Aryl cyclopropyl-amino-isoquinolin amide compound

文档序号：1745511 发布日期：2019-11-26 浏览：30次中文

阅读说明：本技术 芳基环丙基-氨基-异喹啉酰胺化合物 (Aryl cyclopropyl-amino-isoquinolin amide compound ) 是由米契尔·A·德龙吉尔·M·斯特迪文特辛西娅·L·利绍罗维克安德烈·科尔尼洛夫于 2018-03-30 设计创作，主要内容包括：本文提供了芳基环丙基氨基-异喹啉酰胺化合物。特别地,本公开提供了影响细胞中激酶功能的化合物,其可用作治疗剂或与治疗剂一起使用。本公开的化合物可用于治疗多种疾病和病况,包括眼部疾病(例如青光眼)、心血管疾病、以异常生长为特征的疾病(例如癌症)和炎症性疾病。本公开还提供了包含异喹啉酰胺化合物的组合物。(There is provided herein aryl cyclopropyl amino-isoquinolin amide compounds.Particularly, present disclose provides the compound for influencing kinase function in cell, it can be used as therapeutic agent or be used together with therapeutic agent.The compound of the disclosure can be used for treating a variety of diseases and the patient's condition, including eye disease (such as glaucoma), cardiovascular disease, the disease (such as cancer) characterized by misgrowth and diseases associated with inflammation.The disclosure additionally provides the composition comprising isoquinolin amide compound.)

1. according to the compound of formula (I):

Or its tautomer, stereoisomer and pharmaceutically acceptable salt,

Wherein:

X₁、X₂And X₃It independently is H, halogen, nitrile, hydroxyl or C_1-6Alkyl；

Y is-NR^N1S(O)₂-、–NR^N1C(O)-、-O(CR¹ ₂)_n-、-NR^N1(CR¹ ₂)_m-、-C(O)O-、-OC(O)-、-S(O)₂-、-C (O)-、-NR^N1C(O)O(CR¹ ₂)_nOr C_1-6Alkylidene；

Z is direct key or C_1-6Alkylidene；

R is H, halogen, cyano, OR³、C_1-6Alkyl, amino, naphthenic base, heterocycle, aryl or heteroaryl or R can be with R^N1 Or R¹The ring with 5 to 7 member atoms is formed, wherein the ring can be selected from the hetero atom of N, O and S, institute containing at most 2 It is saturated or unsaturated for stating ring；

R^N1It is H or C_1-6Alkyl forms ring with R；

R¹It is H, F or Me or forms ring with R；

R³It is H or C_1-6Alkyl；

N is 0 to 6 integer；And

M is 1 to 6 integer.

2. compound according to claim 1, wherein the compound is the compound of formula (II):

Or its tautomer, stereoisomer and pharmaceutically acceptable salt,

Wherein:

X₁、X₂And X₃It independently is H, halogen, nitrile, hydroxyl or C_1-6Alkyl；

Y is-NR^N1S(O)₂-、–NR^N1C(O)-、-O(CR¹ ₂)_n-、-NR^N1(CR¹ ₂)_m-、-C(O)O-、-OC(O)-、-S(O)₂-、-C (O)-、-NR^N1C(O)O(CR¹ ₂)_nOr C_1-6Alkylidene；

Z is direct key or C_1-6Alkylidene；

R^N1It is H or C_1-6Alkyl forms ring with R；

R¹It is H, F or Me or forms ring with R；

R³It is H or C_1-6Alkyl；

N is 0 to 6 integer；And

M is 1 to 6 integer.

3. compound according to claim 1, wherein the compound is the compound of formula (III):

Or its tautomer, stereoisomer and pharmaceutically acceptable salt,

Wherein:

X₁、X₂And X₃It independently is H, halogen, nitrile, hydroxyl or C_1-6Alkyl；

Y is-NR^N1S(O)₂-、–NR^N1C(O)-、-O(CR¹ ₂)_n-、-NR^N1(CR¹ ₂)_m-、-C(O)O-、-OC(O)-、-S(O)₂-、-C (O)-、-NR^N1C(O)O(CR¹ ₂)_nOr C_1-6Alkylidene；

Z is direct key or C_1-6Alkylidene；

R^N1It is H or C_1-6Alkyl forms ring with R；

R¹It is H, F or Me or forms ring with R；R³It is H or C_1-6Alkyl；

N is 0 to 6 integer；And

M is 1 to 6 integer.

4. according to the compound of formula (IV):

Or its tautomer, stereoisomer and pharmaceutically acceptable salt,

Wherein:

X₁、X₂And X₃It independently is H, halogen, nitrile, hydroxyl or C_1-6Alkyl；

Y is-NR^N1S(O)₂-、–NR^N1C(O)-、-O(CR¹ ₂)_n-、-NR^N1(CR¹ ₂)_m-、-C(O)O-、-OC(O)-、-S(O)₂-、-C (O)-、-NR^N1C(O)O(CR¹ ₂)_nOr C_1-6Alkylidene；

Z is direct key or C_1-6Alkylidene；

R^N1It is H or C_1-6Alkyl forms ring with R；

R¹It is H, F or Me or forms ring with R；R³It is H or C_1-6Alkyl；

N is 0 to 6 integer；And

M is 1 to 6 integer.

5. according to the compound of formula (VII):

Or its tautomer, stereoisomer and pharmaceutically acceptable salt,

Wherein:

X₁、X₂And X₃It independently is H, halogen, nitrile, hydroxyl or C_1-6Alkyl；

Y is-NR^N1S(O)₂-；

Z is direct key or C_1-6Alkylidene；

R^N1It is H or C_1-6Alkyl forms ring with R；

R¹It is H, F or Me or forms ring with R；

R³It is H or C_1-6Alkyl；

N is 0 to 6 integer；And

M is 1 to 6 integer.

6. according to the compound of formula (VIII):

Or its tautomer, stereoisomer and pharmaceutically acceptable salt,

Wherein:

X₁、X₂And X₃It independently is H, halogen, nitrile, hydroxyl or C_1-6Alkyl；

Y is-NR^N1S(O)₂-；

Z is direct key or C_1-6Alkylidene；

R^N1It is H or C_1-6Alkyl forms ring with R；

R¹It is H, F or Me or forms ring with R；

R³It is H or C_1-6Alkyl；

N is 0 to 6 integer；And

M is 1 to 6 integer.

7. according to the compound of formula (IX):

Or its tautomer, stereoisomer and pharmaceutically acceptable salt,

Wherein:

X₁、X₂And X₃It independently is H, halogen, nitrile, hydroxyl or C_1-6Alkyl；

Y is-NR^N1S(O)₂-；

Z is direct key or C_1-6Alkylidene；

R^N1It is H or C_1-6Alkyl forms ring with R；

R¹It is H, F or Me or forms ring with R；

R³It is H or C_1-6Alkyl；

N is 0 to 6 integer；And

M is 1 to 6 integer.

8. compound described in any one of -7 according to claim 1, wherein X¹、X²And X³It is hydrogen.

9. compound described in any one of -7 according to claim 1, wherein X¹It is OH, CN, F, Br, Cl or CH₃。

10. compound described in any one of -7 or 9 according to claim 1, wherein X²It is CN, F, Br, Cl or CH₃。

11. compound described in any one of -7,9 or 10 according to claim 1, wherein X³It is-CF₃、-OCH₃、CN、F、Br、 Cl、OCF₃Or CH₃。

12. compound described in any one of -4 or 8-11 according to claim 1, wherein Y is-NR^N1S(O)₂-。

13. according to compound described in claim 5-7 or 12, wherein R^N1It is H.

14. wherein R is alkyl, aryl, heteroaryl, carbocylic radical or heterocycle according to compound described in claim 5-7,13 or 14 Base.

15. compound described in any one of -4 or 8-11 according to claim 1, wherein Y is-NR^N1C (O) and R is piperidines Base, morpholinyl, thio-furan, aisaa benzothiophenyl, thiophenyl, isoquinolin, quinolyl or pyrrolidinyl.

16. compound described in any one of -4 or 8-11 according to claim 1, wherein Y is-NR^N1C (O) and R is H, C_1-6 Alkyl, naphthenic base or heterocycle or R can be with R^N1The ring with 5 to 7 member atoms is formed, wherein the ring can contain There are at most 2 hetero atoms for being selected from N, O and S, can be saturated or unsaturated.

17. compound according to claim 15 or 16, wherein R^N1It is H.

18. compound described in any one of 5-17 according to claim 1, wherein Z is-CH₂-。

19. compound according to claim 18, wherein R is heterocycle.

20. compound according to claim 18, wherein R is piperidyl or pyrrolidinyl.

21. compound described in any one of -4 or 8-11 according to claim 1, wherein Y is-O (CR¹ ₂)_n-。

22. compound according to claim 21, wherein R is that naphthenic base, heterocycle or heteroaryl or R can be with R¹Shape It can be at the ring with 5 to 7 member atoms wherein the ring can be selected from the hetero atom of N, O and S containing at most 2 It is saturated or unsaturated.

23. the compound according to claim 21 or 22, wherein one or two R¹It is H.

24. compound described in any one of -4 or 8-11 according to claim 1, wherein Y is NR^N1(CR¹ ₂)_m-。

25. compound according to claim 24, wherein R is H, C_1-6Alkyl, naphthenic base, heterocycle, aryl or heteroaryl Base or R can be with R^N1Form the ring with 5 to 7 member atoms, wherein the ring can containing at most 2 selected from N, O and The hetero atom of S can be saturated or unsaturated.

26. the compound according to claim 24 or 25, wherein one or two R¹It is H.

27. compound described in any one of -4 or 8-11 according to claim 1, wherein Y is-C (O) O- or OC (O) -.

28. compound according to claim 27, wherein R is H, naphthenic base, heterocycle, aryl or heteroaryl and wherein Z is direct key.

29. compound described in any one of -4 or 8-11 according to claim 1, wherein Y is NR^N1C(O)O(CR¹ ₂)_n-。

30. compound according to claim 29, wherein R is aryl.

31. compound according to claim 30, wherein R is phenyl.

32. compound according to claim 31, wherein R is substituted phenyl.

33. compound described in any one of -32 according to claim 1, wherein Z is direct key.

34. compound described in any one of -32 according to claim 1, wherein Z is-CH₂-。

35. compound described in any one of -14 according to claim 1, wherein R is heteroaryl or heterocycle.

36. compound according to claim 35, wherein R is pyridyl group, piperidyl, morpholinyl, thiophenyl, isoquinolin Base, quinolyl or pyrrolidinyl.

37. compound described in any one of -14 according to claim 1, wherein R is aryl.

38. the compound according to claim 37, wherein R is phenyl.

39. the compound according to claim 38, wherein R is substituted phenyl.

40. compound described in any one of -4 according to claim 1, wherein R is pyridyl group, and Y is NR^N1C (O)-, R^N1It is H, Z It is-CH₂-, and X¹、X²And X³It is H.

41. compound described in any one of -4 according to claim 1, wherein R is isoquinolyl, and Y is-NR^N1C (O)-, R^N1It is H, Z are direct key and X¹、X²And X³It is H.

42. compound of any of claims 1-3, wherein Y is-NR^N1S(O)₂-、–NR^N1C(O)-、-NR^N1 (CR¹ ₂)_m-、-S(O)₂-、-C(O)-、-NR^N1C(O)O(CR¹ ₂)_nOr C_1-6Alkylidene.

43. compound of any of claims 1-3, wherein R is halogen, cyano, OR³, amino, naphthenic base, heterocycle Base, aryl or heteroaryl or R can be with R^N1Or R¹The ring with 5 to 7 member atoms is formed, wherein the ring can contain There are at most 2 hetero atoms for being selected from N, O and S, the ring is saturated or unsaturated.

44. compound of any of claims 1-3, wherein R¹It is F or Me or forms ring with R.

45. compound of any of claims 1-3, wherein n is 2,3,4,5 or 6.

46. compound, the compound is selected from

And its stereoisomer and pharmaceutically acceptable salt.

47. compound, the compound is selected from the group being made up of:

And its stereoisomer and pharmaceutically acceptable salt.

48. compound, the compound is selected from:

And its stereoisomer and pharmaceutically acceptable salt.

49. compound, the compound is selected from:

And its stereoisomer and pharmaceutically acceptable salt.

50. compound, the compound is selected from:

And its stereoisomer and pharmaceutically acceptable salt.

51. compound, the compound is selected from:

And its stereoisomer and pharmaceutically acceptable salt.

52. compound, the compound is selected from:

And its stereoisomer and pharmaceutically acceptable salt.

53. compound, the compound is selected from:

And its stereoisomer and pharmaceutically acceptable salt.

54. compound, the compound is selected from:

And its stereoisomer and pharmaceutically acceptable salt.

55. compound, the compound is selected from:

And its stereoisomer and pharmaceutically acceptable salt.

56. compound, the compound is selected from:

And its stereoisomer and pharmaceutically acceptable salt.

57. compound, the compound is selected from:

And its stereoisomer and pharmaceutically acceptable salt.

58. compound, the compound is selected from:

And its stereoisomer and pharmaceutically acceptable salt.

59. pharmaceutical composition, it includes compounds described according to claim 1 any one of -58 and pharmaceutically acceptable Excipient.

60. treating the method for eye disorders in subject in need for the treatment of comprising apply claim to the subject Compound or composition described in any one of 1-59.

61. method described in claim 60, wherein the eye disorders are glaucoma, inflammatory ocular disease or neurological Property eye disease.

62. method described in claim 60, wherein the eye disorders are diabetic ocular diseases, Wet Age correlation Macular degeneration or Local Electroretinogram.

63. method described in any one of claim 60-62, wherein the compound or composition be locally applied to it is described The eyes of subject.

64. reducing the method for intraocular pressure in subject with this need comprising apply right to the eyes of the subject It is required that compound or composition described in any one of 1-59.

65. method described in claim 64, wherein the compound or composition is locally applied.

66. a kind of kit, it includes the compound or compositions and operation instruction described in any one of claim 1-59.

67. the compound or its pharmaceutically acceptable salt of formula (X),

Wherein,

R¹It is H ,-C_1-6Alkyl ,-C_1-6Halogenated alkyl, aryl, heteroaryl ,-(C_1-6Alkyl)-pyridyl group ,-(C_1-6Alkyl)-N (R³) R⁴、-(C_1-6Alkyl)-heterocycle or Heterocyclylalkyl；

R²It is H ,-C_1-6Alkyl ,-C_1-6Halogenated alkyl, aryl, heteroaryl ,-(C_1-6Alkyl)-pyridyl group ,-(C_1-6Alkyl)-N (R³) R⁴、-(C_1-6Alkyl)-heterocycle or Heterocyclylalkyl；

Or R¹And R²And nitrogen in connection is formed together heterocycle；

R³It is H, C_1–6Alkyl or-C_1–6Halogenated alkyl；

R⁴It is H, C_1–6Alkyl or-C_1–6Halogenated alkyl；

X is H, C_1–6Alkyl ,-C_1–6Halogenated alkyl, halogen or hydroxyl；

Y is H, C_1–6Alkyl ,-C_1–6Halogenated alkyl, halogen or hydroxyl；And

Z is H, C_1–6Alkyl ,-C_1–6Halogenated alkyl, halogen or hydroxyl.

68. compound described in claim 67 or its pharmaceutically acceptable salt, wherein the compound of formula (X) is formula (XI) Compound:

69. compound described in claim 67 or its pharmaceutically acceptable salt, wherein the compound of formula (X) is formula (XII) Compound:

70. compound described in claim 67 or its pharmaceutically acceptable salt, wherein the compound of formula (X) is formula (XIII) Compound:

71. compound described in claim 67 or its pharmaceutically acceptable salt, wherein the compound of formula (X) is formula (XIV) Compound:

72. compound described in claim 67 or its pharmaceutically acceptable salt, wherein the compound of formula (X) is formula (XV) Compound:

73. compound described in claim 67 or its pharmaceutically acceptable salt, wherein the compound of formula (X) is formula (XVI) Compound:

74. compound described in claim 67 or its pharmaceutically acceptable salt, wherein the compound of formula (X) is formula (XVII) Compound:

75. compound described in claim 67 or its pharmaceutically acceptable salt, wherein the compound of formula (X) is formula (XVIII) compound:

76. compound described in claim 67 or its pharmaceutically acceptable salt, wherein the compound of formula (X) is formula (XIX) Compound:

77. compound described in claim 67 or its pharmaceutically acceptable salt, wherein the compound of formula (X) is formula (XX) Compound:

78. compound described in claim 67 or its pharmaceutically acceptable salt, wherein the compound of formula (X) is formula (XXI) Compound:

79. compound described in claim 67 or its pharmaceutically acceptable salt, wherein the compound of formula (X) is formula (XXII) Compound:

80. compound described in claim 67 or its pharmaceutically acceptable salt, wherein the compound of formula (X) is formula (XXIII) compound:

81. compound described in any one of claim 67-80, wherein

R¹It is H ,-C_1-6Alkyl, aryl, heteroaryl ,-(C_1-6Alkyl)-pyridyl group ,-(C_1-6Alkyl)-N (R³)R⁴、-(C_1-6Alkane Base)-heterocycle or Heterocyclylalkyl；

R²It is H ,-C_1-6Alkyl, aryl, heteroaryl ,-(C_1-6Alkyl)-pyridyl group ,-(C_1-6Alkyl)-N (R³)R⁴、-(C_1-6Alkane Base)-heterocycle or Heterocyclylalkyl；

Or R¹And R²And nitrogen in connection is formed together heterocycle；

R³It is H or C_1-6Alkyl；

R⁴It is H or C_1-6Alkyl；

X is H, C_1-6Alkyl, halogen or hydroxyl；

Y is H, C_1-6Alkyl, halogen or hydroxyl；And

Z is H, C_1-6Alkyl, halogen or hydroxyl.

