Bicycloheteroarylamine compounds as ion channel ligands and uses thereof

• US 20050277643A1
• Filed: 05/04/2005
• Published: 12/15/2005
• Est. Priority Date: 12/24/2003
• Status: Active Grant

• Current Assignee: Evotec AG
• Original Assignee: Renovis, Inc. (Evotec SE)
• Inventors: Wu, Guoxian, Kincaid, John, Wei, Zhi-Liang, Kelly, Michael G., Lonergan, David, Janagani, Satyanarayana, Fang, YunFeng
• Granted Patent: US 7,312,330 B2
• Time in Patent Office: Days
• US Class Current: 514/243
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

Amine compounds are disclosed that have a formula represented by the following: The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, pain, inflammation, traumatic injury, and others.

Claims

1. (canceled)

2. (canceled)

3. (canceled)

78. A compound according to claim 77, wherein R^3″

is substituted or unsubstituted

4. An amine compound capable of modifying ion channels, in vivo, having a formula:

5. A compound according to claim 4 wherein R¹ is substituted aryl or heteroaryl;

R² is H; and

R³ is substituted or unsubstituted aryl.

7. A compound according to claim 5 wherein R³ is substituted aryl, and the substitution on aryl is independently selected from halo, amido, alkyl, alkoxy, sulfonyl, sulfonamidyl, haloalkyl and trihaloalkyl.

8. A compound according to claim 5 wherein R³ is substituted aryl, and the substitution on aryl is independently selected from Cl, F, CF₃, Me, OMe, SO₂R^2′

, NR^2′

R^2′

, and SO₂NR^2′

R^2′

.

9. A compound according to claim 7 or 8 wherein substitution on aryl is at the 2- or the 4-position.

10. A compound according to claim 5 wherein R³ is substituted or unsubstituted heteroaryl.

11. A compound according to claim 10 wherein R³ is substituted or unsubstituted pyridyl.

12. A compound according to claim 11 wherein R³ is substituted 2-pyridyl.

13. A compound according to claim 12, wherein the substitution on 2-pyridyl is at the 3-position.

14. A compound according to claim 12, wherein the substitution on 2-pyridyl is at a ring position selected from the 4-position, the 5-position and the 6-position.

17. A compound according to claim 10, wherein R³ is 3,5- or 3,4-disubstituted 2-pyridyl.

18. A compound according to claim 13, wherein the substitutions on 2-pyridyl are independently selected from halo, amido, alkyl, alkoxy, cyano, sulfonyl, sulfonamidyl, haloalkyl and trihaloalkyl.

19. A compound according to claim 13, wherein the substitutions on 2-pyridyl are independently selected from Cl, F, CN, CF₃, Me, OMe, SO₂R^2′

, NR^2′

R^2′

, and SO₂NR^2′

R^2′

.

20. A compound according to claim 4, wherein W and Z both are CR⁴s.

21. A compound according to claim 4, wherein W is CR⁴ and Z is N.

22. A compound according to claim 4, wherein W is N and Z is CR⁴.

23. A compound according to claim 22, wherein R⁴ is selected from H, cyano, amido, and a group represented by X—

(CR^2′

R^2′

)_n—

R^3″

;

wherein X is a bond, O, S, SO, SO₂, or NR^2′

;

each R^2′

is selected from hydrogen, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aralkyl;

R^3″

is selected from a hydrogen, a hetero substituent and aryl, heteroaryl, heteroalkyl, cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, bicycloalkyl, bicycloheteroalkyl, bicycloalkenyl, bicycloheteroalkenyl, bicycloaryl, and bicycloheteroaryl ring; and

n is selected from 0-4;

provided when X is other than a bond, R^3″

is hetero substituent then n is at least 2.

24. A compound according to claim 23, wherein R⁴ is X—

(CR^2′

R^2′

)_n—

R^3″

.

25. A compound according to claim 24, wherein X is a bond, each R^2′

is H; and

n is 0-4.

