Activators of human pyruvate kinase

{
  "publication_number": "US2012245141A1",
  "country": "US",
  "kind": "A1",
  "title": "Activators of human pyruvate kinase",
  "abstract": "Disclosed are pyruvate kinase M2 activators, which are, bis sulfonamide piperazinyl compounds of Formula (I) and 2,4-disubstituted 4H-thieno[3,2-b]pyrrole-2-(substituted benzyl)pyridazin-3(2H)ones of Formula (II), wherein L and R 1 to R 16 are as defined herein, that are useful in treating a number of diseases that are treatable by the activation of PKM2, for example, cancer and anemia,",
  "claims": [
    "1. A compound of Formula I: wherein R 1 and R 2 are aryl or heteroaryl, optionally substituted with one or more substituents selected from the group consisting of C 1 -C 10 alkyl, C 3 -C 6 alkylene, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 haloalkyl, C 1 -C 10 dihaloalkyl, C 1 -C 10 trihaloalkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkenyl, C 6 -C 10 aryl, heterocyclyl, heteroaryl, heteroaryloxide, alkylenedioxy, OR 4, SR 4, NR 4 R 5, NCOR 4, OCOR 4, SCOR 4, SOR 4, SO 2 R 4, SO 2 NR 4 R 5, NO 2, B(OH) 2, CN, and halogen, and L is a linker comprising an amino group; or a pharmaceutically acceptable salt thereof; with the provisos that R 1 and R 2 are not dimethoxyphenyl and that R 1 and R 2 are not both 4-methylphenyl simultaneously. 2. The compound or salt of claim 1, wherein the compound of formula (I) is a compound of formula (Ia): wherein n=1 to 3, R 1 and R 2 are aryl or heteroaryl, optionally substituted with one or more substituents selected from the group consisting of C 1 -C 10 alkyl, C 3 -C 6 alkylene, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 haloalkyl, C 1 -C 10 dihaloalkyl, C 1 -C 10 trihaloalkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkenyl, C 6 -C 10 aryl, heterocyclyl, heteroaryl, heteroaryloxide, alkylenedioxy, OR 4, SR 4, NR 4 R 5, NCOR 4, OCOR 4, SCOR 4, SOR 4, SO 2 R 4, SO 2 NR 4 R 5, NO 2, B(OH) 2, CN, and halogen, R 3 and R 4 are independently selected from the group consisting of H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkenyl, COR 6, F, and CF 3, or, R 3 and R 4, taken together with the carbon atom to which they are attached, form C═O, R 5 and R 7 to R 10 are independently H, C 1 -C 10 alkyl, or F, R 6 is C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl, or each of R 7 and R 8 and of R 9 and R 10, together form C═O and X is CH or N, or a pharmaceutically acceptable salt thereof. 3. The compound or salt according to claim 2, wherein R 1 and R 2 are phenyl substituted with one or more substituents selected from the group consisting of C 1 -C 10 alkyl, C 1 -C 10 trihaloalkyl, heterocyclyl, heteroaryl, alkylenedioxy, OR 4, SR 4, NR 4 R 5, NCOR 4, OCOR 4, SCOR 4, SOR 4, SO 2 R 4, SO 2 NR 4 R 5, CN, and halogen, R 3 and R 4 are independently selected from the group consisting of H, C 1 -C 10 alkyl, and F, or, taken together with the carbon atom to which they are attached, form C═O, and R 5 and R 7 to R 19 are independently H, C 1 -C 10 alkyl, or F. 4. (canceled) 5. The compound or salt according to claim 3, wherein X is N and n is 1. 