Pyridopyrazine derivatives and their use
AssigneeAEterna Zentaris GmbH
InventorsMatthias GERLACH, Irene Seipelt, Lars Blumenstein, Gilbert Mueller, Eckhard Guenther, Tilmann Schuster, Michael Teifel
Life of this patent
Estimating the term…
Abstract
The present invention provides new pyridopyrazine compounds which are suitable for the treatment or prevention of physiological and/or pathophysiological states mediated and/or modulated by signal transduction pathways and/or enzymes in mammals and in particular in humans.
Claims22
A method of treating or preventing a physiological and/or pathophysiological state mediated by a PI3K-Akt signal transduction pathway or a ras-Raf-Mek-Erk signal transduction pathway in a mammal in need thereof, the method comprising administering to the mammal an effective amount of a compound according formula (I)
- wherein the substituents R1, R2, X have the following meaning:
- X O or S
- R1
- (I) unsubstituted or substituted alkyl, wherein the alkyl group can be substituted with one or more, the same or different F, Cl, Br, I, CF3, CN, NH2, NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-NH2, NH-alkyl-OH, N(alkyl)2, NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHC(O)-alkyl-aryl, NHC(O)-alkyl-heteroaryl, NHSO2-alkyl, NHSO2-cycloalkyl, NHSO2-heterocyclyl, NHSO2-aryl, NHSO2-heteroaryl, NHSO2-alkyl-aryl, NHSO2-alkyl-heteroaryl, NO2, SH, S-alkyl, S-aryl, S-heteroaryl, OH, OCF3, O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aryl, O-alkyl-heteroaryl, O-alkyl-OH, O—(CH2)n—O, OC(O)-alkyl, OC(O)-cycloalkyl, OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl, OC(O)-alkyl-aryl, OC(O)-alkyl-heteroaryl, OSO3H, OSO2-alkyl, OSO2-cycloalkyl, OSO2-heterocyclyl, OSO2-aryl, OSO2-heteroaryl, OSO2-alkyl-aryl, OSO2-alkyl-heteroaryl, OP(O)(OH)2, C(O)-alkyl, C(O)-aryl, C(O)-heteroaryl, CO2H, CO2-alkyl, CO2-cycloalkyl, CO2-heterocyclyl, CO2-aryl, CO2-heteroaryl, CO2-alkyl-cycloalkyl, CO2-alkyl-heterocyclyl, CO2-alkyl-aryl, CO2-alkyl-heteroaryl, C(O)—NH2, C(O)NH-alkyl, C(O)NH-cycloalkyl, C(O)NH-heterocyclyl, C(O)NH-aryl, C(O)NH-heteroaryl, C(O)NH-alkyl-cycloalkyl, C(O)NH-alkyl-heterocyclyl, C(O)NH-alkyl-aryl, C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)2, C(O)N(cycloalkyl)2, C(O)N(aryl)2, C(O)N(heteroaryl)2, SO-alkyl, SO-aryl, SO2-alkyl, SO2-aryl, SO2NH2, SO2NH-alkyl, SO2NH-aryl, SO2NH-heteroaryl, SO2NH-alkyl-aryl, SO3H, SO2O-alkyl, SO2O-aryl, SO2O-alkyl-aryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, n can have the value 1, 2 or 3 and the alkyl-, cycloalkyl-, heterocyclyl-, aryl-, heteroaryl-, alkyl-cycloalkyl-, alkyl-heterocyclyl-, alkyl-aryl- and alkyl-heteroaryl substituents for their part can in turn be substituted,
- (II) unsubstituted or substituted aryl, wherein the aryl group can be substituted with one or more, the same or different F, Cl, Br, I, CF3, CN, NH2, NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-NH2, NH-alkyl-OH, N(alkyl)2, NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHC(O)-alkyl-aryl, NHC(O)-alkyl-heteroaryl, NHSO2-alkyl, NHSO2-cycloalkyl, NHSO2-heterocyclyl, NHSO2-aryl, NHSO2-heteroaryl, NHSO2-alkyl-aryl, NHSO2-alkyl-heteroaryl, NO2, SH, S-alkyl, S-aryl, S-heteroaryl, OH, OCF3, O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aryl, O-alkyl-heteroaryl, O-alkyl-OH, O—(CH2)n—O, O—CH2—CH2—O—CH2—CH2—O—CH2—CH2—OH;