26. A compound according to claim 24, wherein X is a O, S, SO or SO₂;

each R^2′

is H; and

n is 2-4.

27. A compound according to claims 25 or 26, wherein R^3″

is substituted or unsubstituted cycloalkyl, cycloheteroalkyl, aryl or heteroaryl.

28. A compound according to claims 25 or 26, wherein R^3″

is a hetero substituent.

29. A compound according to claim 28, wherein R^3″

is selected from COOH, SO₂Me, SMe, OH, OEt, OMe, NEt₂, NHSO₂Me, CONH₂, CONMe₂ and SO₂NMe₂.

30. A compound according to claim 23, wherein R⁴ represents H, CH₂OMe, OMe, OEt, SMe or OCH₂CO₂Me.

31. A compound according to claim 4, wherein R¹ is substituted aryl and R² is H.

32. A compound according to claim 31, wherein the substitution is at the 3-position or the 4-position.

33. A compound according to claim 31, wherein R¹ is 3,4-disubstituted aryl.

34. A compound according to claim 4, wherein R¹ is substituted heteroaryl and R² is H.

35. A compound according to claim 34, wherein R¹ is substituted pyridyl.

36. A compound according to claim 34, wherein R¹ is substituted 2-pyridyl.

37. A compound according to claim 36, wherein the substitution on pyridyl is selected from the 3-position, the 4-position and the 5-position.

38. A compound according to claim 35, wherein R¹ is substituted 3-pyridyl.

39. A compound according to claim 38, wherein the substitution on pyridyl is at the 4- or 5-position.

40. A compound according to claim 35, wherein R¹ is 3,4- or 3,5-disubstituted 2-pyridyl.

41. A compound according to either of claims 31 or 35, wherein the substitutions are independently selected from halo, amido, alkyl, alkoxy, cyano, sulfonyl, sulfonamidyl, haloalkyl and trihaloalkyl.

42. A compound according to either of claims 31 or 35, wherein the substitutions are independently selected from t-Bu, Cl, F, iso-Pr, CF₃, OMe, OCF₃, OCHF₂, SO₂CF₃, SO₂R^2′

, SO₂NR^2′

R^2′

, CN, C(Me)₂CN and NR¹R².

43. A compound according to claim 4, 5, 11 and 23, wherein A, B and Y all are CH₂s.

97. A compound according to claim 4 selected from the group consisting of:

100. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 4.

101. The pharmaceutical composition of claim 100, wherein the carrier is a parenteral carrier.

102. The pharmaceutical composition of claim 100, wherein the carrier is an oral carrier.

103. The pharmaceutical composition of claim 100, wherein the carrier is a topical carrier.

105. A method for preventing, treating or ameliorating in a mammal a disease or condition which comprises administering to the mammal an effective disease-treating or condition-treating amount of a pharmaceutical composition according to claim 100.

106. The method of claim 105, wherein the disease or condition is a pain condition.

107. The method of claim 105, wherein the disease or condition is an autoimmune disease.

108. The method of claim 105, wherein the disease or condition is an inflammatory disease or condition.

109. The method of claim 105, wherein the disease or condition is a neurological or neurodegenerative disease or condition.

110. A method for preventing, treating or ameliorating in a mammal a disease or condition selected from:

pain including acute, inflammatory and neuropathic pain, chronic pain, dental pain and headache including migraine, cluster headache and tension headache, Parkinson'"'"'s disease, Alzheimer'"'"'s disease and multiple sclerosis;

diseases and disorders which are mediated by or result in neuroinflammation, traumatic brain injury, stroke, and encephalitis;

centrally-mediated neuropsychiatric diseases and disorders, depression mania, bipolar disease, anxiety, schizophrenia, eating disorders, sleep disorders and cognition disorders;

epilepsy and seizure disorders;

