阅读说明：本技术 3-((1R,3R)-1-(2,6-二氟-4-((1-(3-氟丙基)氮杂环丁烷-3-基)氨基)苯基)-3-甲基-1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-基)-2,2-二氟丙烷-1-醇的固体形式及制备包含取代的苯基或吡啶基部分的稠合三环化合物的方法，包括其使用方法 (Solid forms of 3- ((1R,3R) -1- (2, 6-difluoro-4- ((1- (3-fluoropropyl) azetidin-3-yl) amino) phenyl) -3-methyl-1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b ] indol-2-yl) -2, 2-difluoropropan-1-ol and methods) 是由 郑喆根 许杰 H·伊迪恩 K·克拉格 M·达尔齐尔 A·费蒂斯 F·戈斯林 N-K·利 于 2019-06-17 设计创作，主要内容包括：本文提供了3-((1R,3R)-1-(2,6-二氟-4-((1-(3-氟丙基)氮杂环丁烷-3-基)氨基)苯基)-3-甲基-1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-基)-2,2-二氟丙烷-1-醇的固体形式、盐(例如化合物B)和制剂,其方法和合成,以及使用它们治疗癌症的方法。(Provided herein are 3- ((1R,3R) -1- (2, 6-difluoro-4- ((1- (3-fluoropropyl) azetidin-3-yl) amino) phenyl groups) -3-methyl-1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b]Solid forms, salts (e.g., compound B) and formulations of indol-2-yl) -2, 2-difluoropropan-1-ol, methods and syntheses thereof, and methods of using the same for treating cancer.)

1. A compound having the structure:

2. a crystalline form comprising compound B

Having an X-ray powder diffraction pattern comprising peaks at 19.32, 20.26, 21.63, 23.28, or 24.81 ± 0.1 ° 2 θ (± 0.1 ° 2 θ).

3. The crystalline form of claim 2, wherein the crystalline form of compound B has an X-ray powder diffraction pattern having one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty characteristic X-ray powder diffraction peaks as set forth in table 16.

4. The crystalline form of claim 2, wherein the crystalline form of compound B has an X-ray powder diffraction pattern substantially as shown in figure 1.

5. The crystalline form of any one of claims 2-4, wherein the crystalline form of Compound B has a TGA thermogram substantially corresponding to a representative TGA thermogram as depicted in figure 2.

6. The crystalline form of any one of claims 2-5, wherein the crystalline form of Compound B has a DSC thermogram substantially as depicted in figure 3.

7. A crystalline form comprising compound B

Having an X-ray powder diffraction pattern comprising peaks at 11.49, 12.54, 19.16, 19.42, or 24.67 + -0.1 deg. 2 theta (+ -0.1 deg. 2 theta).

8. The crystalline form of claim 7, wherein the crystalline form of Compound B has an X-ray powder diffraction pattern having one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty characteristic X-ray powder diffraction peaks as set forth in Table 11.

9. The crystalline form of claim 7, wherein the crystalline form of Compound A has an X-ray powder diffraction pattern substantially as shown in figure 4.

10. The crystalline form of any one of claims 7-9, wherein the crystalline form of compound a has a TGA thermogram substantially corresponding to a representative TGA thermogram as depicted in figure 5.

11. The crystalline form of any one of claims 7-10, wherein the crystalline form of compound a has a DSC thermogram substantially as depicted in figure 5.

12. A crystalline form comprising compound B

Having an X-ray powder diffraction pattern substantially as shown in figure 10.

13. A crystalline form comprising compound B

Having an X-ray powder diffraction pattern comprising peaks at 11.31, 15.70, 16.54, 19.10, or 22.76 ± 0.1 ° 2 Θ.

14. The crystalline form of claim 13, wherein the crystalline form of compound B has an X-ray powder diffraction pattern having one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty characteristic X-ray powder diffraction peaks as set forth in table 13.

15. The crystalline form of claim 13, wherein the crystalline form of compound B has an X-ray powder diffraction pattern substantially as shown in figure 12.