- OC(O)-alkyl, OC(O)-cycloalkyl, OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl, OC(O)-alkyl-aryl, OC(O)-alkyl-heteroaryl, OC(O)—NH-Alkyl, OSO3H, OSO2-alkyl, OSO2-cycloalkyl, OSO2-heterocyclyl, OSO2-aryl, OSO2-heteroaryl, OSO2-alkyl-aryl, OSO2-alkyl-heteroaryl, OP(O)(OH)2, C(O)-alkyl, C(O)-aryl, C(O)-heteroaryl, O—CO2-alkyl, CO2H, CO2-alkyl, CO2-cycloalkyl, CO2-heterocyclyl, CO2-aryl, CO2-heteroaryl, CO2-alkyl-cycloalkyl, CO2-alkyl-heterocyclyl, CO2-alkyl-aryl, CO2-alkyl-heteroaryl, C(O)—NH2, C(O)NH-alkyl, C(O)NH-cycloalkyl, C(O)NH-heterocyclyl, C(O)NH-aryl, C(O)NH-heteroaryl, C(O)NH-alkyl-cycloalkyl, C(O)NH-alkyl-heterocyclyl, C(O)NH-alkyl-aryl, C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)2, C(O)N(cycloalkyl)2, C(O)N(aryl)2, C(O)N(heteroaryl)2, SO-alkyl, SO-aryl, SO2-alkyl, SO2-heterocyclyl;
- SO2-aryl, SO2NH2, SO2NH-alkyl, SO2NH-aryl, SO2NH-heteroaryl, SO2NH-alkyl-aryl, SO3H, SO2O-alkyl, SO2O-aryl, SO2O-alkyl-aryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, n can have the value 1, 2 or 3 and the alkyl-, cycloalkyl-, heterocyclyl-, aryl-, heteroaryl-, alkyl-cycloalkyl-, alkyl-heterocyclyl-, alkyl-aryl- and alkyl-heteroaryl substituents for their part can in turn be substituted,
- (III) unsubstituted or substituted heteroaryl, wherein the heteroaryl group can be substituted with one or more, the same or different F, Cl, Br, I, CF3, CN, NH2, NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-NH2, NH-alkyl-OH, N(alkyl)2, NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHC(O)-alkyl-aryl, NHC(O)-alkyl-heteroaryl, NHSO2-alkyl, NHSO2-cycloalkyl, NHSO2-heterocyclyl, NHSO2-aryl, NHSO2-heteroaryl, NHSO2-alkyl-aryl, NHSO2-alkyl-heteroaryl, NO2, SH, S-alkyl, S-aryl, S-heteroaryl, OH, OCF3, O-alkyl, O-cycloalkyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aryl, O-alkyl-heteroaryl, OC(O)-alkyl, OC(O)-cycloalkyl, OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl, OC(O)-alkyl-aryl, OC(O)-alkyl-heteroaryl, OSO3H, OSO2-alkyl, OSO2-cycloalkyl, OSO2-heterocyclyl, OSO2-aryl, OSO2-heteroaryl, OSO2-alkyl-aryl, OSO2-alkyl-heteroaryl, OP(O)(OH)2, C(O)-alkyl, C(O)-aryl, C(O)-heteroaryl, CO2H, CO2-alkyl, CO2-cycloalkyl, CO2-heterocyclyl, CO2-aryl, CO2-heteroaryl, CO2-alkyl-cycloalkyl, CO2-alkyl-heterocyclyl, CO2-alkyl-aryl, CO2-alkyl-heteroaryl, C(O)—NH2, C(O)NH-alkyl, C(O)NH-cycloalkyl, C(O)NH-heterocyclyl, C(O)NH-aryl, C(O)NH-heteroaryl, C(O)NH-alkyl-cycloalkyl, C(O)NH-alkyl-heterocyclyl, C(O)NH-alkyl-aryl, C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)2, C(O)N(cycloalkyl)2, C(O)N(aryl)2, C(O)N(heteroaryl)2, Si(Alkyl)3, SO2NH2, SO2NH-alkyl, SO2NH-aryl, SO2NH-heteroaryl, SO2NH-alkyl-aryl, SO3H, SO2O-alkyl, SO2O-aryl, SO2O-alkyl-aryl, alkyl, cycloalkyl, heterocyclyl, alkyl-cycloalkyl, alkyl-heterocyclyl, alkyl-aryl, alkyl-heteroaryl, aryl or heteroaryl, and the alkyl-, cycloalkyl-, heterocyclyl-, alkyl-cycloalkyl, alkyl-heterocyclyl, alkyl-aryl, alkyl-heteroaryl, aryl- and heteroaryl substituents for their part can in turn be substituted,
- and R2:
- (I) unsubstituted or substituted alkyl wherein the alkyl group can be substituted with one or more, the same or different F, Cl, Br, I, CF3, CN, NH2, NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, N(alkyl)2, NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHC(O)-alkyl-aryl, NHC(O)-alkyl-heteroaryl, NHSO2-alkyl, NHSO2-cycloalkyl, NHSO2-heterocyclyl, NHSO2-aryl, NHSO2-heteroaryl, NHSO2-alkyl-aryl, NHSO2-alkyl-heteroaryl, NO2, SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF3, O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aryl, O-alkyl-heteroaryl, OC(O)-alkyl, OC(O)-cycloalkyl, OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl, OC(O)-alkyl-aryl, OC(O)-alkyl-heteroaryl, OSO3H, OSO2-alkyl, OSO2-cycloalkyl, OSO2-heterocyclyl, OSO2-aryl, OSO2-heteroaryl, OSO2-alkyl-aryl, OSO2-alkyl-heteroaryl, OP(O)(OH)2, C(O)-alkyl, C(O)-aryl, C(O)-heteroaryl, CO2H, CO2-alkyl, CO2-cycloalkyl, CO2-heterocyclyl, CO2-aryl, CO2-heteroaryl, CO2-alkyl-cycloalkyl, CO2-alkyl-heterocyclyl, CO2-alkyl-aryl, CO2-alkyl-heteroaryl, C(O)—NH2, C(O)NH-alkyl, C(O)NH-cycloalkyl, C(O)NH-heterocyclyl, C(O)NH-aryl, C(O)NH-heteroaryl, C(O)NH-alkyl-cycloalkyl, C(O)NH-alkyl-heterocyclyl, C(O)NH-alkyl-aryl, C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)2, C(O)N(cycloalkyl)2, C(O)N(aryl)2, C(O)N(heteroaryl)2, SO-alkyl, SO-aryl, SO2-alkyl, SO2-aryl, SO2NH2, SO2NH-alkyl, SO2NH-aryl, SO2NH-heteroaryl, SO2NH-alkyl-aryl, SO3H, SO2O-alkyl, SO2O-aryl, SO2O-alkyl-aryl, cycloalkyl, heterocyclyl,
- (II) unsubstituted or substituted cycloalkyl, wherein the cycloalkyl group can be substituted with one or more, the same or different F, Cl, Br, I, NH2, NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, N(alkyl)2, NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHC(O)-alkyl-aryl, NHC(O)-alkyl-heteroaryl, NHSO2-alkyl, NHSO2-cycloalkyl, NHSO2-heterocyclyl, NHSO2-aryl, NHSO2-heteroaryl, NHSO2-alkyl-aryl, NHSO2-alkyl-heteroaryl, OH, O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-aryl, O-alkyl-heteroaryl, OC(O)-alkyl, OC(O)-cycloalkyl, OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl, OC(O)-alkyl-aryl, OC(O)-alkyl-heteroaryl, OSO3H, OSO2-alkyl, OSO2-cycloalkyl, OSO2-heterocyclyl, OSO2-aryl, OSO2-heteroaryl, OSO2-alkyl-aryl, OSO2-alkyl-heteroaryl, OP(O)(OH)2, CO2H, CO2-alkyl, CO2-cycloalkyl, CO2-heterocyclyl, CO2-aryl, CO2-heteroaryl, CO2-alkyl-cycloalkyl, CO2-alkyl-heterocyclyl, CO2-alkyl-aryl, CO2-alkyl-heteroaryl, C(O)—NH2, C(O)NH-alkyl, C(O)NH-cycloalkyl, C(O)NH-heterocyclyl, C(O)NH-aryl, C(O)NH-heteroaryl, C(O)NH-alkyl-cycloalkyl, C(O)NH-alkyl-heterocyclyl, C(O)NH-alkyl-aryl, C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)2, C(O)N(cycloalkyl)2, C(O)N(aryl)2, C(O)N(heteroaryl)2, alkyl, or aryl,
- its physiologically tolerated salts, in the form of its racemates, in the form of its pure enantiomers and/or diastereomers or in the form of mixtures of these enantiomers and/or diastereomers or in the form of its tautomers.
A Pyridopyrazine selected from the group consisting of compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 190, 191, 192, 193, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, a physiologically acceptable salt thereof, a racemate thereof, it's a pure enantiomer thereof, a diastereomer thereof, a mixture of enantiomers, a mixture of diastereomers, and a tautomer thereof.
The pharmaceutical composition according to 18, further comprising at least one additional pharmacologically active substance.
Dependencies are inferred from the claim text.