prostate, bladder and bowel dysfunction, urinary incontinence, urinary hesitancy, rectal hypersensitivity, fecal incontinence, benign prostatic hypertrophy and inflammatory bowel disease;

respiratory and airway disease and disorders, allergic rhinitis, asthma and reactive airway disease and chronic obstructive pulmonary disease;

diseases and disorders which are mediated by or result in inflammation, arthritis, rheumatoid arthritis and osteoarthritis, myocardial infarction, various autoimmune diseases and disorders, uveitis and atherosclerosis;

itch/pruritus, psoriasis;

alopecia (hair loss);

obesity;

lipid disorders;

cancer;

blood pressure;

spinal cord injury; and

renal disorders which comprises administering to the mammal an effective disease-treating or condition-treating amount of a pharmaceutical composition of claim 100.

111. The method of claim 110, wherein the disease or condition is Parkinson'"'"'s disease.

112. The method of claim 110, wherein the disease or condition is Alzheimer'"'"'s disease.

113. The method of claim 110, wherein the disease or condition is traumatic brain injury.

114. The method of claim 110, wherein the disease or condition is stroke.

115. The method of claim 110, wherein the disease or condition is pain.

116. The method of claim 110, wherein the disease or condition is neuropathic pain.

117. A method of treating a mammal suffering from at least one symptom selected from the group consisting of symptoms of exposure to capsaicin, symptoms of burns or irritation due to exposure to heat, symptoms of burns or irritation due to exposure to light, symptoms of burns, bronchoconstriction or irritation due to exposure to tear gas, and symptoms of burns or irritation due to exposure to acid, which comprises administering to the mammal an effective disease-treating or condition-treating amount of a pharmaceutical composition of claim 100.

118. The method of claim 110, wherein the pain is associated with a condition selected from the group consisting of postmastectomy pain syndrome, stump pain, phantom limb pain, oral neuropathic pain, Charcot'"'"'s pain, toothache, venomous snake bite, spider bite, insect sting, postherpetic neuralgia, diabetic neuropathy, reflex sympathetic dystrophy, trigeminal neuralgia, osteoarthritis, rheumatoid arthritis, fibromyalgis, Guillain-Barre syndrome, meralgia paresthetica, burning-mouth syndrome, bilateral peripheral neuropathy, causalgia, sciatic neuritis, peripheral neuritis, polyneuritis, segmental neuritis, Gombault'"'"'s neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia, egniculate neuralgia, glossopharyngial neuralgia, migranous neuralgia, idiopathic neuralgia, intercostals neuralgia, mammary neuralgia, mandibular joint neuralgia, Morton'"'"'s neuralgia, nasociliary neuralgia, occipital neuralgia, red neuralgia, Sluder'"'"'s neuralgia splenopalatine neuralgia, supraorbital neuralgia, vidian neuralgia, sinus headache, tension headache, labor, childbirth, intestinal gas, menstruation, cancer, and trauma.

126. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 97.

6. (canceled)

15. (canceled)

16. (canceled)

44. An amine compound capable of modifying ion channels, in vivo, having a formula:

45. A compound according to claim 44, wherein the compound is depicted by the formula

46. A compound according to claim 44, wherein the compound is depicted by the formula

47. A compound according to claim 44, wherein the compound is depicted by the formula

48. A compound according to claim 44, wherein the compound is depicted by the formula

49. A compound according to claim 44, wherein the compound is depicted by the formula

50. A compound according to claim 44, wherein the compound is depicted by the formula

58. A compound according to either of claims 44 or 51, wherein W and Z both are CR⁴s.

59. A compound according to either of claims 44 or 51, wherein W is N and Z is CR⁴.

60. A compound according to claim 59, wherein R⁴ is selected from H, cyano, amido, and a group represented by X—

(CR^2′

R^2′

)_n—

R^3″

;

wherein X is a bond, O, S, SO, SO₂, or NR^2′

;

each R^2′

is selected from hydrogen, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aralkyl;

R^3″

is selected from a hydrogen, a hetero substituent and aryl, heteroaryl, heteroalkyl, cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, bicycloalkyl, bicycloheteroalkyl, bicycloalkenyl, bicycloheteroalkenyl, bicycloaryl, and bicycloheteroaryl ring; and

n is selected from 0-4;

provided when X is other than a bond, R^3″

is hetero substituent then n is at least 2.

