Aryl carbonyl derivatives as therapeutic agents

• US 7,384,967 B2
• Filed: 10/06/2003
• Issued: 06/10/2008
• Est. Priority Date: 06/27/2002
• Status: Expired due to Fees

• Current Assignee: vTv Therapeutics LLC (vTv Therapeutics, Inc.)
• Original Assignee: Novo Nordisk A/S
• Inventors: Subramanian, Govindan, Kodra, Janos Tibor, Vedso, Per, Lau, Jesper, Polisetti, Dharma Rao, Andrews, Robert Carl, Santhosh, Kalpathy Chidambareswaran, Guzel, Mustafa, Mjalli, Adnan M. M., Jeppesen, Lone, Ankersen, Michael, Murray, Anthony, Bloch, Paw
• Primary Examiner(s): Anderson; Rebecca
• Assistant Examiner(s): Kosack; Joseph R.
• Application Number:
  US10/679,887
• Publication Number:
  US 20040122235A1
• Time in Patent Office: 1,709 Days
• Field of Search: 514/371, 514/354, 548/196, 546/300
• US Class Current: 514/371
• CPC Class Codes: A61K 31/426 1,3-Thiazoles
• CPC Class Codes: A61K 31/427 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 277/38 Nitrogen atoms
• CPC Class Codes: C07D 277/46 by carboxylic acids, or sulfur or nitrogen analogues thereof
• CPC Class Codes: C07D 277/48 : by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
• CPC Class Codes: C07D 277/52 : to sulfur atoms, e.g. sulfonamides
• CPC Class Codes: C07D 277/54 : Nitrogen and either oxygen or sulfur atoms
• CPC Class Codes: C07D 277/56 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 285/135 : Nitrogen atoms
• CPC Class Codes: C07D 417/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 473/38 : attached in position 6

Abstract

This invention relates to aryl carbonyl derivatives which are activators of glucokinase which may be useful for the management, treatment, control, or adjunct treatment of diseases, where increasing glucokinase activity is beneficial.

Claims

1. A compound of formula (Ib)

2. The compound according to claim 1, wherein R²⁴ is selected from the group consisting of hydrogen, halogen, —

CN, —

CF₃, —

OR², —

NR²R³, C_1-6-alkyl-Z-, cycloalkyl-Z-, heterocyclyl-Z-, aryl-Z-, heteroaryl-Z-, R⁶—

W¹-Z-, R⁶—

W¹—

N(R⁴)-Z-, R⁶—

N(R⁴)-Z, and R⁶—

W¹—

C_1-6-alkylene-Z-.

3. The compound according to claim 2, wherein R²⁴ is selected from the group consisting of hydrogen, halogen, —

OR², —

NR²R³, C_1-6-alkyl-Z-, R⁶—

W¹-Z-, and R⁶—

W¹—

C_1-6-alkylene-Z-.

4. The compound according to claim 3, wherein R²⁴ is selected from the group consisting of F, Cl, Br, and —

CH₃.

5. The compound according to claim 1, wherein R² and R³ independently of each other, are hydrogen, C_1-6-alkyl, aryl-C_1-6-alkylene- or aryl.

6. The compound according to claim 5, wherein R² is hydrogen or C_1-6-alkyl.

7. The compound according to claim 6, wherein R² is hydrogen.

8. The compound according to claim 1, wherein R³ is hydrogen or C_1-6-alkyl.

9. The compound according to claim 8, wherein R³ is hydrogen.

10. The compound according to claim 1, wherein Z is a direct bond, —

O—

, —

S—

, —

SO₂—

, —

C(O)NH—

, —

NHC(O)—

, —

N(H)SO₂—

, —

C(O)—

O—

, —

N(H)SO₂N(H)—

, or —

O—

C(O)—

.

11. The compound according to claim 10, wherein Z is a direct bond, —

NHC(O)—

, or —

NHS(O)₂—

.

12. The compound according to claim 1, wherein R⁴, R⁵, and R⁶ independently of each other are hydrogen or C_1-6-alkyl.

13. The compound according to claim 12, wherein R⁴, R³, and R⁶ are hydrogen.

14. The compound according to claim 1, wherein W¹ is a direct bond, —

O—

, —

C(O)—

, —

SO₂—

, —

C(O)NH—

, —

NHC(O)—

, —

N(H)SO₂—

, —

C(O)—

O—

, or —

O—

C(O)—

.

15. The compound according to claim 14, wherein W₁ is a direct bond or —

C(O)—

O—

.