82. compound described in any one of claim 67-80, wherein

R¹It is H ,-C_1-4Alkyl, aryl, heteroaryl ,-(C_1-4Alkyl)-pyridyl group ,-(C_1-4Alkyl)-N (R³)R⁴、-(C_1-4Alkane Base)-heterocycle or Heterocyclylalkyl；

R²It is H ,-C_1-4Alkyl, aryl, heteroaryl ,-(C_1-4Alkyl)-pyridyl group ,-(C_1-4Alkyl)-N (R³)R⁴、-(C_1-4Alkane Base)-heterocycle or Heterocyclylalkyl；

Or R¹And R²And nitrogen in connection is formed together heterocycle；

R³It is H or C_1-4Alkyl；

R⁴It is H or C_1-4Alkyl；

X is H, C_1-4Alkyl, halogen or hydroxyl；

Y is H, C_1-4Alkyl, halogen or hydroxyl；And

Z is H, C_1-4Alkyl, halogen or hydroxyl.

83. compound described in any one of claim 67-80, wherein

R¹It is H, phenyl, pyridyl group ,-(C_1-6Alkyl)-pyridyl group ,-(C_1-6Alkyl)-N (R³)R⁴、-(C_1-6Alkyl)-heterocycle or Heterocyclylalkyl；And

R²It is H, phenyl, pyridyl group ,-(C_1-6Alkyl)-pyridyl group ,-(C_1-6Alkyl)-N (R³)R⁴、-(C_1-6Alkyl)-heterocycle or Heterocyclylalkyl.

84. compound described in claim 59, wherein

R¹It is H；And

R²It is H, phenyl, pyridyl group ,-(C_1-6Alkyl)-pyridyl group ,-(C_1-6Alkyl)-N (R³)R⁴、-(C_1-6Alkyl)-heterocycle or Heterocyclylalkyl.

85. compound described in any one of claim 67-80, wherein R¹It is H or-C_1-6Alkyl.

86. compound described in any one of claim 67-80, wherein R¹It is-C_1-6Alkyl.

87. compound described in any one of claim 67-80, wherein R¹It is H.

88. compound described in any one of claim 67-80, wherein R²It is phenyl, pyridyl group ,-(C_1-6Alkyl)-pyridine Base ,-(C_1-6Alkyl)-N (R³)R⁴、-(C_1-6Alkyl)-heterocycle or Heterocyclylalkyl.

89. compound described in any one of claim 67-80, wherein pyridyl group is 2- pyridyl group.

90. compound described in any one of claim 67-80, wherein pyridyl group is 3- pyridyl group.

91. compound described in any one of claim 67-80, wherein pyridyl group is 4- pyridyl group.

92. compound described in any one of claim 67-80, wherein R²It is phenyl, pyridyl group ,-(C_1-6Alkyl)-pyridine Base ,-(C_1-6Alkyl)-heterocycle or Heterocyclylalkyl.

93. compound described in any one of claim 67-80, wherein R²It is-(C_1-6Alkyl)-N (R³)R⁴、-(C_1-6Alkane Base)-heterocycle or Heterocyclylalkyl.

94. compound described in any one of claim 67-80, wherein R²It is phenyl, pyridyl group ,-(C_1-6Alkyl)-pyridine Base.

95. compound described in any one of claim 67-80, wherein R²It is pyridyl group.

96. compound described in any one of claim 67-80, wherein R¹And R²And nitrogen in connection is formed together Heterocycle comprising six annular atoms.

97. compound described in any one of claim 67-80, wherein R¹And R²And nitrogen in connection is formed together Heterocycle comprising six annular atoms, wherein one or two annular atom independently are O, S or N.

98. compound described in any one of claim 67-80, wherein R¹And R²And nitrogen in connection is formed together Heterocycle comprising six annular atoms, wherein one or two annular atom are N.

99. compound described in any one of claim 67-80, wherein R³And R⁴It is H.

100. compound described in any one of claim 67-80, wherein R³And R⁴It is independently C_1-6Alkyl.

101. compound described in any one of claim 67-80, wherein R³It is H and R⁴It is C_1-6Alkyl.

102. compound described in any one of claim 67-80, wherein X, Y and Z are H.

103. compound described in any one of claim 67-80, wherein

X is C_1-6Alkyl, halogen or hydroxyl；And

Y and Z is H.

104. compound described in any one of claim 67-80, wherein

X is halogen；And

Y and Z is H.

105. compound described in any one of claim 67-80, wherein X is C_1-6Alkyl, halogen or hydroxyl.

106. compound described in any one of claim 67-80, wherein X is methyl, ethyl, CF₃、CHF₂Or CH₂F。

107. compound described in any one of claim 67-80, wherein Y is methyl, ethyl, CF₃、CHF₂Or CH₂F。

108. compound described in any one of claim 67-80, wherein Z is methyl, ethyl, CF₃、CHF₂Or CH₂F。

109. compound described in any one of claim 67-80, wherein X is halogen.

110. compound described in any one of claim 67-80, wherein X is F or Cl.

111. compound described in any one of claim 67-80, wherein X is Cl.

112. compound described in any one of claim 67-80, wherein

X is methyl or halogen；

Y is methyl or halogen；And

Z is methyl or halogen.

113. compound described in any one of claim 67-80, wherein

X is methyl, F or Cl；

Y is methyl, F or Cl；And

Z is methyl, F or Cl.

114. compound described in any one of claim 67-80, wherein

X is halogen；And

Y is hydroxyl.

115. compound described in any one of claim 67-80, wherein Y is hydroxyl.

116. compound described in any one of claim 67-80, wherein Z is H or F.

117. compound described in claim 67 or its pharmaceutically acceptable salt, wherein the compound is:

118. composition, it includes the compounds described in any one of claim 67-80.

119. pharmaceutical composition, it includes the compositions and pharmaceutically acceptable carrier described in claim 118.

120. treating the method for eye disorders in subject with this need comprising apply claim to the subject Compound described in any one of 67-80.

121. method described in claim 120, wherein the eye disorders are that glaucoma, inflammatory ocular disease, nerve move back Row eye disease, diabetic ocular diseases, wet age related macular degeneration or Local Electroretinogram.

122. method described in claim 120, wherein the compound is locally applied to the eyes of the subject.

123. reducing the method for intraocular pressure in subject with this need comprising apply claim to the subject Compound described in any one of 67-80.

124. method described in claim 123, wherein the compound is locally applied to the eyes of the subject.

125. adjust cell in kinase activity method comprising make the cell with it is any in claim 1-58 or 67-80 Compound contact described in.

126. method described in claim 125, wherein the cell is in subject (such as people experimenter).

127. compound described in claim 1 or its pharmaceutically acceptable salt, wherein the compound is

128. compound described in claim 127, wherein the compound is following dihydrochloride

Background technique

A variety of hormones, neurotransmitter and bioactive substance are controlled by the specific receptor being located in cell membrane, are adjusted Or the function of adjustment living body.The guanine-nucleotide-binding protein (G-protein) that these many receptors pass through activation and coupled receptors Carry out the transmitting of signal in mediated cell.These receptors are commonly known as g protein coupled receptor (GPCR), including alpha-adrenergic Receptor, B-adrenergic receptor, opiate receptor, Cannabined receptor and prostaglandin receptor etc..Activate or inhibit these by The biological effect of body is not direct, is mediated by many intracellular proteins.The importance of these second level albumen by It recognizes, nowadays such adjusting is studied as the intervention point of morbid state.It is most important in these downstream effectors One kind be " kinases " class.

Various kinases play an important role in the adjusting of various physiological functions.For example, kinases and many morbid states are close It is related, including but not limited to: heart indication such as angina pectoris, essential hypertension, myocardial infarction, supraventricular and ventricular rhythm It is not normal, congestive heart failure, atherosclerosis, renal failure, diabetes, respiratory disease indication such as asthma, slow Property bronchitis, bronchial spasm, pulmonary emphysema, airway obstruction, upper respiratory tract indication such as rhinitis, seasonal allergic, inflammation Inflammation, rheumatoid arthritis caused by property disease, injury.The a large amount of compounds developed in the past few years reflect Importance (J.Westra and P.C.Limburg of the p38MAPK inhibitor especially as the new drug of rheumatoid arthritis Mini-Reviews in Medicinal Chemistry, volume 6, the 8th phase, in August, 2006).Other patient's condition include chronic inflammation Disease property enteropathy, glaucoma, hypergastrinemia, gastrointestinal tract indication such as acid/digestion sexual disorder, erosive esophagitis, stomach and intestine Road hypersecretion, mastocytosis, gastrointestinal tract reflux, peptic ulcer, Zollinger-Ellison syndrome, pain, Obesity, bulimia nervosa, depression, obsessive-compulsive disorder, malformation's (such as heart malformations), neurodegenerative disease such as Parkinson's disease With Alzheimer disease, multiple sclerosis, Epstein-Barr infection and cancer (Nature Reviews Drug Discovery 2002,1:493-502).In other diseases state, the effect of kinases is apparent from until now.Retina is The complex organization being made of multiple cellular layers interconnected, hyperspecialization are used to for light and color to be converted into brain perception Electric signal.The damage or death of main photosensitive cell (photoreceptor) can cause a devastating effect to eyesight.Although identification Lead to numerous mutation of hereditary retinal dystrophy, but from primary mutation to the cell and molecule of photoreceptor cell apoptosis Mechanism is unclear, nevertheless, it may relate to wnt access (AS Hackam " The Wnt Signaling Pathway In RetinalDegeneration " IUBMB Life volume 57, the 6th phase/2005 year June).

The success of tyrosine kinase inhibitor STI571 (Gleevec) treatment chronic myelocytic leukemia It is various other to develop treatment that (NatureReviews Drug Discovery, 2003,2:296-313) has evoked a large amount of effort Other kinase inhibitors (Nature Reviews Cancer, 2003,3:650-665) of cancer.The starting of Intracellular signals with Balance between inactivation determines intensity and the duration of reaction of the receptor to stimulation (such as agonist).When desensitizing When, reduce or prevent the mediation or adjusting of the physiological function for being mediated or being adjusted by the G-protein of coupled receptors.For example, when application Agonist with by activating certain receptors come when treating disease or the patient's condition, receptor relatively quickly becomes the desensitization of the effect to GRK, So that agonist application may be no longer result in the therapeutic activation of appropriate receptor.At this point, the application of agonist is no longer able to sufficiently Or efficiently control or influence disease or the patient's condition to be treated.

Janus kinases (or JAK) is the cytoplasm protein tyrosine kinase an of family.JAK family is to immune response Involved in cell proliferation and function cell factor dependence adjust in work.Currently, it is recognized that four JAK families Member is JAK1, JAK2, JAK3 and TYK2 respectively.JAK is usually associated with to dimer or different in couples with cytokine receptor Dimer.Specific cell factor is related to specific JAK pairing.Each of four members of JAK family be involved in The signal transduction of the relevant at least one cell factor of inflammation.The combination of cell factor and JAK dependent cell factor acceptor lures Receptor dimerization is led, this leads to the phosphorylation of tyrosine residue on jak kinase, to influence JAK activation.The JAK of phosphorylation according to Secondary combination simultaneously makes various stat protein phosphorylations, these albumen in nucleus dimerization, internalization and directly adjust gene Transcription, so as to cause downstream effects relevant to diseases associated with inflammation.

In view of effect of the kinases in many morbid states, urgently and it is continuously needed inhibition or adjusts the small of kinase activity Molecule ligand.It is not wishing to be bound by theory, it is believed that activity of the compound of the disclosure to kinases, particularly ROCK and jak kinase Adjusting at least partly contribute its advantages.

Summary of the invention

In one aspect, present disclose provides the compounds according to formula (I):

Or its tautomer, stereoisomer and pharmaceutically acceptable salt,

Wherein:

X₁、X₂And X₃It independently is H, halogen, nitrile, hydroxyl or C_1-6Alkyl；

Y is-NR^N1S(O)₂-、–NR^N1C(O)-、-O(CR¹ ₂)_n-、-NR^N1(CR¹ ₂)_m-、-C(O)O-、-OC(O)-、-S (O)₂-、-C(O)-、-NR^N1C(O)O(CR¹ ₂)_n-、-(R)O-C_1-6Alkylidene, aryl or heteroaryl；

Z is direct key or C_1-6Alkylidene；

R is H, halogen, cyano, OR³、C_1-6Alkyl, amino, naphthenic base, heterocycle, aryl or heteroaryl, carbonyl or R It can be with R^N1Or R¹The ring with 5 to 7 member atoms is formed, middle ring can be selected from the miscellaneous original of N, O and S containing at most 2 Son, ring are saturated or unsaturated；

R^N1It is H or C_1-6Alkyl, NH₂、SO₂Aryl, SO₂Heteroaryl, morpholine or piperidines, or ring is formed with R；

R¹It is H, F or Me or forms ring with R；

R³It is H or C_1-6Alkyl；

N is 0 to 6 integer；And

M is 1 to 6 integer.

In one aspect, present disclose provides the compounds according to formula (Ia):

Or its tautomer, stereoisomer and pharmaceutically acceptable salt,

Wherein:

X₁、X₂And X₃It independently is H, halogen, nitrile, hydroxyl or C_1-6Alkyl；

Y is-NR^N1S(O)₂-、–NR^N1C(O)-、-NR^N1(CR¹ ₂)_m-、-S(O)₂-、-C(O)-、-NR^N1C(O)O(CR¹ ₂)_n- Or C_1-6Alkylidene；

Z is direct key or C_1-6Alkylidene；

R^N1It is H or C_1-6Alkyl, NH₂、SO₂Aryl, SO₂Heteroaryl, morpholine or piperidines, or ring is formed with R；

R¹It is H, F or Me or forms ring with R；

R³It is H or C_1-6Alkyl；

N is 0 to 6 integer；And

M is 1 to 6 integer.

In one aspect, present disclose provides the compounds according to formula (Ib):

Or its tautomer, stereoisomer and pharmaceutically acceptable salt,

Wherein:

X₁、X₂And X₃It independently is H, halogen, nitrile, hydroxyl or C_1-6Alkyl；

Y is-NR^N1S(O)₂-、–NR^N1C(O)-、-O(CR¹ ₂)_n-、-NR^N1(CR¹ ₂)_m-、-C(O)O-、-OC(O)-、-S (O)₂-、-C(O)-、-NR^N1C(O)O(CR¹ ₂)_n-、-(R)O-C_1-6Alkylidene, aryl or heteroaryl

Z is direct key or C_1-6Alkylidene；

R is halogen, cyano, OR³, amino, naphthenic base, heterocycle, aryl or heteroaryl or R can be with R^N1Or R¹Shape At with 5 to 7 member atoms ring, middle ring can containing at most 2 be selected from N, O and S hetero atoms, ring be saturation or It is unsaturated；

R^N1It is H or C_1-6Alkyl, NH₂、SO₂Aryl, SO₂Heteroaryl, morpholine or piperidines, or ring is formed with R；

R¹It is H, F or Me or forms ring with R；

R³It is H or C_1-6Alkyl；

N is 0 to 6 integer；And

M is 1 to 6 integer.

In one aspect, present disclose provides the compounds according to formula (Ic):

Or its tautomer, stereoisomer and pharmaceutically acceptable salt,

Wherein:

X₁、X₂And X₃It independently is H, halogen, nitrile, hydroxyl or C_1-6Alkyl；

Y is-NR^N1S(O)₂-、–NR^N1C(O)-、-O(CR¹ ₂)_n-、-NR^N1(CR¹ ₂)_m-、-C(O)O-、-OC(O)-、-S (O)₂-、-C(O)-、-NR^N1C(O)O(CR¹ ₂)_n-、-(R)O-C_1-6Alkylidene, aryl or heteroaryl

Z is direct key or C_1-6Alkylidene；

R^N1It is H or C_1-6Alkyl, NH₂、SO₂Aryl, SO₂Heteroaryl, morpholine or piperidines, or ring is formed with R；

R¹It is F or Me or forms ring with R；

R³It is H or C_1-6Alkyl；

N is 0 to 6 integer；And

M is 1 to 6 integer.