61. A compound according to claim 60, wherein R⁴ is X—

(CR^2′

R^2′

)_n—

R^3″

.

62. A compound according to claim 61, wherein X is a bond, each R^2′

is H; and

n is 0-4.

63. A compound according to claim 61, wherein X is O, S, SO or SO₂;

each R^2′

is H; and

n is 2-4.

64. A compound according to claim 63, wherein R^3″

is substituted or unsubstituted cycloalkyl, cycloheteroalkyl, aryl or heteroaryl.

65. A compound according to claim 63, wherein R^3″

is a hetero substituent.

66. A compound according to claim 65, wherein R^3″

is selected from COOH, SO₂Me, SMe, OH, OEt, OMe, NEt₂, NHSO₂Me, CONH₂, CONMe₂ and SO₂NMe₂.

67. A compound according to claim 59, wherein R⁴ represents H, CH₂OMe, OMe, OEt, SMe or OCH₂CO₂Me.

68. A compound according to either of claims 44-51, wherein A, B and Y all are CH₂s.

69. A compound according to either of claims 44-51, wherein A and B are independently selected from CH₂ and CHCH₃, and Y is CH₂.

70. A compound according to claim 44, wherein the compound is depicted by the formula

71. A compound according to claim 70, wherein R¹ is selected from substituted and unsubstituted pyridyl.

72. A compound according to claim 71, wherein the substitution is selected from t-Bu, Cl, F, iso-Pr, CF₃, OMe, OCF₃, OCHF₂, SO₂CF₃, SO₂R^2′

, SO₂NR^2′

R^2′

, CN, C(Me)₂CN, and NR¹R².

73. A compound according to claim 70, wherein R¹ is selected from substituted or unsubstituted indolyl, benzimidazolyl, indazolyl, tetrahydroquinoline, and tetrahydraisoquinoline.

74. A compound according to claim 44, wherein the compound is depicted by the formula

75. A compound according to claim 74, wherein R⁴ is —

(CR^2′

R^2′

)_n—

R^3″

.

76. A compound according to claim 75, wherein each R^2′

is H; and

n is 2-4.

77. A compound according to claim 76, wherein R^3″

is substituted or unsubstituted cycloalkyl, cycloheteroalkyl, aryl or heteroaryl.

79. A compound according to claim 76, wherein R^3″

is a hetero substitutent.

80. A compound according to claim 79, wherein R^3″

is selected from COOH, SO₂Me, SMe, OH, OEt, OMe, NEt₂, halo, NHSO₂Me, CONH₂, CONMe₂, SO₂NH₂, and SO₂NMe₂.

81. A compound according to claim 74, wherein W and Z both are CR⁴s.

82. A compound according to claim 74, wherein W is N and Z is CR⁴.

83. A compound according to claim 82, wherein R⁴ is selected from H, cyano, amido, and a group represented by X—

(CR^2′

R^2′

)_n—

R^3″

;

wherein X is a bond, O, S, SO, SO₂, or NR^2′

;

each R^2′

is selected from hydrogen, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aralkyl;

R^3″

is selected from a hydrogen, a hetero substituent and aryl, heteroaryl, heteroalkyl, cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, bicycloalkyl, bicycloheteroalkyl, bicycloalkenyl, bicycloheteroalkenyl, bicycloaryl, and bicycloheteroaryl ring; and

n is selected from 0-4;

provided when X is other than a bond, R^3″

is hetero substituent, then n is at least 2.

84. A compound according to claim 83, wherein R⁴ is X—

(CR^2′

R^2′

)_n—

R^3″

.