6 - 12. (canceled) 13. The compound or salt of claim 2, wherein the compound is of formula (Ic): wherein R 3 to R 10 are H or methyl, R 3 to R 6 and R 9 and R 10 are H or methyl and R 7 form C═O, or R 3 to R 8 are H or methyl and R 9 and R 10 taken together with the carbon atom to which they are attached form C═O. 14 - 15. (canceled) 16. The compound or salt of claim 2, wherein X is CH. 17 - 25. (canceled) 26. A compound of Formula II: wherein: R 11 is selected from the group consisting of H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkenyl, C 6 -C 10 aryl, OR 17, SR 17, SOR 17, SO 2 R 17, NR 17 R 18, NCOR 17, SCOR 17 COR 17, OCOR 17, B(OH) 2, NO 2, NHCOR 17, CN, CHO, hydroxy C 1 -C 10 alkyl, and halogen, R 12 is selected from the group consisting of H, C 1 -C 2 alkyl, allyl, C 3 -C 10 cycloalkyl, NCOR 14, and SO 2 R 14, R 13 to R 16 are selected from the group consisting of H, C 1 -C 10 alkyl, halo C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkenyl, C 6 -C 10 aryl, heteroaryl, OR 17, SR 17, NR 17 R 18, NCOR 17, OCOR 17, SCOR 17, SOR 17, SO 2 R 17, SO 2 NR 17 R 18, CF 3, and halogen, and R 17 and R 18 are independently selected from the group consisting of H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkenyl, and C 6 -C 10 aryl, or a pharmaceutically acceptable salt thereof, with the proviso that when R 11 is methyl, R 12 is methyl or allyl, and R 14 to R 16 are H, then R 13 is not methoxy or fluoro. 27. The compound or salt according to claim 26, wherein R 11 is selected from the group consisting of H, C 1 -C 10 alkyl, OR 17, SR 17, SOR 17, SO 2 R 17, NR 17 R 18, NCOR 17, SCOR 17, COR 17, OCOR 17, B(OH) 2, NO 2, NHCOR 17, CN, CHO, hydroxy C 1 -C 10 alkyl, and halogen, R 12 is selected from the group consisting of H, methyl, NCOR 14, and SO 2 R 14, R 13 to R 16 are selected from the group consisting of H, C 1 -C 10 alkyl, OR 17, SR 17, NR 17 R 18, NCOR 17, OCOR 17, SCOR 17, SOR 17, SO 2 R 17, SO 2 NR 17 R 18, CF 3, and halogen, and R 17 and R 18 are independently selected from the group consisting of H and C 1 -C 10 alkyl. 28. The compound or salt according to claim 26, wherein R 11 is selected from the group consisting of H, C 1 -C 10 alkyl, OR 17, SR 17, SOR 17, COR 17, OCOR 17, B(OH) 2, NO 2, NHCOR 17, CN, CHO, hydroxy C 1 -C 10 alkyl, and halogen, R 12 is H or C 1 -C 2 alkyl, and R 13 to R 16 are selected from the group consisting of H, methyl, CF 3, methoxy, and halogen. 29. The compound or salt according to claim 28, wherein R 11 is selected from the group consisting of H, methyl, ethyl, isopropyl, OCH 3, SCH 3, S(O)CH 3, NO 2, NHCOCH 3, CN, COOCH 3, CHO, CH 2 OH, B(OH) 2, and CH(OH)CH 3, R 12 is methyl, R 13 is 2-fluoro or chloro, and R 14 to R 16 are H. 30. The compound or salt according to claim 27, wherein R 11 and R 12 are methyl, R 13 is H, 2-fluoro, 3-fluoro, 4-fluoro, 2-chloro, 3-chloro, 4-chloro, 4-CF 3, 4-methyl, or 4-methoxy, and R 14 to R 16 are H or halogen. 31. The compound or salt according to claim 30, wherein R 11 and R 12 are methyl, and R 13 and R 14 are 2-fluoro and 4-fluoro, 2-fluoro and 6-fluoro, 2-fluoro and 3-fluoro, 2-choro and 6-fluoro, 2-fluoro and 3-methyl, 2-fluoro and 4-methyl, 2-fluoro and 4-CF 3, and 2-fluoro and 4-methoxy, and R 15 and R 16 are H. 32. The compound or salt according to claim 29, wherein R 11 and R 12 are methyl, R 13 to R 15 are 2-fluoro, 3-fluoro, and 4-fluoro, and R 16 is H. 33. The compound or salt according to claim 29, wherein R 11 and R 12 are methyl, R 13 to R 16 are 2-fluoro, 3-fluoro, 5-fluoro, and 6-fluoro. 34. A pharmaceutical composition comprising a compound or salt according to claim 1, and a pharmaceutically acceptable carrier. 35. A method of treating a disease responsive to activation of human PK-M2 comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1. 