In one aspect, present disclose provides the compounds according to formula (Id):

Or its tautomer, stereoisomer and pharmaceutically acceptable salt,

Wherein:

X₁、X₂And X₃It independently is H, halogen, nitrile, hydroxyl or C_1-6Alkyl；

Y is-NR^N1S(O)₂-、–NR^N1C(O)-、-O(CR¹ ₂)_n-、-NR^N1(CR¹ ₂)_m-、-C(O)O-、-OC(O)-、-S (O)₂-、-C(O)-、-NR^N1C(O)O(CR¹ ₂)_n-、-(R)O-C_1-6Alkylidene, aryl or heteroaryl

Z is direct key or C_1-6Alkylidene；

R^N1It is H or C_1-6Alkyl, NH₂、SO₂Aryl, SO₂Heteroaryl, morpholine or piperidines, or ring is formed with R；

R¹It is H, F or Me or forms ring with R；

R³It is H or C_1-6Alkyl；

N is 2,3,4,5 or 6；And

M is 1 to 6 integer.

In one aspect, present disclose provides the compounds that compound is formula (II):

Or its tautomer, stereoisomer and pharmaceutically acceptable salt,

Wherein:

X₁、X₂And X₃It independently is H, halogen, nitrile, hydroxyl or C_1-6Alkyl；

Y is-NR^N1S(O)₂-、–NR^N1C(O)-、-O(CR¹ ₂)_n-、-NR^N1(CR¹ ₂)_m-、-C(O)O-、-OC(O)-、-S (O)₂-、-C(O)-、-NR^N1C(O)O(CR¹ ₂)_n-、C_1-6Alkylidene alkylidene, aryl or heteroaryl

Z is direct key or C_1-6Alkylidene；

R is H, halogen, cyano, OR³、C_1-6Alkyl, amino, naphthenic base, heterocycle, aryl or heteroaryl or R can be with With R^N1Or R¹The ring with 5 to 7 member atoms is formed, middle ring can be selected from the hetero atom of N, O and S, ring containing at most 2 It is saturated or unsaturated；

R^N1It is H or C_1-6Alkyl forms ring with R；

R¹It is H, F or Me or forms ring with R；

R³It is H or C_1-6Alkyl；

N is 0 to 6 integer；And

M is 1 to 6 integer.

In one aspect, present disclose provides the compounds that compound is formula (III):

Or its tautomer, stereoisomer and pharmaceutically acceptable salt,

Wherein:

X₁、X₂And X₃It independently is H, halogen, nitrile, hydroxyl or C_1-6Alkyl；

Y is-NR^N1S(O)₂-、–NR^N1C(O)-、-O(CR¹ ₂)_n-、-NR^N1(CR¹ ₂)_m-、-C(O)O-、-OC(O)-、-S (O)₂-、-C(O)-、-NR^N1C(O)O(CR¹ ₂)_n-、C_1-6Alkylidene, aryl or heteroaryl

Z is direct key or C_1-6Alkylidene；

R^N1It is H or C_1-6Alkyl forms ring with R；

R¹It is H, F or Me or forms ring with R；

R³It is H or C_1-6Alkyl；

N is 0 to 6 integer；And

M is 1 to 6 integer.

In one aspect, present disclose provides the compounds according to formula (IV):

Or its tautomer, stereoisomer and pharmaceutically acceptable salt,

Wherein:

X₁、X₂And X₃It independently is H, halogen, nitrile, hydroxyl or C_1-6Alkyl；

Y is-NR^N1S(O)₂-、–NR^N1C(O)-、-O(CR¹ ₂)_n-、-NR^N1(CR¹ ₂)_m-、-C(O)O-、-OC(O)-、-S (O)₂-、-C(O)-、-NR^N1C(O)O(CR¹ ₂)_n-、C_1-6Alkylidene, alkylidene, aryl or heteroaryl

Z is direct key or C_1-6Alkylidene；

R^N1It is H or C_1-6Alkyl forms ring with R；

R¹It is H, F or Me or forms ring with R；

R³It is H or C_1-6Alkyl；

N is 0 to 6 integer；And

M is 1 to 6 integer.

In one aspect, present disclose provides the compounds according to formula (VII):

Or its tautomer, stereoisomer and pharmaceutically acceptable salt,

Wherein:

X₁、X₂And X₃It independently is H, halogen, nitrile, hydroxyl or C_1-6Alkyl；

Y is-NR^N1S(O)₂-；

Z is direct key or C_1-6Alkylidene；

R is H, halogen, cyano, OR³、C_1-6Alkyl, amino, naphthenic base, heterocyclylalkyl or heteroaryl or R can be with R^N1Or R¹The ring with 5 to 7 member atoms is formed, middle ring can be selected from the hetero atom of N, O and S containing at most 2, and ring is It is saturated or unsaturated；

R^N1It is H or C_1-6Alkyl forms ring with R；

R¹It is H, F or Me or forms ring with R；R³It is H or C_1-6Alkyl；

N is 0 to 6 integer；And

M is 1 to 6 integer.

In one aspect, present disclose provides the compounds according to formula (VIII):

Or its tautomer, stereoisomer and pharmaceutically acceptable salt,

Wherein:

X₁、X₂And X₃It independently is H, halogen, nitrile, hydroxyl or C_1-6Alkyl；

Y is-NR^N1S(O)₂-；

Z is direct key or C_1-6Alkylidene；

R^N1It is H or C_1-6Alkyl forms ring with R；

R¹It is H, F or Me or forms ring with R；

R³It is H or C_1-6Alkyl；

N is 0 to 6 integer；And

M is 1 to 6 integer.

In one aspect, present disclose provides the compounds according to formula (IX):

Or its tautomer, stereoisomer and pharmaceutically acceptable salt,

Wherein:

X₁、X₂And X₃It independently is H, halogen, nitrile, hydroxyl or C_1-6Alkyl；

Y is-NR^N1S(O)₂-；

Z is direct key or C_1-6Alkylidene；

R^N1It is H or C_1-6Alkyl forms ring with R；

R¹It is H, F or Me or forms ring with R；

R³It is H or C_1-6Alkyl；

N is 0 to 6 integer；And

M is 1 to 6 integer.

In one aspect, there is provided herein the compounds of formula (X):

Or its pharmaceutically acceptable salt,

Wherein,

R¹It is H ,-C_1-6Alkyl ,-C_1-6Halogenated alkyl, aryl, heteroaryl ,-(C_1-6Alkyl)-pyridyl group ,-(C_1-6Alkyl)- N(R³)R⁴、-(C_1-6Alkyl)-heterocycle or Heterocyclylalkyl；

R²It is H ,-C_1-6Alkyl ,-C_1-6Halogenated alkyl, aryl, heteroaryl ,-(C_1-6Alkyl)-pyridyl group ,-(C_1-6Alkyl)- N(R³)R⁴、-(C_1-6Alkyl)-heterocycle or Heterocyclylalkyl；

Or R¹And R²And nitrogen in connection is formed together heterocycle；

R³It is H, C_1–6Alkyl or-C_1–6Halogenated alkyl；

R⁴It is H, C_1–6Alkyl or-C_1–6Halogenated alkyl；

X is H, C_1–6Alkyl ,-C_1–6Halogenated alkyl, halogen or hydroxyl；

Y is H, C_1–6Alkyl ,-C_1–6Halogenated alkyl, halogen or hydroxyl；And

Z is H, C_1–6Alkyl ,-C_1–6Halogenated alkyl, halogen or hydroxyl.

In one aspect, present disclose provides pharmaceutical composition, it includes according to the compound of the disclosure and pharmaceutically may be used The excipient of receiving.

In one aspect, present disclose provides the methods that eye disorders are treated in subject in need for the treatment of comprising To subject's application according to the compound or composition of the disclosure.

In one aspect, present disclose provides the methods that intraocular pressure is reduced in subject with this need comprising gives The eyes of subject apply the compound or composition according to the disclosure.

In one aspect, present disclose provides kits, and it includes disclosure compound or composition and operation instructions.

Detailed description

Publication and patent are referred in the entire disclosure.Herein cited all United States Patent (USP)s are thus with reference side Formula is incorporated to.Unless otherwise stated, all percentages, ratio and ratio used herein are weight percentage.

Provide aryl cyclopropyl amino-isoquinoline morpholine amide.

" alkyl " refers to the saturated aliphatic hydrocarbon comprising straight chain and branched group." alkyl " may be exemplified as such as methyl, second The groups such as base, n-propyl, isopropyl, normal-butyl.Alkyl can be substituted or unsubstituted.There may be more than one substitutions Base.Substituent group can also be substituted with itself.When substituted, substituent group is preferably but not limited to C₁-C₄Alkyl, aryl, heteroaryl, Amino, alkylthio, cyano, halogen, alkoxy or hydroxyl."C₁-C₄Alkyl " refers to the alkyl comprising 1 to 4 carbon atom.

" alkenyl " refers to the aliphatic unsaturated hydrocarbon segment comprising straight chain and branched group.Alkenyl segments must contain at least one A alkene." alkenyl " may be exemplified as groups such as vinyl, positive acrylic, isopropenyl, n-butene bases.Alkenyl can be It is substituted or unsubstituted.There may be more than one substituent groups.When substituted, substituent group is preferably alkyl, halogen or alkane Oxygroup.Substituent group can also be substituted with itself.Substituent group can be located at alkene sheet, can also be located at adjacent member atoms Or on alkynyl moieties."C₂-C₄Alkenyl " refers to the alkenyl containing 2 to 4 carbon atoms.

" alkynyl " refers to the aliphatic unsaturated hydrocarbon segment comprising straight chain and branched group.Alkynyl moieties must contain at least one A alkynes." alkynyl " may be exemplified as groups such as acetenyl, propinyl, positive butynyls.Alkynyl can be substituted or not Replace.There may be more than one substituent groups.Substituent group is not on alkynes itself, and in neighbor members' atom of alkynyl moieties On.When substituted, substituent group is preferably alkyl, amino, cyano, halogen, alkoxy or hydroxyl.Substituent group can also be with itself quilt Replace."C₂-C₄Alkynyl " refers to the alkynyl containing 2-4 carbon atom.

" acyl group " or " carbonyl " refers to group-C (O) R, and wherein R is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbon Ring, miscellaneous carbocyclic ring, C₁-C₄Alkylaryl or C₁-C₄Miscellaneous alkyl aryl.C₁-C₄Alkyl-carbonyl refers to such group, in the group There is the alkyl chain of 1-4 carbon atom before middle carbonyl fragments.

" alkoxy " refers to group-O-R, and wherein R is alkyl, alkenyl, acyl group, alkylalkenyl, Alkyl alkynyl, aryl, carbon Ring, miscellaneous carbocyclic ring, heteroaryl, C₁-C₄Alkylaryl or C₁-C₄Miscellaneous alkyl aryl.

" amino " refer to group-NR ' R ', wherein each R ' be independently hydrogen, amino, hydroxyl, alkoxy, alkyl, alkenyl, Aryl, naphthenic base, Heterocyclylalkyl, heteroaryl, C₁-C₄Alkylaryl or C₁-C₄Miscellaneous alkyl aryl.Two R ' groups itself can be with Connection forms ring.R ' group itself can be further substituted, and in this case, also referred to as the group of guanidine radicals is especially examined Consider in term " amino " range.

" aryl " refers to aromatic carbocyclic radical." aryl " can be exemplified as phenyl.Aryl can be substituted or unsubstituted 's.There may be more than one substituent groups.Substituent group can also be substituted with itself.When substituted, substituent group is preferred but unlimited In alkyl, alkenyl, heteroaryl, acyl group, carboxyl, sulfonyl, sulfuryl amino, alkylthio, trifluoromethyl, carbonylamino, ammonia Base, cyano, halogen or hydroxyl.

" carboxyl " refers to group-C (=O) O-C₁-C₄Alkyl.

" carbonyl " refers to group-C (O) R, wherein each R is independently hydrogen, alkyl, aryl, naphthenic base；Heterocyclylalkyl；It is miscellaneous Aryl, C₁-C₄Alkylaryl or C₁-C₄Miscellaneous alkyl aryl.

" carbonylamino " refers to group-C (O) NR'R', wherein each R' is independently hydrogen, alkyl, aryl, naphthenic base；It is miscellaneous Naphthenic base；Heteroaryl, C₁-C₄Alkylaryl or C₁-C₄Miscellaneous alkyl aryl.Two R ' groups itself can connect to form ring.

“C₁-C₄Alkylaryl " refers to the C with aryl substituent₁-C₄Alkyl passes through so that aryl substituent is bonded Alkyl."C₁-C₄Alkylaryl " can be exemplified as benzyl.

“C₁-C₄Miscellaneous alkyl aryl " refers to the C with heteroaryl substituent₁-C₄Alkyl, so that heteroaryl substituent is by key Conjunction passes through alkyl.

" carbon ring group " or " naphthenic base " refers to saturation or unsaturated hydrocarbon ring.Carbon ring group is monocycle, or condensed, Loop coil or bridge joint bicyclic ring system.Monocyclic carbocyclic radical in ring contain 3 to 10 carbon atoms, preferably 4 to 7 carbon atoms, More preferable 5 to 6 carbon atoms.Bicyclic carbocyclic group contains 8 to 12 carbon atoms, preferably 9 to 10 carbon atoms in ring.Carbocyclic ring Group can be substituted or unsubstituted.There may be more than one substituent groups.Substituent group can also be substituted with itself.Properly Substituent group include halogen, cyano, alkoxy, amino, trifluoromethyl and trifluoromethoxy.Preferred carbon ring group includes cyclopropyl Base, cyclobutyl, cyclopenta, cyclohexyl, cyclohexenyl group and suberyl.Most preferred carbon ring group is cyclohexyl and cyclopenta.Carbon Cyclic group is not aromatic.

" halogen " refers to fluorine, chlorine, bromine or iodine segment.Preferably, halogen is fluorine, chlorine or bromine.

" heteroaryl " or " heteroaromatic " refers to has one or more heteroatomic monocycles or bicyclic aromatic carbon in carbocyclic ring Ring group.Heteroaryl can be substituted or unsubstituted.There may be more than one substituent groups.When substituted, substituent group can It is substituted with itself.It is preferred that but unrestricted substituent group is halogen, cyano, alkoxy, amino, trifluoromethyl, trifluoro methoxy Base, aryl, C₁-C₄Alkylaryl, hydroxyl, carboxyl, carbonylamino or C₁-C₄Alkyl.Preferred heteroaromatic group includes benzo [b] thiophenyl, pyrrole radicals, benzofuranyl, isoquinolyl, imidazole radicals, quinolyl, cinnoline base (cinnolinyl), tetrazole radical (tetrazoyl), triazolyl, thienyl, thiazolyl, purine radicals, pyrimidine radicals, pyridyl group and furyl.It is preferred heteroaromatic Group includes isoquinolyl, benzo [b] thiophenyl；Thienyl, furyl, tetrazole radical, triazolyl and pyridyl group.

" hetero atom " refers to the multivalence other than the carbon in heterocyclic group or the ring of heteroaromatic group or in the chain of isomeric groups Atom.Preferably, hetero atom is selected from the group being made of nitrogen, sulphur and oxygen atom.It can contain containing more than one heteroatomic group There is different hetero atoms.Halogen is monovalent, therefore is not in this sense considered as hetero atom, but has themselves Classification.

" miscellaneous carbocylic radical " or " Heterocyclylalkyl " or " heterocycle " refer to containing at least one heteroatomic saturation or unsaturated hydrocarbons Ring.Miscellaneous carbon ring group is monocycle, or condensed, loop coil or bridge joint bicyclic ring system.The miscellaneous carbon ring group of monocycle is in ring Containing 3 to 10 carbon atoms, preferably 4 to 7 carbon atoms, more preferable 5 to 6 carbon atoms.Bicyclic miscellaneous carbon ring group contains in ring There are 8 to 12 carbon atoms, preferably 9 to 10 carbon atoms.Miscellaneous carbon ring group can be substituted or unsubstituted.There may be more In a substituent group.Substituent group can also be substituted with itself.Suitable substituent group include halogen, nitrile, hydroxyl, alkoxy, amino, Trifluoromethyl and trifluoromethoxy.Preferred miscellaneous carbon ring group includes epoxy group, tetrahydrofuran base, azepine cyclopenta (or pyrroles Alkyl), piperidyl, piperidyl and homopiperidinyl.Preferred miscellaneous carbon ring group includes pyrrolidinyl, piperidyl and high piperazine Piperidinyl.Most preferred miscellaneous carbocylic radical is piperidyl.Miscellaneous carbon ring group is not aromatic.

" hydroxyl " or " hydroxyl " refers to the chemical entities being made of-OH.Alcohol contains hydroxide groups.Hydroxide groups can To be free or shielded.Another title hydroxy is hydroxyl.

" link " (linker) refers to the straight chain of n member atoms, and wherein n is the integer of 1-4.

" member atoms " refer to carbon, nitrogen, oxygen or sulphur atom.Member atoms can be substituted the common fare until them.If More than one stable chemical valence can get for member atoms' (such as sulphur), then be susceptible to all stable chemical valences.If not complete Complete determine replaces, then unspecified substituent group needed for chemical valence is hydrogen.