85. A compound according to claim 84, wherein X is a bond, each R^2′

is H; and

n is 0-4.

86. A compound according to claim 84, wherein X is O, S, SO or SO₂;

each R^2′

is H; and

n is 2-4.

87. A compound according to claim 86, wherein R^3″

is substituted or unsubstituted cycloalkyl, cycloheteroalkyl, aryl or heteroaryl.

88. A compound according to claim 86, wherein R^3″

is a hetero substituent.

89. A compound according to claim 88, wherein R^3″

is selected from COOH, SO₂Me, SMe, OH, OEt, OMe, NEt₂, NHSO₂Me, CONH₂, CONMe₂ and SO₂NMe₂.

90. A compound according to claim 82, wherein R⁴ represents H, CH₂OMe, OMe, OEt, SMe or OCH₂CO₂Me.

91. A compound of either of claims 70 or 74, wherein A, B and Y are all CH₂s.

92. A compound of either of claims 70 or 74, wherein A and B are independently selected from CH₂ and CHCH₃, and Y is CH₂.

93. A compound of claim 74, wherein X′

is N.

94. A compound of claim 74, wherein X′

is CH.

122. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 44.

124. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 70.

125. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 74.

51. An amine compound capable of modifying ion channels, in vivo, having a formula:

52. A compound according to claim 51, wherein the compound is depicted by the formula

53. A compound according to claim 51, wherein the compound is depicted by the formula

54. A compound according to claim 51, wherein the compound is depicted by the formula

55. A compound according to claim 51, wherein the compound is depicted by the formula

56. A compound according to claim 51, wherein the compound is depicted by the formula

57. A compound according to claim 51, wherein the compound is depicted by the formula

123. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 51.

95. An amine compound capable of modifying ion channels, in vivo, having a formula:

96. An amine compound capable of modifying ion channels, in vivo, having a formula:

98. A compound selected from the group consisting of:

7-(3-chloropyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine;

N-(4-tert-butylphenyl)-7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine;

N-(4-tert-butylphenyl)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine;

N-(4-tert-butylphenyl)-7-(3-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine;

N-(4-tert-Butyl-phenyl)-[7-(3-chloro-pyridin-2-yl)-2-methoxymethyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl]-amine;

N-(4-tert-Butyl-phenyl)-[2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl]-amine;

7-(3,3,3-trifluoropropyl)-5,6,7,8-tetrahydro-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrido[3,4-d]pyrimidin-4-amine;

N-(4-tert-Butyl-phenyl)-[7-(3-methanesulfonyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl]-amine;

[7-(3-Methanesulfonyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine;

7-(3-(ethylsulfonyl)pyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine;

[7-(3-Fluoro-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine;

(4-Trifluoromethyl-phenyl)-[7-(3-trifluoromethyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl]-amine;

N-(4-tert-Butylphenyl)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydro-2-(morpholinomethyl)pyrido[3,4-d]pyrimidin-4-amine;

N-(4-(difluoromethoxy)phenyl)-5,6,7,8-tetrahydro-7-(3-(methylsulfonyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4-amine;

7-(3-chloropyridin-2-yl)-N-(4-(difluoromethoxy)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine;

N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-7-(3-(isopropylsulfonyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4-amine;

7-(3-Chloropyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine;

7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydro-N-phenylpyrido[3,4-d]pyrimidin-4-amine;

7-(3-chloropyridin-2-yl)-N-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine;

7-(3-chloropyridin-2-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine;

N-(6-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydro-7-(3-(methylsulfonyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4-amine;

7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydro-N-(4-(trifluoromethylsulfonyl)phenyl)pyrido[3,4-d]pyrimidin-4-amine;

5,6,7,8-tetrahydro-7-(3-(methylsulfonyl)pyridin-2-yl)-N-(4-(trifluoromethylsulfonyl)phenyl)pyrido[3,4-d]pyrimidin-4-amine;