16. The compound according to claim 15, wherein W¹ is a direct bond.

17. The compound according to claim 1, wherein L¹ is -D-C_1-6-alkylene-E-, —

O—

, —

C(O)—

, —

N(R¹¹)—

, or —

C(═

N—

OR¹²)—

.

18. The compound according to claim 1, wherein L¹ is —

O—

.

19. The compound according to claim 1, wherein L¹ is —

S—

.

20. The compound according to claim 1, wherein L¹ is —

C(O)—

.

21. The compound according to claim 1, wherein D is a direct bond.

22. The compound according to claim 1, wherein D is —

O—

.

23. The compound according to claim 1, wherein E is a direct bond.

24. The compound according to claim 1, wherein E is —

O—

.

25. The compound according to claim 1, wherein R¹¹ is hydrogen.

26. The compound according to claim 1, wherein R¹² is hydrogen.

27. The compound according to claim 1, wherein G¹ is C_1-6-alkyl, C_2-4-alkenyl, C_2-6, alkynyl, C_3-10-cycloalkyl or C_3-10-heterocyclyl, optionally substituted with one or more substituents selected from the group consisting of —

CN, —

CF₃, —

OCF₃, —

OR¹⁸, —

NR¹⁸R¹⁹, and C_1-6-alkyl.

28. The compound according to claim 27, wherein G¹ is selected from the group consisting of methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-bully, 3-pentyl, 2-pentyl, 3-methyl-butyl, 2-propenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidyl, pyrrolidyl, piperidyl, hexahydroazepinyl, thiolanyl, tetrahydrothiopyranyl, thiepanyl, 1,4-oxathianyl, 1,3-dioxolanyl, 1,2-dithiolanyl, 1,3-dithiolanyl, hexahydropyridazinyl, imidazolidyl, 1,3-dioxanyl, morpholinyl, 1,3-dithianyl, 1,4-dioxanyl, 1,4-dithianyl, and thiomorpholinyl.

29. The compound according to claim 28, wherein G¹ is selected from the group consisting of methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidyl, piperidyl, hexahydroazepinyl, thiolanyl, tetrahydrothiopyranyl, and thiepanyl.

30. The compound according to claim 29, wherein G¹ is selected from the group consisting of methyl, ethyl, propyl, butyl, isopropyl, isobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, piperidyl, and hexahydroazepinyl.

31. The compound according to claim 30, wherein G¹ is selected from the group consisting of isobutyl, cyclopentyl, and piperidyl.

32. The compound according to claim 30, wherein G¹ is isobutyl.

33. The compound according to claim 30, wherein G¹ is cyclopentyl.

34. The compound according to claim 30, wherein G¹ is piperidyl.

35. The compound according to claim 1, wherein R¹⁸ is hydrogen.

36. The compound according to claim 1, wherein R¹⁹ is hydrogen.

37. The compound according to claim 1, wherein L₂ is —

N—

(R²⁰)—

, —

C_1-6-alkylene-N(R²⁰)—

, —

C_2-6-alkenylene-N(R²⁰)—

, or —

C_1-6-alkynylene-N(R²⁰)—

.

38. The compound according to claim 37, wherein L² is —

N—

(R²⁰)—

.

39. The compound according to claim 1, wherein L² is a direct bond.

40. The compound according to claim 1, wherein L₃ is —

C(O)—

.

41. The compound according to claim 1, wherein L³ is —

C(O)—

C(O)—

.

42. The compound according to claim 1, wherein L₃ is —

C(O)CH₂C(O)—

.

43. The compound according to claim 1, wherein R¹ is hydrogen or C_1-6-alkyl optionally substituted with one or more substituents selected from the group consisting of R³³, R³⁴, and R³⁵.

44. The compound according to claim 43, wherein R⁵² and R⁵³, when attached to the seine nitrogen atom, together with the nitrogen atom to which they are attached may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, and optionally containing one or two double bonds.

45. The compound according to claim 43, wherein R⁵² and R⁵³ independently of each other are hydrogen, C_1-6-alkyl, aryl-C_1-6-alkylene-heteroaryl-C_1-6-alkylene-heteroaryl, or aryl.

46. The compound according to claim 45, wherein R⁵² and R⁵³ independently of each other are hydrogen, C_1-6-alkyl, aryl-C_1-6-alkylene- or aryl.