" ring " refers to cricoid group membership atom.Ring can be carbocyclic ring, aromatics or heterocycle or heteroaromatic, can be and takes It is generation or unsubstituted, and can be saturated or unsaturated.There may be more than one substituent groups.The engagement of ring and main chain Place can be thick and/or loop coil.Ring can be monocycle or bicyclic.Ring contains at least three member atoms and at most 10 member's originals Son.The ring of monocycle can contain 3-7 member atoms, and bicyclic ring can contain 8-12 member atoms.Bicyclic ring itself can To be thick and/or loop coil.

" alkylthio " refers to group-S-alkyl.

" sulfonyl " refers to-S (O)₂R' group, wherein R' is alkoxy, alkyl, aryl, carbocyclic ring, miscellaneous carbocyclic ring；Heteroaryl, C₁-C₄Alkylaryl or C₁-C₄Miscellaneous alkyl aryl.

" sulfuryl amino " reference-S (O)₂NR ' R ', wherein each R' independently is alkyl, aryl, heteroaryl, C₁-C₄Alkane Base aryl or C₁-C₄Miscellaneous alkyl aryl.

" pharmaceutically acceptable carrier " refers to the carrier that can be used for preparing pharmaceutical composition, and the carrier is usually and composition Other compositions it is compatible, it is harmless to recipient, and neither it is biologically undesired nor other aspect it is undesired. " pharmaceutically acceptable carrier " includes a kind of and more than one carrier.Embodiment include for part, eye, parenteral, Intravenously, in peritonaeum intramuscular, sublingual, nose and oral administration carrier." pharmaceutically acceptable carrier " further includes being used to prepare The reagent of water-borne dispersions and aseptic powdery for injecting or dispersing.

As used herein, " excipient " includes the additive that can be used for preparing the physiological compatible of pharmaceutical composition.Medicine The example of acceptable carrier and excipient can be for example in Remington Pharmaceutical Science the (the 16th on Version) in find.

As used herein, " therapeutically effective amount ", which refers to, effectively influences, reduces or inhibits kinase activity or kinases is prevented to swash The dosage of compound or composition living.As used herein, which can also refer to generate in animal (preferably people) The effective quantity of required vivo effect (such as reducing intraocular pressure).

As used herein, " application " refers to the application as needed for the compound for realizing desired effect.

As used herein, " eye disease " include but is not limited to glaucoma, allergy, cancer eye, eyes neurological Property disease, such as diabetic ocular diseases, macular degeneration (AMD), inflammation and xerophthalmia.

Term " disease relevant to kinase activity or the patient's condition " is for indicating by inhibiting one or more kinases can be whole Or the disease or the patient's condition of part treatment.

Term " control disease or the patient's condition " is for indicating the activity for changing one or more kinases to influence disease or the patient's condition.

Term " exposing cell " for indicate in vitro or in vivo (i.e. in subject, such as mammal, including people, Rabbit, cat and dog) exposing cell.

Compound

In one aspect, the compound according to formula (I) is provided:

Or its tautomer, stereoisomer and pharmaceutically acceptable salt,

Wherein:

X₁、X₂And X₃It independently is H, halogen, nitrile, hydroxyl or C_1-6Alkyl；

Y is-NR^N1S(O)₂-、–NR^N1C(O)-、-O(CR¹ ₂)_n-、-NR^N1(CR¹ ₂)_m-、-C(O)O-、-OC(O)-、-S (O)₂-、-C(O)-、-NR^N1C(O)O-、C_1-6Alkylidene, aryl or heteroaryl；

Z is direct key or C_1-6Alkylidene；

R is H, halogen, cyano, OR³、C_1-6Alkyl, acyl group, amino, naphthenic base, heterocycle, aryl or heteroaryl or R It can be with R^N1Or R¹The ring with 5 to 7 member atoms is formed, middle ring can be selected from the miscellaneous original of N, O and S containing at most 2 Son, ring are saturated or unsaturated；

R^N1It is H or C_1-6Alkyl forms ring with R；

R¹It is H, F or Me or forms ring with R；

R³It is H or C_1-6Alkyl；

N is 0 to 6 integer；And

M is 1 to 6 integer.

In one aspect, present disclose provides the compounds according to formula (Ia):

Or its tautomer, stereoisomer and pharmaceutically acceptable salt,

Wherein:

X₁、X₂And X₃It independently is H, halogen, nitrile, hydroxyl or C_1-6Alkyl；

Y is-NR^N1S(O)₂-、–NR^N1C(O)-、-NR^N1(CR¹ ₂)_m-、-S(O)₂-、-C(O)-、-NR^N1C(O)O(CR¹ ₂)_n- Or C_1-6Alkylidene；

Z is direct key or C_1-6Alkylidene；

R^N1It is H or C_1-6Alkyl, NH₂、SO₂Aryl, SO₂Heteroaryl, morpholine or piperidines, or ring is formed with R；

R¹It is H, F or Me or forms ring with R；

R³It is H or C_1-6Alkyl；

N is 0 to 6 integer；And

M is 1 to 6 integer.

In one aspect, present disclose provides the compounds according to formula (Ib):

Or its tautomer, stereoisomer and pharmaceutically acceptable salt,

Wherein:

X₁、X₂And X₃It independently is H, halogen, nitrile, hydroxyl or C_1-6Alkyl；

Y is-NR^N1S(O)₂-、–NR^N1C(O)-、-O(CR¹ ₂)_n-、-NR^N1(CR¹ ₂)_m-、-C(O)O-、-OC(O)-、-S (O)₂-、-C(O)-、-NR^N1C(O)O(CR¹ ₂)_n-、-(R)O-C_1-6Alkylidene, aryl or heteroaryl

Z is direct key or C_1-6Alkylidene；

R^N1It is H or C_1-6Alkyl, NH₂、SO₂Aryl, SO₂Heteroaryl, morpholine or piperidines, or ring is formed with R；

R¹It is H, F or Me or forms ring with R；

R³It is H or C_1-6Alkyl；

N is 0 to 6 integer；And

M is 1 to 6 integer.

In one aspect, present disclose provides the compounds according to formula (Ic):

Or its tautomer, stereoisomer and pharmaceutically acceptable salt,

Wherein:

X₁、X₂And X₃It independently is H, halogen, nitrile, hydroxyl or C_1-6Alkyl；

Y is-NR^N1S(O)₂-、–NR^N1C(O)-、-O(CR¹ ₂)_n-、-NR^N1(CR¹ ₂)_m-、-C(O)O-、-OC(O)-、-S (O)₂-、-C(O)-、-NR^N1C(O)O(CR¹ ₂)_n-、-(R)O-C_1-6Alkylidene, aryl or heteroaryl

Z is direct key or C_1-6Alkylidene；

R^N1It is H or C_1-6Alkyl, NH₂、SO₂Aryl, SO₂Heteroaryl, morpholine or piperidines, or ring is formed with R；

R¹It is F or Me or forms ring with R；

R³It is H or C_1-6Alkyl；

N is 0 to 6 integer；And

M is 1 to 6 integer.

In one aspect, present disclose provides the compounds according to formula (Id):

Or its tautomer, stereoisomer and pharmaceutically acceptable salt,

Wherein:

X₁、X₂And X₃It independently is H, halogen, nitrile, hydroxyl or C_1-6Alkyl；

Y is-NR^N1S(O)₂-、–NR^N1C(O)-、-O(CR¹ ₂)_n-、-NR^N1(CR¹ ₂)_m-、-C(O)O-、-OC(O)-、-S (O)₂-、-C(O)-、-NR^N1C(O)O(CR¹ ₂)_n-、-(R)O-C_1-6Alkylidene, aryl or heteroaryl

Z is direct key or C_1-6Alkylidene；

R^N1It is H or C_1-6Alkyl, NH₂、SO₂Aryl, SO₂Heteroaryl, morpholine or piperidines, or ring is formed with R；

R¹It is H, F or Me or forms ring with R；

R³It is H or C_1-6Alkyl；

N is 2,3,4,5 or 6；And

M is 1 to 6 integer.

In one aspect, the compound according to formula (II) is provided:

Or its tautomer, stereoisomer and pharmaceutically acceptable salt,

Wherein:

X₁、X₂And X₃It independently is H, halogen, nitrile, hydroxyl or C_1-6Alkyl；

Y is-NR^N1S(O)₂-、–NR^N1C(O)-、-O(CR¹ ₂)_n-、-NR^N1(CR¹ ₂)_m-、-C(O)O-、-OC(O)-、-S (O)₂-、-C(O)-、-NR^N1C(O)O-、C_1-6Alkylidene, aryl or heteroaryl；

Z is direct key or C_1-6Alkylidene；

R^N1It is H or C_1-6Alkyl forms ring with R；

R¹It is H, F or Me or forms ring with R；

R³It is H or C_1-6Alkyl；

N is 0 to 6 integer；And

M is 1 to 6 integer.

In one aspect, the compound according to formula (III) is provided:

Or its tautomer, stereoisomer and pharmaceutically acceptable salt,

Wherein:

X₁、X₂And X₃It independently is H, halogen, nitrile, hydroxyl or C_1-6Alkyl；

Y is-NR^N1S(O)₂-、–NR^N1C(O)-、-O(CR¹ ₂)_n-、-NR^N1(CR¹ ₂)_m-、-C(O)O-、-OC(O)-、-S (O)₂-、-C(O)-、-NR^N1C(O)O-、C_1-6Alkylidene, aryl or heteroaryl,

Z is direct key or C_1-6Alkylidene；

R^N1It is H or C_1-6Alkyl forms ring with R；

R¹It is H, F or Me or forms ring with R；

R³It is H or C_1-6Alkyl；

N is 0 to 6 integer；And

M is 1 to 6 integer.

In one aspect, the compound according to formula (IV) is provided:

Or its tautomer, stereoisomer and pharmaceutically acceptable salt,

Wherein:

X₁、X₂And X₃It independently is H, halogen, nitrile, hydroxyl or C_1-6Alkyl；

Y is-NR^N1S(O)₂-、–NR^N1C(O)-、-O(CR¹ ₂)_n-、-NR^N1(CR¹ ₂)_m-、-C(O)O-、-OC(O)-、-S (O)₂-、-C(O)-、-NR^N1C(O)O-、C_1-6Alkylidene, aryl or heteroaryl；

Z is direct key or C_1-6Alkylidene；

R^N1It is H or C_1-6Alkyl forms ring with R；

R¹It is H, F or Me or forms ring with R；R³It is H or C_1-6Alkyl；

N is 0 to 6 integer；And

M is 1 to 6 integer.

In one aspect, the compound according to formula (V) is provided:

Or its tautomer, stereoisomer and pharmaceutically acceptable salt,

Wherein:

X₁、X₂And X₃It independently is H, halogen, nitrile, hydroxyl or C_1-6Alkyl；

Y is-NR^N1S(O)₂-、–NR^N1C(O)-、-O(CR¹ ₂)_n-、-NR^N1(CR¹ ₂)_m-、-C(O)O-、-OC(O)-、-S (O)₂-、-C(O)-、-NR^N1C(O)O-、C_1-6Alkylidene, aryl or heteroaryl；

Z is direct key or C_1-6Alkylidene；

R^N1It is H or C_1-6Alkyl forms ring with R；

R¹It is H, F or Me or forms ring with R；

R³It is H or C_1-6Alkyl；

N is 0 to 6 integer；And

M is 1 to 6 integer.

In one aspect, the compound according to formula (VI) is provided:

Or its tautomer, stereoisomer and pharmaceutically acceptable salt,

Wherein:

X₁、X₂And X₃It independently is H, halogen, nitrile, hydroxyl or C_1-6Alkyl；

Y is-NR^N1S(O)₂-、–NR^N1C(O)-、-O(CR¹ ₂)_n-、-NR^N1(CR¹ ₂)_m-、-C(O)O-、-OC(O)-、-S (O)₂-、-C(O)-、-NR^N1C(O)O-、C_1-6Alkylidene, aryl or heteroaryl

Z is direct key or C_1-6Alkylidene；

R^N1It is H or C_1-6Alkyl forms ring with R；

R¹It is H, F or Me or forms ring with R；

R³It is H or C_1-6Alkyl；

N is 0 to 6 integer；And

M is 1 to 6 integer.

In one aspect, the compound according to formula (VII) is provided:

Or its tautomer, stereoisomer and pharmaceutically acceptable salt,

Wherein:

X₁、X₂And X₃It independently is H, halogen, nitrile, hydroxyl or C_1-6Alkyl；

Y is-NR^N1S(O)₂-、–NR^N1C(O)-、-O(CR¹ ₂)_n-、-NR^N1(CR¹ ₂)_m-、-C(O)O-、-OC(O)-、-S (O)₂-、-C(O)-、-NR^N1C(O)O-、C_1-6Alkylidene, aryl or heteroaryl

Z is direct key or C_1-6Alkylidene；

R^N1It is H or C_1-6Alkyl forms ring with R；

R¹It is H, F or Me or forms ring with R；

R³It is H or C_1-6Alkyl；

N is 0 to 6 integer；And

M is 1 to 6 integer.

In one aspect, the compound according to formula (VIII) is provided:

Or its tautomer, stereoisomer and pharmaceutically acceptable salt,

Wherein:

X₁、X₂And X₃It independently is H, halogen, nitrile, hydroxyl or C_1-6Alkyl；

Y is-NR^N1S(O)₂-、–NR^N1C(O)-、-O(CR¹ ₂)_n-、-NR^N1(CR¹ ₂)_m-、-C(O)O-、-OC(O)-、-S (O)₂-、-C(O)-、-NR^N1C(O)O-、C_1-6Alkylidene, aryl or heteroaryl

Z is direct key or C_1-6Alkylidene；

R^N1It is H or C_1-6Alkyl forms ring with R；

R¹It is H, F or Me or forms ring with R；

R³It is H or C_1-6Alkyl；

N is 0 to 6 integer；And

M is 1 to 6 integer.

In one aspect, the compound according to formula (IX) is provided:

Or its tautomer, stereoisomer and pharmaceutically acceptable salt,

Wherein:

X₁、X₂And X₃It independently is H, halogen, nitrile, hydroxyl or C_1-6Alkyl；

Y is-NR^N1S(O)₂-、–NR^N1C(O)-、-O(CR¹ ₂)_n-、-NR^N1(CR¹ ₂)_m-、-C(O)O-、-OC(O)-、-S (O)₂-、-C(O)-、-NR^N1C(O)O-、C_1-6Alkylidene, aryl or heteroaryl；

Z is direct key or C_1-6Alkylidene；

R^N1It is H or C_1-6Alkyl forms ring with R；

R¹It is H, F or Me or forms ring with R；

R³It is H or C_1-6Alkyl；

N is 0 to 6 integer；And

M is 1 to 6 integer.

In about formula (I)-(IX) embodiment, X¹、X²And X³One or more of be hydrogen.About formula (I)- (IX) in embodiment, X¹It is OH, CN, F, Br, Cl or CH₃.In about formula (I)-(IX) embodiment, X²Be CN, F, Br, Cl or CH₃.In about formula (I)-(IX) embodiment, X³It is-CF₃、-OCH₃、CN、F、Br、Cl、OCF₃Or CH₃。

In about formula (I)-(IX) embodiment, R^N1It is H.Alternatively, R^N1It is C_1-6Alkyl can be substituted 's.

In about formula (I)-(IX) embodiment, R is amino.Alternatively, R is heteroaryl, heterocycle or aryl, such as Phenyl, pyridyl group, piperidyl, morpholinyl, thiophenyl, isoquinolin, quinolyl or pyrrolidinyl.About formula (I)-(IX) reality It applies in mode, R is H, C_1-6Alkyl, naphthenic base or heterocycle or R can be with R^N1The ring with 5 to 7 member atoms is formed, Its middle ring can be selected from the hetero atom of N, O and S containing at most 2, can be saturated or unsaturated.

In about formula (I)-(IX) embodiment, Z is direct key.Alternatively, Z is C_1-6Alkylidene, such as-CH₂-。

In about formula (I)-(IX) embodiment, Y is-NR^N1S(O)₂-.About formula (I)-(IX) embodiment In, Y is-NR^N1S(O)₂And R^N1It is H.In many embodiments, Y is-NR^N1S(O)₂And R is alkyl, aryl, heteroaryl Base, carbocylic radical (carbocyclyl) or heterocycle.

In about formula (I)-(IX) embodiment, Y is-NR^N1C(O)-.About formula (I)-(IX) embodiment In, Y is-NR^N1C (O)-and R are piperidyl, morpholinyl, thiophenyl, isoquinolin, quinolyl, thio-furan, aisaa benzothiophenyl Or pyrrolidinyl.In about formula (I)-(IX) embodiment, Y is-NR^N1C (O)-and R is H, C_1-6Alkyl, naphthenic base or Heterocycle or R can be with R^N1Form the ring with 5 to 7 member atoms, middle ring can containing at most 2 selected from N, O and The hetero atom of S can be saturated or unsaturated.In many embodiments, Y is-NR^N1C (O)-, R is piperidyl, R^N1It is H, Z is-CH₂And X₁、X₂And X₃It is H.In many embodiments, Y is-NR^N1C (O)-R is isoquinolin, R^N1It is H, Z is direct key, and X¹、X²And X³It is H.