7-(3-Chloropyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4-amine;

[7-(3-Chloro-pyridin-2-yl)-2-methanesulfonyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine;

6-(3-chloropyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-amine;

7-(3-Chloropyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-methoxypyrido[3,4-d]pyrimidin-4-amine;

N-(4-tert-Butylphenyl)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4-amine;

N-(4-tert-Butylphenyl)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydro-2-methoxypyrido[3,4-d]pyrimidin-4-amine;

(7-Benzyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amine;

7-Benzyl-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methoxymethyl)pyrido[3,4-d]pyrimidin-4-amine;

7-(3-Chloropyridin-2-yl)-N²-(2-(dimethylamino)ethyl)-N⁴-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine;

7-(3-Chloropyridin-2-yl)-N⁴-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-N²-(2-morpholinoethyl)pyrido[3,4-d]pyrimidine-2,4-diamine;

7-(3-Chloropyridin-2-yl)-N⁴-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-N²,N²-dimethylpyrido[3,4-d]pyrimidine-2,4-diamine;

7-(3-Chloropyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methoxymethyl)pyrido[3,4-d]pyrimidin-4-amine;

5,6,7,8-tetrahydro-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-m-tolylpyrido[3,4-d]pyrimidin-4-amine;

4-(4-(Trifluoromethyl)phenylamino)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2-carbonitrile;

7-Benzyl-5,6,7,8-tetrahydro-N-(quinolin-3-yl)pyrido[3,4-d]pyrimidin-4-amine;

7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydro-N-phenethylpyrido[3,4-d]pyrimidin-4-amine;

N-(4-chlorophenethyl)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine;

N-(4-chlorobenzyl)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine;

N-(3,4-dichlorophenyl)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine;

7-(3-chloropyridin-2-yl)-N-(3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine;

N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-7-phenylpyrido[3,4-d]pyrimidin-4-amine;

N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-7-o-tolylpyrido[3,4-d]pyrimidin-4-amine;

N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-7-m-tolylpyrido[3,4-d]pyrimidin-4-amine;

N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-7-p-tolylpyrido[3,4-d]pyrimidin-4-amine;

7-(3-Chloropyridin-2-yl)-2-ethoxy-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine;

N-(6-tert-butylpyridin-3-yl)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine;

N-(3-(trifluoromethyl)phenethyl)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine;

7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydro-N-(3-phenylpropyl)pyrido[3,4-d]pyrimidin-4-amine;

7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydro-N-(2-phenoxyethyl)pyrido[3,4-d]pyrimidin-4-amine;

7-(Cyclohexylmethyl)-5,6,7,8-tetrahydro-N-(quinolin-3-yl)pyrido[3,4-d]pyrimidin-4amine;

5,6,7,8-Tetrahydro-7-phenethyl-N-(quinolin-3-yl)pyrido[3,4-d]pyrimidin-4-amine;

5,6,7,8-tetrahydro-7-(3-phenylpropyl)-N-(quinolin-3-yl)pyrido[3,4-d]pyrimidin-4-amine;

2-(4-(7-(3-Chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ylamino)phenyl)-2-methylpropanenitrile;

4-(4-(Trifluoromethyl)phenylamino)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-ol;

7-(7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ylamino)-4,4-dimethylisoquinoline-1,3(2H,4H)-dione;

7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydro-N-(1,2,3,4-tetrahydro-4,4-dimethylquinolin-7-yl)pyrido[3,4-d]pyrimidin-4-amine;

7-(3-Chloropyridin-2-yl)-5,6,7,8-tetrahydro-N-(1,2,3,4-tetrahydro-1,4,4-trimethylquinolin-7-yl)pyrido[3,4-d]pyrimidin-4-amine;

1-(7-(7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ylamino)-3,4-dihydro-4,4-dimethylisoquinolin-2 (1H)-yl)ethanone;