16. The crystalline form of any one of claims 13-15, wherein the crystalline form of compound B has a TGA thermogram substantially corresponding to a representative TGA thermogram as depicted in figure 13.

17. The crystalline form of any one of claims 13-16, wherein the crystalline form of compound B has a DSC thermogram substantially as depicted in figure 13.

18. A crystalline form comprising compound B

Having an X-ray powder diffraction pattern substantially as shown in figure 14.

19. A crystalline form comprising compound B

Having an X-ray powder diffraction pattern comprising peaks, in terms of 2 Θ, at 12.52, 15.90, 19.66, 20.65, or 24.99 ± 0.1 °.

20. The crystalline form of claim 19, wherein the crystalline form of compound B has an X-ray powder diffraction pattern having one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty characteristic X-ray powder diffraction peaks as set forth in table 14.

21. The crystalline form of claim 19, wherein the crystalline form of compound B has an X-ray powder diffraction pattern substantially as shown in figure 16.

22. The crystalline form of any one of claims 19-21, wherein the crystalline form of compound B has a TGA thermogram substantially corresponding to a representative TGA thermogram as depicted in figure 17.

23. The crystalline form of any one of claims 19-22, wherein the crystalline form of compound B has a DSC thermogram substantially as depicted in figure 18.

24. A crystalline form comprising compound B

Having an X-ray powder diffraction pattern comprising peaks at 11.46, 12.51, 19.29, 19.42, or 20.23 + -0.1 deg. 2 theta.

25. The crystalline form of claim 24, wherein the crystalline form of compound B has an X-ray powder diffraction pattern having one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty characteristic X-ray powder diffraction peaks as set forth in table 15.

26. The crystalline form of any one of claims 24-25, wherein the crystalline form of compound B has an X-ray powder diffraction pattern substantially as shown in figure 19.

27. The crystalline form of any one of claims 24-26, wherein the crystalline form of compound a has a TGA thermogram substantially corresponding to a representative TGA thermogram as depicted in figure 20.

28. A crystalline form comprising Compound C

Having an X-ray powder diffraction pattern comprising peaks at 16.09, 18.92, 19.69, 19.86, or 23.16 ± 0.1 ° 2 Θ θ.

29. The crystalline form of claim 28, wherein the crystalline form of compound C has an X-ray powder diffraction pattern having one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty characteristic X-ray powder diffraction peaks as set forth in table 30.

30. The crystalline form of claim 28, wherein the crystalline form of compound C has an X-ray powder diffraction pattern substantially as shown in figure 27.

31. Amorphous solid containing compound A

32. The amorphous solid of claim 31, wherein the amorphous solid of compound a has an X-ray powder diffraction pattern substantially as shown in figure 32.

33. The amorphous solid of claim 31, wherein the amorphous solid of compound a has a TGA and DSC thermogram substantially as depicted in figure 33.

34. A pharmaceutical composition comprising the solid form of any one of claims 1 to 33 and at least one pharmaceutically acceptable excipient.

35. A method for treating lung, ovarian, endometrial, prostate, uterine or breast cancer in a patient suffering from said cancer, said method comprising administering to said cancer patient an effective amount of a compound of any one of claims 1 to 33 or a pharmaceutical composition of claim 34.

36. A method for treating breast cancer in a breast cancer patient, the method comprising administering to the cancer patient an effective amount of a compound of any one of claims 1 to 33 or the pharmaceutical composition of claim 34.

37. The method of claim 36, wherein the breast cancer is hormone receptor positive breast cancer, HER 2-positive breast cancer, triple negative breast cancer.

38. The method of claim 36, wherein the breast cancer is metastatic breast cancer.

39. The method of any one of claims 36-38, wherein the compound or pharmaceutical composition is administered as a component of adjuvant therapy.

40. The method of any one of claims 36-38, wherein the compound or pharmaceutical composition is administered as a component of neoadjuvant therapy.