In about formula (I)-(IX) embodiment, Y is-O (CR¹ ₂)_n-.In many embodiments, Y is-O (CR¹ ₂)_nAnd R is that naphthenic base, heterocycle or heteroaryl or R can be with R¹The ring with 5 to 7 member atoms is formed, Its middle ring can be selected from the hetero atom of N, O and S containing at most 2, can be saturated or unsaturated.

In about formula (I)-(IX) embodiment, Y is-NR^N1(CR¹ ₂)_m-.About formula (I)-(IX) embodiment party In formula, Y is-NR^N1(CR¹ ₂)_mAnd R is H, C_1-6Alkyl, naphthenic base, heterocycle, aryl or heteroaryl or R can be with R^N1 The ring with 5 to 7 member atoms is formed, middle ring can be selected from the hetero atom of N, O and S containing at most 2, can be full It is sum or unsaturated.

In about formula (I)-(IX) embodiment, Y is-C (O) O- or-OC (O)-.About formula (I)-(IX) reality It applies in mode, Y is-C (O) O- or-OC (O)-and R is H, naphthenic base, heterocycle, aryl or heteroaryl, and wherein Z is straight Connect key.

In some embodiments in these areas, Y is-NR^N1S(O)₂-、–NR^N1C(O)-、-NR^N1(CR¹ ₂)_m-、-S (O)₂-、-C(O)-、-NR^N1C(O)O(CR¹ ₂)_nOr C_1-6Alkylidene.

In some embodiments in these areas, R is halogen, cyano, OR³, amino, naphthenic base, heterocycle, aryl or Heteroaryl or R can be with R^N1Or R¹The ring with 5 to 7 member atoms is formed, middle ring can be selected from containing at most 2 N, the hetero atom of O and S, ring are saturated or unsaturated.

In some embodiments in these areas, R¹It is F or Me or forms ring with R.

In some embodiments in these areas, n is 2,3,4,5 or 6.

Compound according to the disclosure includes those shown in table 1.

Table 1.

According to the compound of the disclosure further include:

On the other hand, there is provided herein the compounds of formula (Xa):

Or its pharmaceutically acceptable salt,

Wherein,

R¹It is H ,-C_1-6Alkyl ,-C_1-6Halogenated alkyl, aryl, heteroaryl ,-(C_1-6Alkyl)-pyridyl group ,-(C_1-6Alkyl)- N(R³)R⁴、-(C_1-6Alkyl)-heterocycle or Heterocyclylalkyl；

R²It is H ,-C_1-6Alkyl ,-C_1-6Halogenated alkyl, aryl, heteroaryl ,-(C_1-6Alkyl)-pyridyl group ,-(C_1-6Alkyl)- N(R³)R⁴、-(C_1-6Alkyl)-heterocycle or Heterocyclylalkyl；

Or R¹And R²And nitrogen in connection is formed together-heterocycle or use-C_1-6Alkyl-substituted heterocycle；

R³It is H, C_1–6Alkyl or-C_1–6Halogenated alkyl；

R⁴It is H, C_1–6Alkyl or-C_1–6Halogenated alkyl；

X is H, C_1–6Alkyl ,-C_1–6Halogenated alkyl, halogen or hydroxyl；

Y is H, C_1–6Alkyl ,-C_1–6Halogenated alkyl, halogen or hydroxyl；And

Z is H, C_1–6Alkyl ,-C_1–6Halogenated alkyl, halogen or hydroxyl.

In one embodiment, the compound of formula (Xa) is the compound of formula (X):

Or its pharmaceutically acceptable salt,

Wherein,

R¹It is H ,-C_1-6Alkyl ,-C_1-6Halogenated alkyl, aryl, heteroaryl ,-(C_1-6Alkyl)-pyridyl group ,-(C_1-6Alkyl)- N(R³)R⁴、-(C_1-6Alkyl)-heterocycle or Heterocyclylalkyl；

R²It is H ,-C_1-6Alkyl ,-C_1-6Halogenated alkyl, aryl, heteroaryl ,-(C_1-6Alkyl)-pyridyl group ,-(C_1-6Alkyl)- N(R³)R⁴、-(C_1-6Alkyl)-heterocycle or Heterocyclylalkyl；

Or R¹And R²And nitrogen in connection is formed together-heterocycle；

R³It is H, C_1–6Alkyl or-C_1–6Halogenated alkyl；

R⁴It is H, C_1–6Alkyl or-C_1–6Halogenated alkyl；

X is H, C_1–6Alkyl ,-C_1–6Halogenated alkyl, halogen or hydroxyl；

Y is H, C_1–6Alkyl ,-C_1–6Halogenated alkyl, halogen or hydroxyl；And

Z is H, C_1–6Alkyl ,-C_1–6Halogenated alkyl, halogen or hydroxyl.

In one embodiment, the compound of formula (X) is the compound of formula (XI):

Or its pharmaceutically acceptable salt.

In one embodiment, the compound of formula (X) is the compound of formula (XII):

Or its pharmaceutically acceptable salt.

In one embodiment, the compound of formula (X) is the compound of formula (XIII):

Or its pharmaceutically acceptable salt.

In one embodiment, the compound of formula (X) is the compound of formula (XIV):

Or its pharmaceutically acceptable salt.

In one embodiment, the compound of formula (X) is the compound of formula (XV):

Or its pharmaceutically acceptable salt.

In one embodiment, the compound of formula (X) is the compound of formula (XVI):

Or its pharmaceutically acceptable salt.

In one embodiment, the compound of formula (X) is the compound of formula (XVII):

Or its pharmaceutically acceptable salt.

In one embodiment, the compound of formula (X) is the compound of formula (XVIII):

Or its pharmaceutically acceptable salt.

In one embodiment, the compound of formula (X) is the compound of formula (XIV):

Or its pharmaceutically acceptable salt.

In one embodiment, the compound of formula (X) is the compound of formula (XX):

Or its pharmaceutically acceptable salt.

In one embodiment, the compound of formula (X) is the compound of formula (XXI):

Or its pharmaceutically acceptable salt.

In one embodiment, the compound of formula (X) is the compound of formula (XXII):

Or its pharmaceutically acceptable salt.

In one embodiment, the compound of formula (X) is the compound of formula (XXIII):

Or its pharmaceutically acceptable salt.

In various some embodiments provided herein, in solid of the compound about the cyclopropyl rings of the compound The heart is trans- (±).In various some embodiments provided herein, cyclopropyl rings of the compound about the compound Stereocenter be (R, R).In various some embodiments provided herein, cyclopropyl of the compound about the compound The Stereocenter of ring is (S, S).

In various some embodiments provided herein,

R¹It is H ,-C_1-6Alkyl, aryl, heteroaryl ,-(C_1-6Alkyl)-pyridyl group ,-(C_1-6Alkyl)-N (R³)R⁴、-(C_1-6 Alkyl)-heterocycle or Heterocyclylalkyl；

R²It is H ,-C_1-6Alkyl, aryl, heteroaryl ,-(C_1-6Alkyl)-pyridyl group ,-(C_1-6Alkyl)-N (R³)R⁴、-(C_1-6 Alkyl)-heterocycle or Heterocyclylalkyl；

Or R¹And R²And nitrogen in connection is formed together heterocycle；

R³It is H or C_1-6Alkyl；

R⁴It is H or C_1-6Alkyl；

X is H, C_1-6Alkyl, halogen or hydroxyl；

Y is H, C_1-6Alkyl, halogen or hydroxyl；And

Z is H, C_1-6Alkyl, halogen or hydroxyl.

In various some embodiments provided herein,

R¹It is H ,-C_1-4Alkyl, aryl, heteroaryl ,-(C_1-4Alkyl)-pyridyl group ,-(C_1-4Alkyl)-N (R³)R⁴、-(C_1-4 Alkyl)-heterocycle or Heterocyclylalkyl；

R²It is H ,-C_1-4Alkyl, aryl, heteroaryl ,-(C_1-4Alkyl)-pyridyl group ,-(C_1-4Alkyl)-N (R³)R⁴、-(C_1-4 Alkyl)-heterocycle or Heterocyclylalkyl；

Or R¹And R²And nitrogen in connection is formed together heterocycle；

R³It is H or C_1-4Alkyl；

R⁴It is H or C_1-4Alkyl；

X is H, C_1-4Alkyl, halogen or hydroxyl；

Y is H, C_1-4Alkyl, halogen or hydroxyl；And

Z is H, C_1-4Alkyl, halogen or hydroxyl.

In various some embodiments provided herein,

R¹It is H, phenyl, pyridyl group ,-(C_1-6Alkyl)-pyridyl group ,-(C_1-6Alkyl)-N (R³)R⁴、-(C_1-6Alkyl)-heterocycle Base or Heterocyclylalkyl；And

R²It is H, phenyl, pyridyl group ,-(C_1-6Alkyl)-pyridyl group ,-(C_1-6Alkyl)-N (R³)R⁴、-(C_1-6Alkyl)-heterocycle Base or Heterocyclylalkyl.

In various some embodiments provided herein,

R¹It is H；And

R²It is H, phenyl, pyridyl group ,-(C_1-6Alkyl)-pyridyl group ,-(C_1-6Alkyl)-N (R³)R⁴、-(C_1-6Alkyl)-heterocycle Base or Heterocyclylalkyl.

In various some embodiments provided herein, R¹It is H or-C_1-6Alkyl.

In various some embodiments provided herein, R¹It is-C_1-6Alkyl.

In various some embodiments provided herein, R¹It is H.

In various some embodiments provided herein, R²It is phenyl, pyridyl group ,-(C_1-6Alkyl)-pyridyl group ,- (C_1-6Alkyl)-N (R³)R⁴、-(C_1-6Alkyl)-heterocycle or Heterocyclylalkyl.

In various some embodiments provided herein, pyridyl group is 2- pyridyl group.

In various some embodiments provided herein, pyridyl group is 3- pyridyl group.

In various some embodiments provided herein, pyridyl group is 4- pyridyl group.

In various some embodiments provided herein, R²It is phenyl, pyridyl group ,-(C_1-6Alkyl)-pyridyl group ,- (C_1-6Alkyl)-heterocycle or Heterocyclylalkyl.

In various some embodiments provided herein, R²It is-(C_1-6Alkyl)-N (R³)R⁴、-(C_1-6Alkyl)-miscellaneous Ring group or Heterocyclylalkyl；

In various some embodiments provided herein, R²It is phenyl, pyridyl group ,-(C_1-6Alkyl)-pyridyl group.

In various some embodiments provided herein, R²It is pyridyl group.

In various some embodiments provided herein, R¹And R²And nitrogen in connection is formed together and includes The heterocycle of six annular atoms.

In various some embodiments provided herein, R¹And R²And nitrogen in connection is formed together and includes The heterocycle of six annular atoms, wherein one or two annular atom independently are O, S or N.

In various some embodiments provided herein, R¹And R²And nitrogen in connection is formed together and includes The heterocycle of six annular atoms, wherein one or two annular atom are N.

In various some embodiments provided herein, R³And R⁴It is H.

In various some embodiments provided herein, R³And R⁴It is independently C_1-6Alkyl.

In various some embodiments provided herein, R³It is H and R⁴It is C_1-6Alkyl.

In various some embodiments provided herein, X, Y and Z are H.

In various some embodiments provided herein,

X is C_1-6Alkyl, halogen or hydroxyl；And

Y and Z is H.

In various some embodiments provided herein,

X is halogen；And

Y and Z is H.

In various some embodiments provided herein, X is C_1-6Alkyl, halogen or hydroxyl.

In various some embodiments provided herein, X is methyl, ethyl, CF₃、CHF₂Or CH₂F。

In various some embodiments provided herein, Y is methyl, ethyl, CF₃、CHF₂Or CH₂F。

In various some embodiments provided herein, Z is methyl, ethyl, CF₃、CHF₂Or CH₂F。

In various some embodiments provided herein, X is halogen.

In various some embodiments provided herein, X is F or Cl.

In various some embodiments provided herein, X is Cl.

In various some embodiments provided herein,

X is methyl or halogen；

Y is methyl or halogen；And

Z is methyl or halogen.

In various some embodiments provided herein,

X is methyl, F or Cl；

Y is methyl, F or Cl；And

Z is methyl, F or Cl.

In various some embodiments provided herein,

X is halogen；And

Y is hydroxyl.

In various some embodiments provided herein, Y is hydroxyl.

In various some embodiments provided herein, Z is H or F.

In some respects, provided herein is the compounds of formula (1):

Or its pharmaceutically acceptable salt；

Wherein

Y is-C_1-6Alkyl ,-O- ,-(CH₂)_1–2OC(O)N(H)-、-(CH₂)_1–2N (H)-,-C (O) N (H)-(i.e. amide) Or-C (O) O- (i.e. ester)；

X¹It is H ,-OH ,-C_1-3Alkyl (such as methyl) or halogen (such as F, Br or Cl)；

X²It is H or halogen (such as F, Cl or Br)；

X³It is H or halogen (such as F, Cl or Br)；

Z is key ,-S (O)₂, vinyl, acetenyl, methylene, ethylidene or propylidene or Z and the nitrogen being connect with Z It is formed together-C_2-6Heterocyclylalkyl；And

R is-OH ,-NH₂、—NH(C_1-3Alkyl) ,-N (C_1-3Alkyl) (C_1-3Alkyl) ,-C (O) O- (C_1-6Alkane Base) ,-N (H) C (O)-(C_1-6Alkyl) ,-C_1-3Alkyl, pyridyl group, phenyl, halogenophenyl, methoxyphenyl, monohaloalkyl first Phenyl, dihalo methoxyphenyl, three halogenated methoxy phenyl, monohaloalkyl methyl, dihalomethyl, trihalomethyl group, Thienyl, halogenated thiophene base, thiazolyl, aisaa benzothiophenyl, isoquinolyl ,-C_2-6Heterocyclylalkyl, oxygen diaryl (such as oxygen two Phenyl, oxygen dinaphthyl or benzene Benzopyranyl) or R be unsubstituted-C_2-6Heterocyclylalkyl or use-C_1-6Alkyl, halogen, benzyl Base, halogeno-benzyl, pyridyl group, carbonyl, monohaloalkyl methyl, dihalomethyl, trihalomethyl group or-C (O) O- (C_1-6Alkyl) In it is one or more replace-C_2-6Heterocyclylalkyl；

Or Y and Z are key together, and R is-OH ,-NH₂、—NH(C_1-3Alkyl) ,-N (C_1-3Alkyl) (C_1-3- Alkyl) ,-N (H) C (O)-(C_1-6Alkyl) ,-C (O) NH₂、—C_1-3Alkyl, pyridyl group, phenyl, halogenophenyl, methoxyl group Phenyl, monohaloalkyl methoxyphenyl, dihalo methoxyphenyl, three halogenated methoxy phenyl, monohaloalkyl methyl, dihalo first Base, trihalomethyl group, thienyl, halogenated thiophene base, thiazolyl, aisaa benzothiophenyl, isoquinolyl ,-C_2-6Heterocyclylalkyl, oxygen Diaryl (such as oxygen diphenyl, oxygen dinaphthyl or benzene Benzopyranyl) or R are unsubstituted-C_2-6Heterocyclylalkyl or use- C_1-6Alkyl, halogen, benzyl, halogeno-benzyl, pyridyl group, carbonyl, monohaloalkyl methyl, dihalomethyl, trihalomethyl group or-C (O)O-(C_1-6Alkyl) in it is one or more replace-C_2-6Heterocyclylalkyl.

In some embodiments, Y is-C (O) N (H)-(i.e. amide).In some embodiments, Y is-C (O) O- (i.e. ester).In some embodiments, Y is-C_1-6Alkyl.In some embodiments, Y is-(CH₂)_1–2OC(O)N(H)- Or-(CH₂)_1–2N(H)-.In some embodiments, Y is-O-.

In some embodiments, Y and Z is key together.

In some embodiment, X¹It is-OH, methyl, F, Br or Cl.

In some embodiments, X²It is F, Cl or Br.

In some embodiments, X³It is F, Cl or Br.

In some embodiments, Z is-S (O)₂—.In some embodiments, Z is key.In some embodiments In, Z is vinyl, acetenyl, methylene, ethylidene or propylidene.In some embodiments, Z and together with the nitrogen of Z connection Formation-C_2-6Heterocyclylalkyl.

In some embodiments, R is-OH ,-NH₂、—NH(C_1-3Alkyl) ,-N (C_1-3Alkyl) (C_1-3Alkane Base) ,-C (O) O- (C_1-6Alkyl) ,-N (H) C (O)-(C_1-6Alkyl) or-C_1-3Alkyl.In some embodiments, R It is-OH ,-NH₂、—NH(C_1-3Alkyl) ,-N (C_1-3Alkyl) (C_1-3Alkyl) ,-N (H) C (O)-(C_1-6Alkyl) or- C_1-3Alkyl.In some embodiments, R is pyridyl group, phenyl, halogenophenyl, methoxyphenyl, monohaloalkyl methoxybenzene Base, dihalo methoxyphenyl, three halogenated methoxy phenyl, monohaloalkyl methyl, dihalomethyl, trihalomethyl group, thienyl, Halogenated thiophene base, thiazolyl, aisaa benzothiophenyl, isoquinolyl ,-C_2-6Heterocyclylalkyl, oxygen diaryl (such as oxygen diphenyl, oxygen Dinaphthyl or benzene Benzopyranyl).In some embodiments, R is unsubstituted-C_2-6Heterocyclylalkyl or use-C_1-6Alkyl, Halogen, benzyl, halogeno-benzyl, pyridyl group, carbonyl, monohaloalkyl methyl, dihalomethyl, trihalomethyl group or-C (O) O- (C_1-6- Alkyl) in it is one or more replace-C_2-6Heterocyclylalkyl.