7-(3-Chloropyridin-2-yl)-5,6,7,8-tetrahydro-N-(1,2,3,4-tetrahydro-4,4-dimethylquinolin-7-yl)pyrido[3,4-d]pyrimidin-4-amine;

N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-7-(3-(methylsulfonyl)pyridin-2-yl)-2-(methylthio)pyrido[3,4-d]pyrimidin-4-amine;

2-Ethoxy-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-7-(3-(methylsulfonyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4-amine;

7-(3-Chloropyridin-2-yl)-5,6,7,8-tetrahydro-N-(3,4-dihydro-4-methyl-2H-benzo[b][1,4]oxazin-7-yl)pyrido[3,4-d]pyrimidin-4-amine;

Methyl 2-(4-(4-(trifluoromethyl)phenylamino)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yloxy)acetate;

6-(7-(3-Chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ylamino)-3,3-dimethylindolin-2-one;

1-(6-(7-(3-Chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ylamino)-3,3-dimethylindolin-1-yl)ethanone;

7-(3-Chloropyridin-2-yl)-5,6,7,8-tetrahydro-N-(3,3-dimethylindolin-6-yl)pyrido[3,4-d]pyrimidin-4-amine;

7-(3-Chloropyridin-2-yl)-5,6,7,8-tetrahydro-N-(1,3,3-trimethylindolin-6-yl)pyrido[3,4-d]pyrimidin-4-amine;

7-(4-(Trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydro-N-(2,3-dihydrobenzo[b][1,4]dioxin-7-yl)pyrido[3,4-d]pyrimidin-4-amine;

7-(4-(Trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydro-N-(3-methoxyphenyl)pyrido[3,4-d]pyrimidin-4-amine;

7-(5-(Trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydro-N-(3-methoxyphenyl)pyrido[3,4-d]pyrimidin-4-amine;

7-(3-Chloropyridin-2-yl)-5,6,7,8-tetrahydro-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrido[3,4-d]pyrimidin-4-amine;

2-(4-(4-(Trifluoromethyl)phenylamino)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yloxy)acetic acid;

7-(3-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydro-N-(4-(trifluoromethylsulfonyl)-phenyl)pyrido[3,4-d]pyrimidin-4-amine;

N-(4-(difluoromethoxy)phenyl)-7-(3-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine;

7-(3-Chloropyridin-2-yl)-5,6,7,8-tetrahydro-N-(4-(trifluoromethoxy)-phenyl)pyrido[3,4-d]pyrimidin-4-amine;

7-(3-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydro-N-(4-(trifluoromethoxy)-phenyl)pyrido[3,4-d]pyrimidin-4-amine;

and pharmaceutically acceptable salts, solvates and stereoisomers and tautomers thereof.

127. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 98.

99. A compound selected from the group consisting of:

7-(3-chloropyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine;

N-(4-tert-butylphenyl)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine;

N-(4-tert-Butyl-phenyl)-[7-(3-chloro-pyridin-2-yl)-2-methoxymethyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl]-amine;

N-(4-tert-Butyl-phenyl)-[7-(3-methanesulfonyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl]-amine;

[7-(3-Methanesulfonyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine;

7-(3-(ethylsulfonyl)pyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine;

N-(4-tert-Butylphenyl)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4-amine;

N-(4-tert-Butylphenyl)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydro-2-methoxypyrido[3,4-d]pyrimidin-4-amine;

7-(3-Chloropyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methoxymethyl)pyrido[3,4-d]pyrimidin-4-amine;

4-(4-(Trifluoromethyl)phenylamino)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2-carbonitrile;

7-(3-Chloropyridin-2-yl)-2-ethoxy-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine;

and pharmaceutically acceptable salts, solvates and stereoisomers and tautomers thereof.

128. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 99.

104. (canceled)

119. (canceled)

120. (canceled)

121. (canceled)