47. The compound according to claim 46, wherein R⁵² and R⁵³ independently of each other are hydrogen or C_1-6-alkyl.

48. The compound according to claim 1, wherein R⁵² is hydrogen.

49. The compound according to claim 48, wherein R⁵² is hydrogen and R⁵³ is hydrogen.

50. The compound according to claim 48, wherein R⁵³ is hydrogen.

51. The compound according to claim 43, wherein R¹ is hydrogen.

52. The compound according to claim 1, wherein R⁴³ is selected from the group consisting of —

SR⁵⁴, —

S(O)₂R⁵⁴, halogen, —

C_1-6-alkylene-C(O)OR⁵⁴, and —

C(O)OR⁵⁴;

or heterocyclyl-C_1-6-alkylene-, wherein heterocyclyl is selected from the group consisting of imidazolyl, piperidyl, piperazinyl, and morpholinyl, and of which the heterocyclyl moieties optionally may be substituted with one or more substituents independently selected from R⁷⁰;

or heteroaryl or heteroaryl-C_1-6-alkylene-, wherein heteroaryl is selected from the group consisting of thiazolyl, triazolyl, and tetrazolyl, and of which the heteroaryl moieties optionally may be substituted with one or more substituents selected from the group consisting of halogen, —

C(O)OR⁵⁴, —

CN, —

CF₃, —

OCF₃, —

NO₂, —

OR⁵⁴, —

NR⁵⁴R⁵⁵ and C_1-6-alkyl.

53. The compound according to claim 1, wherein R⁴³ is heteroaryl or heteroaryl-C_1-6-alkylene-optionally substituted with one or more substituents selected from the group consisting of halogen, —

C(O)OR⁵⁴, —

CN, —

CF₃, —

OCF₃, —

NO₂, —

OR⁵⁴, —

NR⁵⁴R⁵⁵ and C_1-6-alkyl.

54. The compound according to claim 53, wherein R⁴³ is heteroaryl optionally substituted with one or more substituents selected from the group consisting of halogen, —

C(O)OR⁵⁴, —

CN, —

CF₃, —

OCF₃, —

NO₂, —

OR⁵⁴, —

NR⁵⁴R⁵⁵ and C_1-6-alkyl.

55. The compound according to claim 53, wherein R⁴³ is heteroaryl-C_1-6-alkylene-optionally substituted with one or more substituents selected from the group consisting of halogen, —

C(O)OR⁵⁴, —

CN, —

CF₃, —

OCF₃, —

NO₂, —

OR⁵⁴, —

NR⁵⁴R⁵⁵ or C_1-6-alkyl.

56. The compound according to claim 52, wherein R⁴³ is —

C_1-6-alkylene-C(O)OR⁵⁴.

57. The compound according to claim 56, wherein R⁴³ is —

CH₂—

C(O)OR⁵⁴.

58. The compound according to claim 1, wherein R⁷⁰ is ═

O, methyl or C(O)OR^75.

59. The compound according to claim 1, wherein R⁷⁰ is —

C(O)OH.

60. The compound according to claim 1, wherein R⁷⁰ is —

(CH₂)_1-3C(O)OH.

61. The compound according to claim 1, wherein R⁵⁴ and R⁵⁵ independently of each other are hydrogen, C_1-6-alkyl, heterocyclyl, heterocyclyl-C_1-6-alkylene-, heteroaryl, or aryl, each of which is optionally substituted with one or more substituents independently selected from R⁷¹, or

R⁵⁴ and R⁵⁵ independently of each other are hydrogen or —

(CHAR⁷²)_u—

(CHR⁷³)_v—

W⁶.

62. The compound according to claim 1, wherein R⁵⁴ and R⁵⁵ independently of each other are hydrogen, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, 3-pentyl, 2-pentyl, or 3-methyl-butyl.

63. The compound according to claim 62, wherein R⁵⁴ and R⁵⁵ independently of each other are hydrogen, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, or tert-butyl.

64. The compound according to claim 63, wherein R⁵⁴ and R⁵⁵ independently of each other are hydrogen, methyl or ethyl.

65. The compound according to claim 64, wherein R⁵⁴ is hydrogen.

66. The compound according to claim 1, wherein R⁵⁴ and R⁵⁵ independently of each other are oxetanyl, tetrahydrofuranyl tetrahydropyranyl, oxepanyl, azetidyl, pyrrolidyl, piperidyl, hexahydroazepinyl, thietanyl, thiolanyl, tetrahydrothiopyranyl, thiepanyl, 1,4-oxathianyl, 1,3-dioxolanyl, 1,2-dithiolanyl, 1,3-dithiolanyl, hexahydro-pyridazinyl, imidazolidyl, 1,3-dioxanyl, morpholinyl, 1,3-dithianyl, 1,4-dioxanyl, 1,4-dithianyl, or thiomorpholinyl, each of which is optionally substituted with one or more substituents independently selected from R⁷¹.