In some embodiments, the compound of the formula (1) provided is the compound of formula (2):

Or its pharmaceutically acceptable salt.

In some embodiments, the compound of the formula (1) provided is the compound of formula (3):

Or its pharmaceutically acceptable salt.

In some embodiments, the compound of the formula (1) provided is the compound of formula (4):

Or its pharmaceutically acceptable salt；

Wherein

R-Z-N(R^N1) it is unsubstituted-C_2-6Heterocyclylalkyl or use-C_1-6Alkyl, halogen, phenyl, halogenophenyl, benzyl Base, halogeno-benzyl, pyridyl group, carbonyl, monohaloalkyl methyl, dihalomethyl, trihalomethyl group or-C (O) O- (C_1-6Alkyl) In it is one or more replace-C_2-6Heterocyclylalkyl.

In some embodiments, the compound of the formula (1) provided is the compound of formula (5):

Or its pharmaceutically acceptable salt.

In some embodiments, the compound of the formula (1) provided is the compound of formula (6):

Or its pharmaceutically acceptable salt.

In some embodiments, the compound of the formula (1) provided is the compound of formula (7):

Or its pharmaceutically acceptable salt.

In some embodiments, the compound of the formula (1) provided is the compound of formula (8):

Or its pharmaceutically acceptable salt.

In some embodiments, the compound of the formula (1) provided is the compound of formula (9):

Or its pharmaceutically acceptable salt.

In some embodiments, the compound of the formula (1) provided is the compound of formula (10):

Or its pharmaceutically acceptable salt.

In some embodiments, the compound of the formula (1) provided is the compound of formula (11):

Or its pharmaceutically acceptable salt.

On the other hand, there is provided herein the compounds of formula (1 '):

Or its pharmaceutically acceptable salt；

Wherein

Y is-(CH₂)_1–2N (H)-or-C (O) N (H)-(i.e. amide)；

X¹It is H ,-OH ,-C_1-3Alkyl (such as methyl) or halogen (such as F, Br or Cl)；

X²It is H or halogen (such as F, Cl or Br)；

X³It is H ,-C_1-3Alkyl (such as methyl) or halogen (such as F, Cl or Br)；

Z is key, vinyl, acetenyl, methylene, ethylidene or propylidene or Z and the shape together with the nitrogen of Z connection At-C_2-6Heterocyclylalkyl；And

In some embodiments, Y and Z is key together.

In some embodiment, X¹It is-OH, methyl, F, Br or Cl.

In some embodiments, X²It is F, Cl or Br.

In some embodiments, X³It is F, Cl or Br.

In some embodiments, the compound of the formula (1 ') provided is the compound of formula (12):

Or its pharmaceutically acceptable salt.

In some embodiments, the compound of the formula (1 ') provided is the compound of formula (13):

Or its pharmaceutically acceptable salt.

In various some embodiments provided herein, compound be table 1, table 2, table 3, table 4, table 5, table 6, table 7, Compound provided in table 8, table 9, table 10, table 11, table 12, table 13, table 14, table 15, table 16, table 17 or table 18 or its medicine Acceptable salt on.

Isomers

Compound as described herein can be with one or more specific geometry, optical, enantiomerism, diastereomeric Isomery, epimerism, atropic (atropic), stereoisomer, tautomer, conformation or epimerism shape Formula exists, including but not limited to: cis form and trans forms；E form and Z-shaped formula；C form, t form and r form；Bridge in ring Connect form (endo-form) and the outer bridged-style (exo-form) of ring；R form, S-shaped formula and meso-form；D-shaped formula and L shape Formula；D form and l form；(+) form and (-) form；Ketone form, Enol forms and enol salt form；Conformal formula and anti-form； Synclinal form and anticlinal form；Alpha form and beta form；Axial bond and calm key-shaped formula；Boat form form, chair form form, torsion type shape Formula, envelope type form and half-chair form；And their combination, hereinafter collectively referred to as " isomers " (or " isomeric form ").

In one embodiment, compound described herein can be the enantiomerism of stereoisomer described herein The isomers of enrichment.For example, the compound can have at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% Enantiomerism is excessive.As used herein, enantiomter, which refers to its molecular structure each other, has a pair of mirror Chemical compound.

In one embodiment, the preparation of compound disclosed herein, which is rich in, has choosing corresponding with selected Stereocenter Determine the isomers of the compound of spatial chemistry (such as R or S).For example, the compound with correspond to at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% selected Stereocenter is selected vertical The purity of the compound of body chemistry.

In one embodiment, composition as described herein includes being rich at selected Stereocenter to have selected solid The preparation of the compound disclosed herein of one or more structures of chemical (such as R or S).Exemplary R/S configuration can be The configuration provided in example described herein.

As used herein, " enriched preparation " in motif compound one kind, two kinds, it is three or more selected The selected spatial configuration of Stereocenter is enrichment.Illustratively selected Stereocenter and its exemplary stereo configuration can be selected from (such as in example as described herein) provided herein is those of.Enrichment refers in preparation for example, at least 60% compound point Son has the selected spatial chemistry of selected Stereocenter.In one embodiment, be at least 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%.Enrichment refers to the level of theme molecule, and unless in addition It indicates, does not otherwise indicate that process limits.

Compound can be different using racemic form or as individual mapping by stereoselective syntheses or by splitting Structure body or diastereoisomer preparation.For example, compound can be split into their component enantiomerism by standard technique Then body or diastereoisomer carry out classification knot such as by forming stereoisomer pair with optical active alkali forming salt Brilliant and free acid regeneration.Chromatographic isolation can also be then carried out and remove chirality to help by forming alloisomerism ester or amide Agent splits compound.Alternatively, chiral chromatographic column, which can be used, splits compound.Enantiomter also can be used lipase from It is obtained in the Kinetic Resolution of the racemate of corresponding esters.

In addition to below for tautomeric form discussion, especially excluded from the term as used herein " isomers " It is structure (or composition) isomers, i.e., difference is connected between atom, rather than just the different isomery in the position of atom in space Body.For example, referring to methoxyl group (- OCH₃) be not construed as referring to its constitutional isomer --- methylol (- CH₂OH).It is similar Ground refers to that Chloro-O-Phenyl is not construed as referring to its constitutional isomer (chlorphenyl).However, referring to that a class formation very may be used It can include belonging to such structural isomeric form (for example, C₃Alkyl or propyl include n-propyl and isopropyl；C₄Alkyl or fourth Base includes normal-butyl, isobutyl group, sec-butyl and tert-butyl；Methoxyphenyl include o-methoxyphenyl, m-methoxyphenyl and P-methoxyphenyl).

Above-mentioned exclusion is not related to tautomeric form, for example, ketone form, Enol forms and enol salt form, such as example Following tautomerism centering: ketone/enol, imines/enamine, amide/imino group alcohol, amidine/amidine, nitroso/oxime, thioketones/alkene mercaptan, N- nitroso/hydroxyazo and nitro/aci-nitro group.

Note that in term " isomers " particularly including be the compound replaced with one or more isotopes.For example, H can be any isotope form, including¹H、²H (D) and³H(T)；C can be any isotope form, including¹²C、¹³C and¹⁴C；O can be any isotope form, including¹⁶O and¹⁸O；Etc..

Salt

Compound described herein can be the form of salt, such as pharmaceutically acceptable salt.Term is " pharmaceutically acceptable Salt " include reactive compound with the acid of relative nontoxic or alkali preparation salt, depending on what is found on compound described herein Specified substituent.By making salt contact and separate in a usual manner parent compound with alkali or acid, compound can be regenerated Neutral form.The parent fo of the compound is different from various salt forms in certain physical properties, such as in polar solvent Solubility, but for the purpose of the disclosure, salt is equal in other respects with the parent fo of compound.It can pharmaceutically connect The example for the salt received is in Berge et al., 1977, " Pharmaceutically Acceptable Salts. " J.Pharm.Sci. It volume 66, is had been discussed in the 1-19 pages.In one embodiment, compound exists in the form of mono-salt.In many embodiment party In formula, compound exists with two salt forms.

For example, if compound is anion, or with can be the functional group of anion (for example,-COOH can be with It is COO^-), then it can be with suitable salt forming cation.The example of suitable inorganic cation include but is not limited to alkali metal from Son such as Na⁺And K⁺, alkaline earth cation such as Ca²⁺And Mg²⁺And other cations.The example of suitable organic cation includes But ammonium ion is not limited to (that is, NH₄ ⁺) and replace ammonium ion (for example, NH₃R₁ ⁺、NH₂R₂ ⁺、NHR₃ ⁺、NR₄ ⁺).It is some suitably to take The example of the ammonium ion in generation is derived from those of following ammonium ion replaced: ethamine, diethylamine, triethylamine, butylamine, second two Amine, ethanol amine, diethanol amine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine and tromethamine and binary amino acid, it is all Such as lysine and arginine.

If compound is cationic, or has and can be cation (for example,-NH₂It can be-NH₃ ⁺) function Group, then can be with suitable anion forming salt.The example of suitable inorganic anion includes but is not limited to be derived from following nothing Those of machine acid inorganic anion: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfurous acid, nitric acid, nitrous acid, phosphoric acid and phosphorous acid.

The example of suitable organic anion includes but is not limited to be derived from those of following organic acid organic anion: 2- Acetoxy-benzoic acid, acetic acid, ascorbic acid, aspartic acid, benzoic acid, camphorsulfonic acid, cinnamic acid, citric acid, edetic acid(EDTA), second Disulfonic acid, ethanesulfonic acid, fumaric acid, anhydroglucose, gluconic acid, glutamic acid, glycolic, hydroxymaleic acid, hydroxynaphthoic acid, hydroxyl Ethanesulfonic acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, methanesulfonic acid, glactaric acid, oleic acid, oxalic acid, palmitinic acid, double hydroxyl naphthalenes Acid, pantothenic acid, phenylacetic acid, benzene sulfonic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, to toluene sulphur Acid and valeric acid.The example of suitable polymerization organic anion includes but is not limited to be derived from those of following polymeric acid: tannic acid, Carboxymethyl cellulose.

Unless otherwise stated, referring to specific compound also includes its salt form.

Chemoproection form

It may be convenient or desired that reactive compound is prepared, purified and/or handled in the form of chemoproection.Term " is changed Learn protection form " herein with the use of conventional chemical meaning, and be related in specified conditions (for example, pH, temperature, radiation, molten Agent etc.) under protect one or more reactive functional groups from it is undesirable chemical reaction influence compound.In practice, it adopts Functional group is reversibly set to become non-reacted under given conditions with well-known chemical method, otherwise the functional group can be It is reactive.In chemoproection form, one or more reactive functional groups are the forms of protected group or blocking group (also referred to as masked group or masking group, or be blocked group or barrier group).By protecting reactive functional groups, not In the case where influencing protected group, it can carry out being related to the reaction of other not protected reactive functional groups；Usually rear In continuous step, blocking group can be removed in the case where having no substantial effect on the rest part of molecule.See, for example, Protective Groupsin Organic Synthesis (T.Green and P.Wuts；3rd edition；John Wiley and Sons, 1999).Unless otherwise specified, referring to that specific compound further includes its chemoproection form.

It is many institute's weeks that various such " protection ", " barrier " or " masking " methods, which are widely used and in organic synthesis, Know.For example, the change with two non-equivalence reactive functional groups (the two is all reactive under given conditions) can be made Object derivatization is closed so that one of functional group " being protected " and therefore under the specified conditions be non-reactive；So After protected, which can be used as effectively only with the reactant of a reactive functional groups.The reaction needed for completing (relates to And another functional group) after, protected group " can deprotect " so that it restores its original degree of functionality.

Hydroxyl can be used as ether (- OR) or ester (- OC (O) R) and be protected, such as conduct: tertbutyl ether；Benzylic ether, two Benzyl ether or trityl ether；Trimethyl silane ether or t-butyldimethyl silane ether；Or acetonyl ester (- OC (O) CH₃,- OAc)。

Aldehydes or ketones group can be respectively with acetal (RCH (OR)₂) or ketal (R₂C(OR)₂) form protected, wherein carbonyl (R₂C=O) diether (R is converted into and reacting with such as primary alconol₂C(OR)₂).In the presence of an acid, by using a large amount of Excessive water is easy to make aldehydes or ketones group to regenerate to hydrolyze.

Amido can be protected for example in the form of amide (- NRC (O) R) or carbamate (- NRC (O) OR), for example, making Are as follows: methyl nitrosourea (- NHC (O) CH₃)；Benzyloxy-amide (- NHC (O) OCH₂C₆H₅,-NH-Cbz)；As tert-butoxy amide (- NHC(O)OC(CH₃)₃,-NH-Boc)；2- biphenyl -2- propoxyl group amide (- NHCO (O) C (CH₃)₂C₆H₄C₆H₅,-NH-Bpoc)；Make For 9- fluorenyl methoxy amide (- NH-Fmoc)；As 6- nitro aryl acyloxy amide (6-nitroveratryloxy amide) (-NH-Nvoc)；As 2- trimethylsilylethoxy amide (- NH-Teoc)；As 2,2,2- tri-chloroethoxy base amide (- NH-Troc)；As allyloxy amide (- NH-Alloc)；As 2 (- phenyl sulfonyl) ethyoxyl amides (- NH-Psec)； Alternatively, in a suitable case (for example, cyclammonium), as nitroxid (> N-0 < <).

Carboxylic acid group can be protected with ester-formin, such as conduct: Arrcostab (such as methyl esters；Tertiary butyl ester)；Alkyl halide Base ester (such as alkyl halide base ester)；Trialkylsilanyl Arrcostab；Or alkyl aryl (such as benzyl ester；Nitrobenzyl ester)； Or as amide, such as methyl nitrosourea.

Thiol group can be protected in the form of thioether (- SR), for example, conduct: benzyl thioether；Acetylamino methyl ether (- S-CH₂NHC(O)CH₃)。

Prodrug and other modifications

In addition to salt form, the compound of prodrug forms is can also be provided in the present invention.The prodrug of compound described herein is those It is easy to happen chemical change in physiological conditions to provide the compound of compound described herein.Prodrug can pass through chemistry or life Object chemical method is converted into the compound of the disclosure in ex vivo environment.For example, when being placed in prodrug with or without conjunction When in the transdermal patch reservoir (transdermal patch reservoir) of suitable enzyme or chemical reagent, can slowly it be turned Turn to the compound of the disclosure.

Compound as described herein can also be modified by adding functional group appropriate to enhance selectivity organism spy Property.These modifications are known in the art, and including increase to given biosystem (such as blood, lymphatic system, maincenter mind Through system) in bio-osmosis, increase oral availability, increase solubility with allow by injection application, change metabolism and/or Change the modification of those of discharge rate.The example of these modifications includes but is not limited to polyethylene glycol, uses Pivalate (pivolate) or fatty acid substituents derivatization, the hetero atom that is converted in the hydroxylating and aromatic ring of carbamate, aromatic ring Replace.

Synthesis

Compound can be synthesized according to exemplified synthesis schemes shown in embodiment.

It will be apparent to those skilled in the art for the other methods of synthesis various compound herein. The synthesis chemical conversion and blocking group methodology (protection and deprotection) that can be used for synthesizing compound are known in the art, packets Those of described in including below for example: R.Larock, Comprehensive Organic Transformations, VCH Publishers(1989)；T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis, second edition, John Wiley and Sons (1991)；L.Fieser and M.Fieser, Fieser and Fieser's Reagents for Organic Synthesis,John Wiley and Sons(1994)；And L.Paquette edits Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and its later release.

Application method and activity

Compound disclosed herein and there is kinase inhibiting activity comprising their compositions, therefore can be used for adjusting kinases Effect, and for treating and/or prevent the disease influenced by kinases or the patient's condition.Above compound and composition can be used for adjusting The effect in the cell in cell or intracorporal living body in vitro of section (for example, influence or inhibit) kinases.Specifically, in a reality It applies in mode, provides the method for inhibiting zymogenesis, this method comprises: effective to culture medium (such as measurement culture medium) application The compound disclosed herein of amount of suppression, or make the sheet of effective inhibitory amount in the cell of living body in vitro in cell or in vivo Compound disclosed in text is contacted with cell.In one embodiment, the kinases of inhibition is rho kinases.In another embodiment party In formula, the kinases of inhibition is JAK (such as JAK2) kinases.

