un sólido de color blanco. ESI: [M + H]+ m/z 492,2. 1H RMN (500 MHz, CD3OD) δ 8,71 (d, J = 4,9, 1H), 8,03 (s, 1H), 7,91 (s, 1H), 7,44 (s, 1H), 7,13 (s, 2H), 2,37 (s, 3H), 2,22 (d,
Los compuestos en la siguiente Tabla o Tablas se prepararon de manera análoga a la descrita en el Ejemplo 117:
TABLA 117
- Ej.
- R1 R3 Actividad de rhSYK [M+H] + Obs. Forma(s)
- R2=H
- 117-1
-
CF3
imagen90 +++ 450,1 Base Libre
- 117-3
-
CF3
imagen91 +++ 492,2 Base Libre
- 117-4
- CF3 4-CONH2-cHex (cis) +++ 462,1 Base Libre
- 117-5
- CF3 4-CONH2-cHex (trans) +++ 462,1 Base Libre
- 117-7
-
CF3
imagen92 +++ 521,1 Base Libre
100
- 117-8
-
CF3
imagen93 +++ 492,2 Base Libre
- 117-9
-
CF3
imagen94 +++ 492,2 Base Libre
- 117-10
-
CF3
imagen95 +++ 492,2 Base Libre
- 117-11
-
CF3
imagen96 +++ 506,2 Base Libre
- 117-12
-
CF3
imagen97 +++ 506,2 Base Libre
- 117-13
- iPr +++ 509,2 Base Libre
- R2 = Br
Ejemplo 118
cis-4-hidroxi-4-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2-il]-N-[3-(2-oxopirrolidin-1il)propil]ciclohexanocarboxamida
A N-(3-aminopropil)-2-pirrolidinona (14,1 µl, 0,12 mmol) se le añadió una solución de ácido cis-4-hidroxi-4-[5-(3-metil
10 5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2-il]ciclohexanocarboxílico (48 mg, 0,1 mmol) en N,Ndimetilformamida (1 ml). Se añadió N,Ndiisopropiletilamina (35 µl, 0,2 mmol) y después la solución se enfrió a 0 ºC. Se añadió anhídrido cíclico del ácido 1-propanofosfónico (70 µl, 0,12 mmol), y la mezcla se calentó a temperatura ambiente y se agitó durante 16 h, se filtró, después se purificó por HPLC de fase inversa desencadenada en masa (C-18) para dar el producto del título (21,5 mg, 0,036 mmol, rendimiento del 36 %) en forma de un sólido de color
15 amarillo pálido. MS ESI: [M + H]+ m/z 603,2. 1H RMN (600 MHz, DMSO) δ 10,22 (s, 1H), 8,80 (d, J = 4,9, 1H), 7,91
101
dosis (10 µM a 0,508 nM) y ajuste de curva logística de cuatro parámetros usando el analizador de datos de ensayo de Merck. La actividad de rhSYK (CI50) se expresa como +++ (100 nM o menos), ++ (entre 100 y 1000 nM), + (entre 1 y 10 µM). CI50 para los compuestos representativos de la presente invención se proporciona como se muestra a continuación:
- Nombre del Compuesto
- CI50 de Syk
- 3-hidroxi-3-[5-(3-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2-il]pirrolidin-1-carboxamida
- 11 nM
- Ácido {4-hidroxi-4-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2-il]azepan-1il}acético
- 216 nM
- Ácido (1S,4R)-4-hidroxi-2,2-dimetil-4-(5-{3-metil-5-[(4-metilpirimidin-2-il)amino]-fenil}-1,3-tiazol-2il)ciclohexanocarboxílico
- 1 nM
- 1-(5- {3-[(4-terc-butilpirimidin-2-il)amino]-5-metilfenil}-1,3-tiazol-2-il)-ciclobutanol
- 25 nM
- (1S,4R)-N-(cianometil)-4-hidroxi-2,2-dimetil-4-(5-{3-metil-5-[(4-metilpirimidin-2-il)amino]fenil}-1,3-tiazol-2il)ciclohexanocarboxamida
- 2 nM
- cis-4-hidroxi-4-[5-(3-metil-5-{[4-(pentafluoroetil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2il]ciclohexanocarboxilato de cistercbutilo
- 2427 nM
- Ácido (1S,4R)-4-hidroxi-2,2-dimetil-4-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2il]ciclohexanocarboxílico
- < 0,5 nM
- Ácido trans-4-hidroxi-1-metil-4-[5-(3-{[4-(trifluorometil)pirimidin-2-il]amino}-fenil)-1,3-tiazol-2il]ciclohexanocarboxílico
- 4 nM
- Ácido cis-4-hidroxi-1-metil-4-[5-(3-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2il]ciclohexanocarboxílico
- 2 nM
- cis-4-[(hidroxiacetil)amino]-1-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2-il] ciclohexanocarboxamida
- 2 nM
- (1S,4R)-4-hidroxi-2,2-dimetil-4-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2-il]-N[3-(2-oxopirrolidin-1-il)propil]ciclohexanocarboxamida
- 1 nM
- Ácido (1S,2R,4R)-4-hidroxi-2-metil-4-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2il]ciclohexanocarboxílico y enantiómero
- 1 nM, < 0,5 nM
- Ácido (1S,4R)-4-metoxi-2,2-dimetil-4-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2il]ciclohexanocarboxílico
- 2 nM
- Ácido (1R,4S)-4-hidroxi-2,2-dimetil-4-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}fenil)-1,3-tiazol-2il]ciclohexanocarboxílico
- 2 nM
- Clorhidrato de N{3-[2-(1-aminociclobutil)-1,3-tiazol-5-il]-5-metilfenil}-4-ciclopropil-pirimidin-2-amina
- 3 nM
- (1R,4S)-4-hidroxi-2,2-dimetil-4-[5-(3-metil-5-{[4-(trifluorometil)-pirimidin-2-il]amino}fenil)-1,3-tiazol-2il]ciclohexanocarboxilato de etilo
- 49 nM
- 5-(aminometil)-5-[5-(3-metil-5-{[4-(trifluorometil)pirimidin-2-il]amino}-fenil)-1,3-tiazol-2-il]azepan-2-ona
- 50 nM
- Ácido (1S,4R)-4-{5-[3-({4-[(1S)-1-fluoroetil]pirimidin-2-il}amino)-5-metilfenil]-1,3-tiazol-2-il}-4-hidroxi-2,2dimetilciclohexanocarboxílico
- <0,5 nM
- Ácido (1S,4R)-4-{5-[3-({4-[(1R)-1-fluoroetil]pirimidin-2-il}amino)-5-metilfenil]-1,3-tiazol-2-il}-4-hidroxi-2,2dimetilciclohexanocarboxílico
- <0,5 nM
120
Claims (1)
-
imagen1 imagen2 imagen3
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| US28726709P | 2009-12-17 | 2009-12-17 | |
| US287267P | 2009-12-17 | ||
| PCT/US2010/060454 WO2011075515A1 (en) | 2009-12-17 | 2010-12-15 | Aminopyrimidines as syk inhibitors |
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