36. The method of claim 35, wherein the compound is of formula Ia wherein n=1 to 3, R 1 and R 2 are aryl, phenyl, or heteroaryl, optionally substituted with one or more substituents selected from the group consisting of C 1 -C 10 alkyl, C 3 -C 6 alkylene, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 haloalkyl, C 1 -C 10 dihaloalkyl, trihaloalkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkenyl, C 6 -C 10 aryl, heterocyclyl, heteroaryl, heteroaryloxide, alkylenedioxy, OR 4, SR 4, NR 4 R 5, NCOR 4, OCOR 4, SCOR 4, SOR 4, SO 2 R 4, SO 2 NR 4 R 5, NO 2, B(OH) 2, CN, and halogen, R 3 and R 4 are independently selected from the group consisting of H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkenyl, COR 6, F, and CF 3, or, R 3 and R 4, taken together, form C═O, R 5 and R 7 to R 10 are independently H, C 1 -C 10 alkyl, or F, R 6 is C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl, or each of R 7 and R 8 and of R 9 and R 10, together form C═O and X is CH or N. 37. A method of treating a disease responsive to activation of human PK-M2 comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 26. 38. (canceled) 39. A compound of formula III: wherein R 21 and R 22 are aryl, substituted with one or more substituents selected from the group consisting of C 1 -C 10 alkyl, C 3 -C 6 alkylene, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 haloalkyl, C 1 -C 10 dihaloalkyl, C 1 -C 10 trihaloalkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkenyl, C 6 -C 10 aryl, heterocyclyl, heteroaryl, heteroaryloxide, alkylenedioxy, OR 23, SR 23, NR 23 R 24, NCOR 23, OCOR 23, SCOR 23, SO 2 R 23, SO 2 NR 23 R 24, NO 2, B(OH) 2, CN and halogen, wherein R 23 and R 24 are independently H, C 1 -C 10 alkyl, F, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkenyl, COR 6, and CF 3, or a pharmaceutically acceptable salt thereof. 40. A compound of the formula: or a pharmaceutically acceptable salt thereof. 41. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound or salt of claim 40. 42. A method of treating a disease responsive to activation of human PKM2 comprising administering to a patient in need thereof a therapeutically effective amount of a compound or salt of claim 40. 43. (canceled) 44. The compound or salt according to claim 26, wherein R 11 is S(O)CH 3, R 12 is methyl, R 13 is 3-amino or methoxy, and R 14 to R 16 are H. 45. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound or salt of claim 26. 46. The method of claim 37, wherein the disease is cancer. 47. The method of claim 46, wherein the cancer is selected from the group consisting of renal cancer, ovarian cancer, breast cancer, CNS cancer, leukemia, prostate cancer, non-small cell lung cancer, colon cancer, and melanoma,"
  ],
  "cpc": [
    "A61K 31/496",
    "A61K 31/445",
    "A61K 31/495",
    "A61K 31/5025",
    "A61P 33/00",
    "A61P 35/00",
    "A61P 35/02",
    "A61P 43/00",
    "A61P 7/06",
    "C07D 295/26",
    "C07D 319/18",
    "C07D 495/14"
  ],
  "assignees": [
    "THOMAS CRAIG J",
    "AULD DOUGLAS S",
    "INGLESE JAMES",
    "SKOUMBOURDIS AMANDA P",
    "JIANG JIAN-KANG",
    "BOXER MATTHEW B",
    "US HEALTH"
  ],
  "filing_date": "2012-03-29",
  "publication_date": "2012-09-27",
  "priority_date": "2008-10-09",
  "application_number": "US-201213433656-A",
  "family_id": "41462200",
  "citations": [
    "US2009163545A1",
    "US8642660B2"
  ]
}