JAK inhibitor can be used for treating various diseases related with JAK or illnesss.JAK diseases related example includes It is related to the disease of immune system, including such as organ-graft refection's (such as allograft rejection and graft-versus-host disease Disease).Other JAK diseases related examples include autoimmune disease, such as multiple sclerosis, rheumatoid joint Inflammation, adolescent arthritis, arthritic psoriasis, type-1 diabetes mellitus, lupus, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn's disease (Crohn ' s disease), myasthenia gravis, immunoglobulin nephropathy, myocarditis, autoimmune first shape Adenopathy disease, chronic obstructive pulmonary disease (COPD) and its similar disease.In some embodiments, autoimmune disease is joint It is scorching.

Other JAK diseases related examples include the anaphylaxis patient's condition, and such as asthma, wet Shen dermatitis, connects food hypersenstivity Touching property dermatitis, atopic dermatitis (dystopy Shi Shen) and rhinitis.JAK diseases related other examples include viral disease, Such as Ai Baisitan epstein-Barr virus (Epstein Barr Virus, EBV), hepatitis B, hepatitis C, HIV, HTLV 1, water The band-like trace of trace-aches viral (Varicella-Zoster Virus, VZV) and human papilloma virus (Human Papilloma Virus, HPV).

JAK is diseases related or other examples of the patient's condition include being characterized in that disease or symptom below: entity tumor (example Such as prostate cancer, kidney, liver cancer, cancer of pancreas, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, spongioblastoma, card The western sarcoma of wave (Kaposi ' s sarcoma), Ka Siermanshi disease (Castleman ' s disease), uterine leio muscle Tumor, melanoma (melanoma) etc.), hematology's cancer (such as lymthoma, leukaemia (the white blood of such as acute lymphoblastic Sick (ALL), acute myelogenous leukemia (AML) or Huppert's disease) and cutaneum carcinoma (such as skin T cell lymphoma (CTCL) and cutaneous B-cell lymphoma).Exemplary CTCL includes that Sezary syndrome (Sezary syndrome) and gill fungus sample are true Bacterium disease (mycosis fungoides).JAK is diseases related or other examples of the patient's condition include pulmonary hypertension.

JAK is diseases related or other examples of the patient's condition include inflammation associated cancer.In some embodiments, cancer It is related to inflammatory bowel disease.In some embodiments, inflammatory bowel disease is ulcerative colitis.In some embodiments, Inflammatory bowel disease is Crohn's disease.In some embodiments, inflammation associated cancer is colitis related cancer.One In a little embodiments, inflammation associated cancer is colon cancer or colorectal cancer.In some embodiments, cancer be gastric cancer, Stomach and intestine carcinoid tumor, gastrointestinal stromal tumors (GIST), gland cancer, carcinoma of small intestine or the carcinoma of the rectum.

The compound of the disclosure be used to inhibiting cell, in tissue or subject (such as people) kinases method, this method packet Including contacts cell and one or more compounds of effective a certain amount of disclosure for inhibiting kinases.In an embodiment In, compound is applied with pharmaceutically acceptable composition, such as pharmaceutically in acceptable carrier or with pharmaceutically may be used The carrier of receiving is applied together.

In another embodiment, the method that the compound of the disclosure is used to adjust zymogenesis in cell, this method Including contacting cell with effective one or more compounds for adjusting the disclosure of zymogenesis in cell.In an embodiment party In formula, the compound of the disclosure is applied with pharmaceutically acceptable composition, for example, pharmaceutically in acceptable carrier or with Pharmaceutically acceptable carrier is applied together.

The treatment or prevention of disease or the patient's condition that the compound of the disclosure can be used for include related with kinase activity any Disease or the patient's condition or the disease or the patient's condition influenced by kinases.The example of these diseases includes neurodegenerative disease, such as A Er Thatch sea Mo's disease；Eye disease, such as diabetic ocular diseases, wet age related macular degeneration or dry age are related Property macular degeneration, inflammatory ocular disease, retinal degeneration and glaucoma；Cardiovascular disease；And cancer.Other example includes Skeletal diseases, obesity, hepatopathy, kidney trouble, pancreatitis, gastric disease, hypertension, birth control, natural on-off cycles of hair growth disease, nose fill Blood, neurogenic bladder disease, enterogastric diseases, skin disease and respiratory disease indication.

In some embodiments, the compound of the disclosure will be applied with one or more other therapeutic agents.It closes Suitable other therapeutic agents include but is not limited to: beta-blocker, α-agonist, carbonic anhydrase inhibitor, prostaglandin-like compound, Miotic or cholinergic agents, adrenergic compounds, neuroprotective compounds or anti-inflammatory compound.

Beta-Blocking agent.These compounds are considered the generation by reducing aqueous humor to reduce intraocular pressure (IOP).Example includes Left-handed Bu Luoer (BETAGAN^TM), timolol (BETIMOL^TM, TIMOPTIC^TM), betaxolol (BETOPTIC^TM) and U.S.A replace Luo Er (OPTIPRANOLOL^TM)。

α-agonist.These compounds are considered the generation by reducing aqueous humor and increase draining to reduce IOP.Example packet Include Apraclonidine (IOPIDINE^TM) and Brimonidine (ALPHAGAN^TM)。

Carbonic anhydrase inhibitor.These compounds are considered reducing IOP also by the generation for reducing aqueous humor.Example includes Dorzolamide (TRUSOPT^TM) and brinzolamide (AZOPT^TM)。

Prostaglandin-like compound.These compounds are considered by increasing the aqueous humor outflow via uveal scleral approach To reduce IOP.Example includes AR-102, Latanoprost (XALATAN^TM), bimatoprost (LUMIGAN^TM), his fluorine forefront Parathyrine (ZIOPTAN^TM) and travoprost (TRAVATAN^TM)。

Miotic or cholinergic agents.These reagents are considered working and making pupil contraction, this is opened in eye Drainage channel.Example includes pilocarpinum (ISOPTO CARPINE^TM, PILOPINE^TM) and carbachol ((ISOPTO CARBACHOL^TM)。

Adrenergic compounds.These compounds, such as Dipivefrine (PROPINE^TM), it is considered by reducing water flow Out and increase drain to play a role.

Neuroprotective compounds or anti-inflammatory compound.These compounds, such as VEGF Trap (EYLEA^TM), it is view The therapeutic agent of the film patient's condition (such as macular degeneration), and it is designed to anti-vegf therapeutic agent, or anti-with similar type Growth or anti-inflammatory activity.

Therefore, there is provided herein the methods that eye disorders are treated in subject with this need comprising gives subject Apply compound, composition or pharmaceutical composition provided herein.

Moreover, there is provided herein the methods for reducing intraocular pressure in subject with this need comprising applied to subject With compound provided herein, composition or pharmaceutical composition.

In one aspect, there is provided herein the methods that eye disorders are treated in subject with this need comprising gives Subject applies compound provided herein or its pharmaceutically acceptable salt.

In some embodiments, eye disorders are glaucomas.

On the other hand, there is provided herein the methods that intraocular pressure is reduced in subject with this need comprising gives Subject applies compound provided herein or its pharmaceutically acceptable salt.

In some embodiments in these areas, compound is locally applied to the eyes of subject.

In some embodiments, there is provided herein in subject with this need treat eye disorders method, Compound or its pharmaceutically acceptable salt including applying any formula provided herein to subject.

In some embodiments, there is provided herein in subject with this need treat eye disorders method, Including to subject apply table 1, table 2, table 3, table 4, table 5, table 6, table 7, table 8, table 9, table 10, table 11, table 12, table 13, table 14, The compound or its pharmaceutically acceptable salt provided in table 15, table 16, table 17 or table 18.

In some embodiments, there is provided herein the method that intraocular pressure is reduced in subject with this need, packets Include the compound or its pharmaceutically acceptable salt that any formula provided herein is applied to subject.

In some embodiments, there is provided herein the method that intraocular pressure is reduced in subject with this need, packets It includes to subject's application table 1, table 2, table 3, table 4, table 5, table 6, table 7, table 8, table 9, table 10, table 11, table 12, table 13, table 14, table 15, the compound or its pharmaceutically acceptable salt provided in table 16, table 17 or table 18.

In some embodiments of these methods, method further includes applying one or more other therapeutic agents.Some In embodiment, one or more other therapeutic agents are beta-blocker, α-agonist, carbonic anhydrase inhibitor, prostaglandin or preceding Column parathyrine sample compound, miotic or cholinergic agents, adrenergic compounds or neuroprotective compounds or anti-inflammatory chemical combination Object.In some embodiments, one or more other therapeutic agents are prostaglandin or prostaglandin-like compound.In some realities It applies in mode, prostaglandin-like compound is AR-102, Latanoprost, bimatoprost, tafluprost or song Fu Qianlie Element.

The method that autoimmune disease is treated in subject with this need is also provided herein comprising to tested Person applies compound, composition or pharmaceutical composition provided herein.

In some embodiments, there is provided herein the sides that autoimmune disease is treated in subject with this need Method comprising the compound or its pharmaceutically acceptable salt of any formula provided herein are applied to subject.

In some embodiments, there is provided herein the sides that autoimmune disease is treated in subject with this need Method comprising to subject apply table 1, table 2, table 3, table 4, table 5, table 6, table 7, table 8, table 9, table 10, table 11, table 12, table 13, The compound or its pharmaceutically acceptable salt provided in table 14, table 15, table 16, table 17 or table 18.

In some embodiments, autoimmune disease is multiple sclerosis, rheumatoid arthritis, teenager pass Save inflammation, arthritic psoriasis, type-1 diabetes mellitus, lupus, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn's disease (Crohn ' s disease), myasthenia gravis, immunoglobulin nephropathy, myocarditis, autoimmune thyroid disorders disease or slow Property obstructive lung disease.

Composition and application

Another or a variety of therapeutic agents can be administered simultaneously or sequentially with the compound of the disclosure.Sequence is applied It is applied before or after the compounds of this invention.In some embodiments, another or a variety of therapeutic agents can be with this Invention compound is applied in identical composition.In other embodiments, other therapeutic agent and the disclosure are being applied May exist time interval between compound.

In some embodiments, applied together with the compound of the disclosure other therapeutic agent by make relatively low-dose its He can apply the longer time for therapeutic agent.

Composition is also provided herein, it includes compound provided herein or its pharmaceutically acceptable salts.At one In embodiment, composition provided herein is the pharmaceutical composition comprising pharmaceutically acceptable carrier.

One or more physiologically acceptable carriers can be used or excipient is prepared in a usual manner according to this public affairs Open the pharmaceutical composition used.Therefore, compound and its physiologically acceptable salt and solvate can be prepared for Apply in the following manner: for example, solid dosing, eye drops, in local oil-based formulation, injection (including pharmacological eluting arrangement Be injected into the specific organization of entire body or eyes), sucking (by mouth or nose), implantation material or oral, buccal, parenteral Or rectal administration.Technology and preparation usually can be in " Remington'sPharmaceutical Sciences ", (Meade Publishing Co., Easton, PA) in find.

The approach of compound (component A) application and the form of composition of the disclosure determine used carrier (component B) Type.Composition can be the diversified forms suitable for following manner, for example, systemic administration (for example, oral, rectum, nose, Sublingual, buccal, implantation material or parenteral, or enter by ocular injection a chamber of eyes, such as intravitreal injection, In camera oculi anterior injection or injection aqueous humor) or local application (such as it is applied topically to skin, eye, liposome delivery system or ion It imports).

Carrier for systemic administration generally includes at least one of the following terms: a) diluent, b) lubricant, c) it is viscous Mixture, d) disintegrating agent, e) colorant, f) fragrance, g) sweetener, h) antioxidant, j) preservative, k) glidant, m) solvent, n) Suspending agent, o) wetting agent, p) surfactant and their combination etc..All carriers are optional in systemic composition 's.

Ingredient a) is diluent.Diluent suitable for solid dosage forms includes: sugar, such as glucose, lactose, dextrose (dextrose) and sucrose；Glycols, such as propylene glycol；Calcium carbonate；Sodium carbonate；Sugar alcohol, such as glycerol；Mannitol；And sorb Sugar alcohol.The amount of ingredient a) is typically about 50% to about 90% in systemic or topical composition.

Ingredient b) is lubricant.The example of proper lubrication agent for solid dosage forms is solid lubricant, comprising: titanium dioxide Silicon, talcum, stearic acid and its magnesium salts and calcium salt, calcium sulfate；And fluid lubricant, such as polyethylene glycol and vegetable oil are such as spent Oil generation, cottonseed oil, sesame oil, olive oil, corn oil and cupu oil.The amount of ingredient b) is usually in systemic or topical composition About 5% to about 10%.

Ingredient c) is adhesive.Adhesive suitable for solid dosage forms includes: polyvinylpyrrolidone；Zeopan； Starch, such as cornstarch and potato starch；Gelatin；Bassora gum；And cellulose and its derivates, such as carboxymethyl cellulose Sodium, ethyl cellulose, methylcellulose, microcrystalline cellulose and sodium carboxymethylcellulose.The amount of ingredient c) in systemic composition Typically about 5% to about 50%, and 99% is up in eye Solid Dosage Forms.

Ingredient d) is disintegrating agent.Suitable disintegrators for solid dosage forms include: agar, alginic acid and its sodium salt, effervesce Mixture, cross-linked carboxymethyl cellulose sodium (croscarmelose), polyvinylpyrrolidone (crospovidone), carboxymethyl form sediment Powder sodium, sodium starch glycollate, clay and ion exchange resin.The amount of ingredient d) is typically about in systemic or topical composition 0.1% to about 10%.

The ingredient e) of solid dosage forms is colorant, such as FD&C dyestuff.When in use, in systemic or topical composition at Amount e) is divided to be typically about 0.005% to about 0.1%.

The ingredient f) of solid dosage forms is flavoring agent, such as menthol, peppermint and flavoring agent of fruit.When in use, systemic Or the amount of ingredient f) is typically about 0.1% to about 1.0% in topical composition.

The ingredient g) of solid dosage forms is sweetener, such as Aspartame and saccharin.Ingredient in systemic or topical composition G) amount is typically about 0.001% to about 1%.

Ingredient h) is antioxidant, such as butylated hydroxyanisol (" BHA "), butylated hydroxytoluene (" BHT ") and Vitamin E.The amount of ingredient h) is typically about 0.1% to about 5% in systemic or topical composition.

Ingredient j) is preservative, such as benzalkonium chloride, methyl p-hydroxybenzoate and sodium benzoate.Systemic or local group The amount for closing ingredient j) in object is typically about 0.01% to about 5%.

The ingredient k) of solid dosage forms is glidant, such as silica.The amount of ingredient k) in systemic or topical composition Typically about 1% to about 5%.

Ingredient m) is solvent, such as water, isotonic saline solution, ethyl oleate, glycerol, hydroxylated castor oil, alcohols (such as second Alcohol) and phosphate buffer solution.The amount of ingredient m) is typically about 0 to about 100% in systemic or topical composition.

Ingredient n) is suspending agent.Suitable suspending agent includesRC-591 is (from philadelphia, pa FMC Corp.) and sodium alginate.The amount of ingredient n) is typically about 1% to about 8% in systemic or topical composition.

Ingredient o) is surfactant, such as lecithin, polysorbate80 and lauryl sodium sulfate and is come from The Atlas Powder Company's of Wilmington, DelawareSuitable surfactant include with Those surfactants disclosed in Publication about Document: C.T.F.A.Cosmetic Ingredient Handbook, 1992,587- Page 592；Remington's Pharmaceutical Sciences, the 15th edition, 1975, the 335-337 pages；And 1, Emulsifiers&Detergents, 1994, North American Edition of McCutcheon's Volume, the 236-239 pages.The amount of ingredient o) is typically about 0.1% to about 5% in systemic or topical composition.

Although the amount of component A and B will be used for according to the selection of the type of the systemic composition of preparation in systemic composition The specific derivatives of component A and the ingredient of component B and change, but in general, systemic composition includes 0.01% to 50% The component B of component A and 50% to 99.99%.

Composition for parenteral application generally comprises: A) 0.1% to 10% the compounds of this invention；And B) 90% To 99.9% carrier, which includes a) diluent and m) solvent.In one embodiment, component a) includes propylene glycol, It and m) include ethyl alcohol or ethyl oleate.

Composition for oral administration can have various dosage forms.For example, solid form include tablet, capsule, particle and Bulk powder.These peroral dosage forms include safe and effective amount, typically at least about 5%, the more particularly group of about 25% to about 50% Divide A).Oral dosage combination object also includes the component B of about 50% to about 95%), more particularly about 50% to about 75%.

Tablet can be compression, tablet grinding, enteric coating, sweet tablet, film coating or Multiple Compression 's.Tablet generally comprises component A and component B --- the carrier comprising the ingredient selected from the group being made of the following terms: a) dilutes Agent, b) lubricant, c) adhesive, d) disintegrating agent, e) colorant, f) fragrance, g) sweetener, k) glidant (glidants) and it Combination.Specific diluent includes calcium carbonate, sodium carbonate, mannitol, lactose and cellulose.Specific adhesive includes forming sediment Powder, gelatin and sucrose.Specific disintegrating agent includes alginic acid and cross-linked carboxymethyl cellulose.Specific lubricant includes stearic acid Magnesium, stearic acid and talcum powder.Specific colorant is FD&C dyestuff, can be added into improve appearance.Chewable tablets preferably comprises: G) sweetener, such as Aspartame and saccharin；Or f) flavoring agent, such as menthol, peppermint, flavoring agent of fruit or they Combination.