67. The compound according to claim 66, wherein R⁵⁴ and R⁵⁵ independently of each other are tetrahydropyranyl, oxepanyl, piperidyl, hexahydroazepinyl, tetrahydrothiopyranyl, thiepanyl, 1,4-oxathianyl, 1,3-dithiolanyl, hexahydro-pyridazinyl, 1,3-dioxanyl, morpholinyl, 1,3-dithianyl, 1,4-dioxanyl, 1.4-dithianyl, or thiomorpholinyl, each of which is optionally substituted with one or more substituents independently selected from R⁷¹.

68. The compound according to claim 67, wherein R⁵⁴ and R⁵⁵ independently of each other are tetrahydropyranyl, piperidyl, tetrahydrothiopyranyl, 1,4-oxathianyl, hexahydro-pyridazinyl, morpholinyl, 1,4-dioxanyl, 1,4-dithianyl, or thiomorpholinyl, each of which is optionally substituted with one or more substituents independently selected from R⁷¹.

69. The compound according to claim 68, wherein R⁵⁴ and R⁵⁵ independently of each other are tetrahydropyranyl, piperidyl, tetrahydrothiopyranyl or morpholinyl, each of which is optionally substituted with one or more substituents independently selected from R⁷¹.

70. The compound according to claim 69, wherein R⁵⁴ and R⁵⁵ independently of each other are piperidyl or morpholinyl, each of which is optionally substituted with one or more substituents independently selected from R⁷¹.

71. The compound according to claim 70, wherein R⁵⁴ and R⁵⁵ independently of each other are piperidyl or morpholinyl.

72. The compound according to claim 1, wherein R⁵⁴ and R⁵⁵ independently of each other are furanyl, thienyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indolyl, purinyl, or indazolyl, each of which is optionally substituted with one or more substituents independently selected from R⁷¹.

73. The compound according to claim 72, wherein R⁵⁴ and R⁵⁵ independently of each other are furanyl, thienyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, benzofuranyl, indolyl, or purinyl, each of which is optionally substituted with one or more substituents independently selected from R⁷¹.

74. The compound according to claim 73, wherein R⁵⁴ and R⁵⁵ independently of each other are imidazolyl, triazolyl, tetrazolyl, thiazolyl, pyridinyl, pyrimidinyl, benzofuranyl, indolyl, or purinyl, each of which is optionally substituted with one or more substituents independently selected from R⁷¹.

75. The compound according to claim 74, wherein R⁵⁴ and R⁵⁵ independently of each other are imidazolyl, triazolyl, tetrazolyl, thiazolyl, pyridinyl, pyrimidinyl, or purinyl, each of which is optionally substituted with one or more substituents independently selected from R⁷¹.

76. The compound according to claim 75, wherein R⁵⁴ and R⁵⁵ independently of each other are imidazolyl, triazolyl, tetrazolyl, thiazolyl, pyridinyl, pyrimidinyl, each of which is optionally substituted with one or more substituents independently selected from R⁷¹.

77. The compound according to claim 76, wherein R⁵⁴ is imidazolyl optionally substituted with one or more substituents independently selected from R⁷¹.

78. The compound according to claim 76, wherein R⁵⁴ is thiazolyl optionally substituted with one or more substituents independently selected from R⁷¹.

79. The compound according to claim 76, wherein R⁵⁴ is tetrazolyl optionally substituted with one or more substituents independently selected from R⁷¹.

80. The compound according to claim 76, wherein R⁵⁴ is thiazolyl optionally substituted with one or more substituents independently selected from R⁷¹.

81. The compound according to claim 76, wherein R⁵⁴ is pyridinyl optionally substituted with one or more substituents independently selected from R⁷¹.

82. The compound according to claim 76, wherein R⁵⁴ is pyrimidinyl optionally substituted with one or more substituents independently selected from R⁷¹.

83. The compound according to claim 75, wherein R⁵⁴ is purinyl optionally substituted with one or more substituents independently selected from R⁷¹.

84. The compound according to claim 1, wherein R⁷¹ is methyl or ═

O.

85. The compound according to claim 1, wherein R⁷¹ is —

C(O)OH.

86. The compound according to claim 1, wherein R⁷¹ is —

(CH₂)_1-3C(O)OH.