Capsule (including implantation material, time controlled released and sustained release preparation) generally comprises component A and carrier, and the carrier is comprising bright One or more above-mentioned a) diluents included in the capsule of glue.Particle generally comprises component A, and preferably also comprising k) helping stream Agent, such as silica, to improve flow behavior.Implantation material can be biodegradable or not biodegradable type. Any of biocompatibility formulation can be used to prepare implantation material.

Selection for ingredient in the carrier of oral cavity composition depends on secondary consideration factor, such as taste, cost and storage Stability is deposited, these are not important for the purpose of the present invention.Skilled artisan would know how select suitable ingredient Without excessive experiment.

Solid composite can also be coated by conventional method, be usually coated with pH or time dependence, so that component A exists It is discharged in gastrointestinal tract near required application, or in different points and time release to extend required effect.Coating usually packet Containing one or more components selected from the group being made of the following terms: cellulose acetate phthalate, polyvinyl acetate neighbour's benzene Dicarboxylic acid esters, hydroxypropyl methylcellulose phthalate, ethyl cellulose,Coating (is available from moral The Rohm&Haas G.M.B.H. of state Darmstadt), wax and shellac.

Composition for oral administration can also have liquid form.For example, suitable liquid form include: aqueous solution, Lotion, the solution rebuild by non-effervescence granular, the suspension reconstructed by non-effervescence granular, is rebuild by effervescence granular suspension Effervescent formulation, elixir, tincture, syrup etc..Liquid oral compositions generally comprise component A and component B, i.e., comprising selected from by following The carrier of the ingredient of the group of items composition: a) diluent, e) colorant, f) flavoring agent, g) sweetener, j) preservative, m) solvent, N) suspending agent and o) surfactant.Oral liquid composition preferably comprises one kind selected from the group being made of the following terms Or Multiple components: e) colorant, f) flavoring agent and g) sweetener.

Other compositions for realizing the systemic delivery of motif compound include: injection type, sublingual dosage forms, oral cavity Dosage form and intranasal dosage form.This composition generally comprises one or more soluble filler substances, such as a) diluent, including sugarcane Sugar, D-sorbite and mannitol；C) adhesive, such as Acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl are fine Dimension element.Such composition can further include: b) lubricant, e) colorant, f) flavoring agent, g) sweetener, h) antioxidant and K) glidant.

In an embodiment of the invention, the compound of the disclosure is locally applied.It can be topically applied to eyes Topical composition can be any form known in the art, non-limiting example includes solid, the drops that can be gelled, spraying Agent, ointment or the sustained release unit or non-time-release unit that are placed in eye conjunctiva fornix or other appropriate locations.

The topical composition that can be topically applied to skin can be any form, comprising: solid, solution, oil, frost, ointment, Gel, washing lotion, shampoo, leave and rinse conditioner, cream, detergent, moisturizer, spray, skin patch etc..Part Composition includes: component A (above compound) and component B (carrier).The carrier of topical composition preferably facilitates compound infiltration Thoroughly into eyes.Component B can further include one or more optional components.

The effective quantity of compound according to the present invention will change with the variation of the following terms: the specific disease treated Disease, the age of treated patient and physical condition, the severity of the illness, duration for the treatment of while the property for the treatment of, Administration method, specific pharmaceutically acceptable carrier used and similar factor in professional knowledge and attending physician's Special knowledge.For example, the effective quantity of the compound of the disclosure for systemic administration is daily about 0.01 to about 1000 μ g/kg Weight, preferably daily about 0.1 to about 100 μ g/kg weight, most preferably daily about 1 to about 50 μ g/kg weight.Based on medicine for power Technology known to the technical staff with preparation capable of permeating skin field is learned, transdermal dosage compositions are designed to obtain similar serum or blood plasma water It is flat.The blood plasma level of systemic administration is estimated in 0.01ng/mL to 100ng/mL, more preferable 0.05ng/mL to 50ng/mL, most It is preferred that in the range of 0.1ng/mL to 10ng/mL.Although these dosage are based on daily administration rate, the compounds of this invention can also With the application of other intervals, such as twice daily, twice a week, once a week or monthly.Those of ordinary skill in the art will The appropriate effective amount of other administration intervals can be calculated.

The compounds of this invention can be used for reducing or reducing the method for intraocular pressure.The compounds of this invention can be to be effectively reduced eye The amount of internal pressure is applied to subject in need for the treatment of.Therefore, these compounds can be used for treating glaucoma.Treat the excellent of glaucoma Selecting administration method is local application.

The definite measurement of every kind of component is certainly in various factors in topical composition.The component A being added in topical composition Amount depend on component A IC₅₀(usually being indicated with nanomole (nM) unit).For example, if the IC of drug₅₀It is 1nM, then group Divide the amount of A to would be about 0.001% to about 0.3%.If the IC of drug₅₀Be 10nM, then component A) amount be about 0.01% to about 1%.If the IC of drug₅₀For 100nM, then the amount of component A is about 0.1% to about 10%.If the amount of fruit component A is defined above Range except (that is, lower), then the effect of reducing treatment.Skilled artisan understands how calculate and understand IC₅₀.Group The rest part (up to 100%) for closing object is component B.

The composition of the actual amount of per unit dose medicament administration is enough to provide with the amount of the component A carrier being used in combination. The technology and composition for being used to prepare the dosage form that can be used for method of disclosure are described in below with reference in document:Modern Pharmaceutics, the 9th and 10 chapters, Banker&Rhodes, eds. (1979)；Lieberman etc.,Pharmaceutical Dosage Forms:Tablets(1981)；And Ansel,Introduction to Pharmaceutical Dosage Forms, second edition, (1976).

Component B may include single component or the combination of two or more ingredients.In topical composition, component B includes Topical carrier.Suitable topical carrier includes one or more ingredients selected from the group being made of the following terms: phosphate-buffered Salt water, isotonic water, deionized water, monofunctional alcohol, symmetrical alcohols, aloe gel, allantoin, glycerol, oleovitamin A and vitamin E oil, mineral oil, propylene glycol, PPG-2 myristyl propionate, Isosorbide dimethyl ether, castor oil, their combination etc..More specifically Ground, the carrier for dermal application include propylene glycol, isobide dimethyl ester and water, or even more specifically, phosphate buffer salt Water, isotonic water, deionized water, monofunctional alcohol and symmetrical alcohol.

The carrier of topical composition also may include one or more ingredients selected from the group being made of the following terms: q) moisturizing Agent, r) propellant, s) solvent, t) moisturizer, u) thickener, v) powder, w) fragrance, x) pigment and y) preservative.

Ingredient q) is emollient.The amount of ingredient q) is typically about 5% to about 95% in skin base topical composition.Suitably Emollient includes stearyl alcohol, Monoolein, glycerin monostearate, propyl- 1,2- glycol, butyl- 1,3- glycol, ermine oil, ten Six alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, stearic iso-16 alkyl esters, oleyl alcohol, isopropyl laurate, the moon The own ester of cinnamic acid, decyl oleate, octadecane -2- alcohol, different cetanol, cetyl palmitate, n-butyl sebacate, nutmeg Isopropyl propionate, isopropyl palmitate, Emerest 2310, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame Oil, coconut oil, peanut oil, castor oil, acetulan, petroleum, mineral oil, butyl myristate, isostearic acid, palm Acid, linoleic acid isopropyl ester, Lauryl lactate, Tetradecyl lactate, decyl oleate, myristyl myristate and they Combination.Specific skin soothing agents include stearyl alcohol and dimethyl silicone polymer.

Ingredient r) is propellant.The amount of ingredient r) is typically about 0 to about 95% in topical composition.Suitable propellant packet Include propane, butane, iso-butane, dimethyl ether, carbon dioxide, nitrous oxide and their combination.

Ingredient s) is solvent.The amount of ingredient s) is typically about 0 to about 95% in topical composition.Suitable solvent includes Water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, two Methyl sulfoxide, dimethylformamide, tetrahydrofuran and their combination.Specific solvent includes ethyl alcohol and homotopy alcohol (homotopic alcohols)。

Ingredient t) is moisturizer.The amount of ingredient t) is usually 0 to 95% in topical composition.Suitable moisturizer includes sweet Oil, D-sorbite, 2-Pyrrolidone -5- carboxylic acid sodium, soluble collagen, dibutyl phthalate, gelatin and their group It closes.Specific moisturizer includes glycerol.

Ingredient u) is thickener.The amount of ingredient u) is typically about 0 to about 95% in topical composition.

Ingredient v) is powder.The amount of ingredient v) is usually 0 to 95% in topical composition.Suitable powder includes β-ring paste Essence, hydroxypropyl cyclodextrin, chalk, talcum, diatomite, kaolin, starch, natural gum, colloidal silicon dioxide, Sodium Polyacrylate, four Alkylammonium montmorillonite, trialkyl aryl montmorillonite, the aluminium-magnesium silicate of chemical modification, organically modified montmorillonite clay clay, hydration silicon Sour aluminium, fumed silica, carboxy vinyl polymer, sodium carboxymethylcellulose, ethylene glycol monostearate and their group It closes.For ophthalmic applications, specific powder includes beta-cyclodextrin, hydroxypropyl cyclodextrin and Sodium Polyacrylate.For gel dose eye With preparation, Sodium Polyacrylate can be used.

Ingredient w) is fragrance.The amount of ingredient w) is typically about 0 to about 0.5% in topical composition, and specifically about 0.001 To about 0.1%.For ophthalmic applications, it is often used without fragrance.

Ingredient x) is pigment.Pigment suitable for dermal application includes inorganic pigment, organic color lake (lake) pigment, pearly-lustre Pigment and their mixture.Inorganic pigment for use in the present invention includes these nothings selected from the group being made of the following terms Machine pigment: rutile or anatase titania are encoded to CI 77,891 according to the color index of reference CI；Black, yellow, Red and brown iron oxide, is encoded to CI 77,499,77,492 and 77,491 according to reference CI；Manganese violet (CI 77,742)；Group Ultramarine (CI 77,007)；Chromium oxide (CI 77,288)；Chromium hydrate (CI 77,289)；With barba hispanica (CI 77,510) and it Mixture.

Organic pigment for use in the present invention and color lake include selected from those of the group being made of the following terms organic pigment The color lake and: D&C Red No.19 (CI 45,170), D&C Red No.9 (CI 15,585), D&C Red No.21 (CI 45, 380)、D&C Orange No.4(CI 15,510)、D&C Orange No.5(CI 45,370)、D&C Red No.27 (CI45,410)、D&C Red No.13(CI 15,630)、D&C Red No.7(CI 15,850)、D&C Red No.6(CI 15,850)、D&C Yellow No.5(CI 19,140)、D&C Red No.36(CI 12,085)、D&C Orange No.10 (CI45,425)、D&C Yellow No.6(CI 15,985)、D&C Red No.30(CI 73,360)、D&C Red No.3 (CI45,430), dyestuff or color lake (CI 75,570) and their mixture based on cochineal famille rose.

Pearlescent pigment for use in the present invention includes selected from those of the group being made of the following terms pearlescent pigment: white pearl Delustering pigment is such as coated with the mica of titanium oxide, bismuth oxychloride；Color pearly pigment is such as coated with the odenite of iron oxide, is coated with The odenite of electric blue, chromium oxide etc., the odenite of the organic pigment with the above-mentioned type and the titanium cloud based on bismuth oxychloride Mother and their mixture.The amount of pigment is typically about 0 to about 10% in topical composition.For ophthalmic applications, usually not Use pigment.

In particularly preferred embodiment of the invention, it is prepared for the local medicine composition for ocular administration, the office Portion's pharmaceutical composition generally comprises component A and B (carrier), such as purified water, and one selected from the group being made of the following terms Kind or Multiple components: y) sugar or sugar alcohol, such as glucan, especially mannitol and macrodex；Z) cellulose or derivatives thereof； Aa) salt；Bb) EDETATE SODIUM (disodium ethylene diamine tetraacetate)；And cc) pH adjusting additive.

The z of local medicine composition suitable for ocular administration) example of cellulose derivative includes: carboxymethyl cellulose Sodium, ethyl cellulose, methylcellulose and hydroxypropyl methyl cellulose, (especially) hydroxypropyl methyl cellulose.

The aa of local medicine composition suitable for ocular administration) example of salt includes monosodium phosphate, disodium hydrogen phosphate and phosphorus Sour trisodium, sodium chloride, potassium chloride and their combination.

Cc) example that pH adjusts additive includes so that the pH for being used for the local medicine composition of ocular administration to be adjusted to The HCl or NaOH of the amount of 4.5-7.5.

Component A may include in kit, which includes the compound, above-mentioned systemic or local of formula (I)-(IX) Composition or both；And the treatment of beauty and medical conditions will be provided for mammal (the especially mankind) using the kit Information, instruction or both.Information and instruction can be the form etc. of written form, graphic form or both.In addition to this or Alternative, kit may include drug, composition or both；And the method for administration about drug or composition information, refer to Enable or both, it is therefore preferred to have treat or prevent the beauty of mammal (such as people) and the beneficial effect of medical conditions.

The present invention is explained further by following illustrative embodiment, these examples are considered unrestricted.

Brief Description Of Drawings

Fig. 1 shows by injecting (1R, 2R)-N- (fluorine isoquinolin -6- base) -2- (4- (pyridylmethyl) benzene in camera oculi anterior Base) cyclopropane -1- formamide formulation realize rabbit IOP variation (reduction).

Embodiment

All temperature are degree Celsius.Reagent and starting material are purchased from commercial source or according to disclosed literature procedure system It is standby.

Unless otherwise stated, micro- by the way that compound is re-dissolved in a small amount of DMSO and passes through 0.45 in due course Rice (nylon plate) syringe-driven filter filtering is to carry out HPLC purifying.Then such as 50mm Varian Dynamax is used HPLC21.4mm Microsorb Guard-8C₈Column purification solution.As needed, 40-80%MeOH:H is selected₂The typical case of O is initial Elution mixture is used for target compound.The Initial Gradient is kept for 0.5 minute, then increases to 100% in 5 minutes MeOH:0%H₂O.100%MeOH is kept 2 minutes again, then rebalances and return to initial start gradient.Typical total operation Time is 8 minutes.Obtained fractions are analyzed, is appropriately combined, then evaporates, the substance purified.

Sample variation device and cryoprobe are installed Bruker 600MHz (^-1H) spectrometer, Varian INOVA 600MHz(¹H) NMR spectrometer, Varian INOVA 500MHz (¹H) NMR spectrometer, Varian Mercury 300MHz (¹H) NMR spectrometer or Varian Mercury 200MHz (¹H) on NMR spectrometer record proton magnetic resonance (¹H NMR) spectrum.Institute There is spectrum to measure in shown solvent.Although chemical shift is reported with the ppm low field of tetramethylsilane, they are referred to¹H The residual protons peak at the coordinative solvent peak of NMR.Coupling constant is between proton with hertz (Hz) report.

Use the Waters Acquity with Alliance 2695HPLC and 2998 photodiode array detectors QDA MS ESI instrument obtains analytic type LCMS spectrum.Spectrum is analyzed at 254nm and 230nm.Passing through sample has protection Waters Atlantis T3 4.6x75 3.5 μm of columns of mm of column (Atlantis T3 4.6x20mm5 μm).Gradient flowing Phase A (the H of 0.1% formic acid₂O solution) and Mobile phase B (ACN) progress, flow velocity 0.8mL/min.Two gradients will be as described below:

The setting of MS probe is usual are as follows: orifice potential 15V, the capillary voltage of positive mode are 0.8KV, cathode mode Voltage be 0.4kV.Probe temperature is 600 DEG C, and source temperature is 120 DEG C.It is following prepare illustrate intermediate preparation method and The preparation method of aryl cyclopropyl aminoisoquinoline yl amide derivatives.

When used in this application, following abbreviations have following given meaning:

AcOH is acetic acid；

Bn is benzyl；

1,2, DCE be 1,2 dichloroethanes

DCM is methylene chloride；

DCC is N, N'- dicyclohexylcarbodiimide；

DME is 1,2- dimethoxy-ethane；

DMF is N,N-dimethylformamide；

DMSO is dimethyl sulfoxide；

DBU is 11 carbon -7- alkene of 1,8- diazabicyclo [5.4.0]；

DMAP is 4-dimethylaminopyridine；

EDC/EDAC is N- (3- dimethylaminopropyl)-N'- ethyl-carbodiimide hydrochloride；

EtOAc is ethyl acetate；

EtOH is ethyl alcohol；

HOBt is I-hydroxybenzotriazole；

IOP is intraocular pressure

MeOH is methanol；

Rt is room temperature；

TBu or t-Bu is tert-butyl；

TFA is trifluoroacetic acid；

THF is tetrahydrofuran；

TLC is thin-layer chromatography, and

TMSOI is Trimethylsulfoxonium Iodide.

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