87. The compound according to claim 1, wherein u is 0 or 1.

88. The compound according to claim 87, wherein u is 0.

89. The compound according to claim 87, wherein u is 1.

90. The compound according to claim 1, wherein v is 0 or 1.

91. The compound according to claim 90, wherein v is 0.

92. The compound according to claim 90, wherein v is 1.

93. The compound according to claim 1, wherein u is 0 and v is 1.

94. The compound according to claim 1, wherein u and v are both 0.

95. The compound according to claim 1, wherein R⁷² and R⁷³ are independently selected from hydrogen, hydroxy or —

C(O)OR⁷⁵.

96. The compound according to claim 95, wherein R⁷² and R⁷³ are independently selected from hydrogen or —

C(O)OR⁷⁵.

97. The compound according to claim 95, wherein R⁷² and R⁷³ are hydrogen.

98. The compound according to claim 1, wherein W⁶ is —

O—

R⁷⁵, —

C(O)O—

R⁷⁵, —

C(O)—

R⁷⁵, —

NR⁷⁵R⁷⁶, —

NHCH₂C(O)R⁷⁵, —

NHC(O)R⁷⁵, —

S(O)₂R⁷⁵, —

NHS(O)₂R⁷⁵;

or W⁶ is heterocyclyl.

99. The compound according to claim 98, wherein W₆ is —

O—

R⁷⁵, —

C(O)O—

R⁷⁵, —

C(O)—

R⁷⁵, —

NR⁷⁵R⁷⁶, —

NHCH₂C(O)R⁷⁵, —

NHC(O)R⁷⁵, —

S(O)₂R⁷⁵, —

NHS(O)₂R⁷⁵;

or W₆ is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, azetidyl, pyrrolidyl, piperidyl, hexahydroazepinyl, thietanyl, thiolanyl, tetrahydrothiopyranyl, thiepanyl, 1,4-oxathianyl, 1,3-dioxolanyl, 1,2-dithiolanyl, 1,3-dithiolanyl, hexahydro-pyridazinyl, imidazolidyl, 1,3-dioxanyl, morpholinyl, 1,3-dithianyl, 1,4-dioxanyl, 1,4-dithianyl, or thiomorpholinyl.

100. The compound according to claim 98, wherein W₆ is —

O—

R⁷⁵, —

C(O)O—

R⁷⁵, —

C(O)—

R⁷⁵, —

NR⁷⁵R⁷⁶, —

NHCH₂C(O)R⁷⁵, —

NHC(O)R⁷⁵, —

S(O)₂R⁷⁵, —

NHS(O)₂R⁷⁵;

or W⁶ is tetrahydropyranyl, oxepanyl, piperidyl, hexahydroazepinyl, tetrahydrothiopyranyl, thiepanyl, 1,4-oxathianyl, morpholinyl, 1,4-dioxanyl, 1,4-dithianyl, or thiomorpholinyl.

101. The compound according to claim 100, wherein W⁶ is —

O—

R⁷⁵, —

C(O)O—

R⁷⁵, —

C(O)—

R⁷⁵;

—

NR⁷⁵R⁷⁶, —

NHCH₂C(O)R⁷⁵, —

NHC(O)R⁷⁵, —

S(O)₂R⁷⁵, —

NHS(O)₂R⁷⁵;

or W⁶ is tetrahydropyranyl, piperidyl, tetrahydrothiopyranyl, or morpholinyl.

102. The compound according to claim 101, wherein W⁶ is —

O—

R⁷⁵, —

C(O)O—

R⁷⁵, —

NR⁷⁵R⁷⁶, —

NHC(O)R⁷⁵, —

S(O)₂R⁷⁵;

or

W₆ is tetrahydropyranyl, piperidyl, tetrahydrothiopyranyl, or morpholinyl.

103. The compound according to claim 102, wherein W⁶ is —

O—

R⁷⁵, or —

C(O)O—

R⁷⁵.

104. The compound according to claim 103, wherein W⁶ is —

C(O)O—

R⁷⁵.

105. The compound according to claim 1, wherein R⁷⁵ and R⁷⁶ are independently selected from the group consisting of hydrogen, —

OH, and C_1-6-alkyl optionally substituted with —

NH₂.

106. The compound according to claim 105, wherein R⁷⁵ and R⁷⁶ are independently selected from the group consisting of hydrogen, —

OH, and methyl.

107. The compound according to claim 106, wherein R⁷⁵ and R⁷⁶ are independently selected from the group consisting of hydrogen and —

OH.

108. The compound according to claim 107, wherein R⁷⁵ is hydrogen.