41. The method of any one of claims 36-40, wherein the breast cancer is at grade 0, I, II, III, or IV.

42. The method of claim 37, wherein the hormone receptor positive breast cancer is HER2 negative.

43. The method of any one of claims 36-42, wherein the patient has previously been treated with one or more anti-cancer drugs or radiation therapy.

44. The method of any one of claims 36-43, wherein the patient has undergone surgery prior to treatment with the compound of any one of claims 1 to 33.

45. The method of any one of claims 36-44, wherein the compound of any one of claims 1-33 is administered in combination with one or more of radiation therapy, hormonal therapy, or an anti-cancer agent.

46. The method of claim 45, wherein the anti-cancer drug comprises administration of one or more of: doxorubicin, pegylated liposomal doxorubicin, epirubicin, paclitaxel, albumin-bound paclitaxel, docetaxel, 5-fluorouracil, cyclophosphamide, cisplatin, carboplatin, vinorelbine, capecitabine, gemcitabine, ixabepilone, eribulin, olaparib, methotrexate, anastrozole, exemestane, toremifene, letrozole, tamoxifen, 4-hydroxytamoxifene, raloxifene, droloxifene, troloxifene, keoxifene (keoxifene), ftutamide, nilutamide, bicalutamide, lapatinib, vinblastine, goserelin, leuprorelin, pefilgrastim, filgrastim, vinorexol.

47. The method of claim 45, wherein the anti-cancer agent comprises one or more of an AKT inhibitor, a CDK4/6 inhibitor, a PARP inhibitor, an aromatase inhibitor.

48. The method of claim 45, wherein the anti-cancer agent is Pomaciclib, Ribociclib, or Pabociclib.

49. The method of claim 45, wherein the anti-cancer agent is patatinib.

50. The method of claim 45, wherein the anti-cancer agent is everolimus or fulvestrant.

51. The method of claim 45, wherein the anti-cancer agent is Enmetuzumab, trastuzumab, pertuzumab, Attuzumab.

52. The method of claim 45, wherein the anti-cancer agent is alemtuzumab, bevacizumab, cetuximab, panitumumab, rituximab, tositumomab, or a combination thereof.

53. The compound or solid form of any one of claims 1 to 33 for use in a method of treating breast cancer, the method comprising administering an effective amount of the compound or solid form to a patient having breast cancer.

54. A process for preparing a compound of formula (IV) or a salt thereof, the process comprising:

(a) reacting a reaction mixture comprising a compound of formula (I), an organic solvent and thionyl chloride according to the following step 1 to form a compound of formula (IIa), and reacting a reaction mixture comprising a compound of formula (IIa), a catalyst, an oxidant and a solvent according to the following step 2 to form a compound of formula (II)

Wherein

R^1aAnd R^1bEach independently of the others is hydrogen, halogen, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy, -CN, C_3-6Cycloalkyl or C_3-6Spirocycloalkyl radicals, and

n is an integer of 2 or 3; and

(b) reacting a reaction mixture comprising a compound of formula (II) and a compound of formula (III) in an organic solvent according to the following step 3 to form a compound of formula (IV) or a salt thereof

Wherein

B is a substituted or unsubstituted indolyl, benzofuranyl, benzothienyl, indazolyl, azaindolyl, benzimidazolyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, thienopyridazinyl, thienopyrimidinyl, thienopyrazinyl, furopyridazinyl, furopyrimidinyl or furopyrazinyl group,

R^2aand R^2bEach independently of the other is hydrogen,Halogen, -OH, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Hydroxyalkyl, -CN, C_3-6Cycloalkyl or C_3-6A spiro-cycloalkyl group,

R^3aand R^3bIndependently of one another is hydrogen, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Hydroxyalkyl, -CN, C_3-6Cycloalkyl radical, C_3-6Heterocycloalkyl, phenyl, C_3-6Heteroaryl or C_3-6Spirocycloalkyl radicals, and

when R is^3aAnd R^3bAt the same time, the asterisks indicate the chiral centers.

55. The method of claim 54, wherein B is a substituted or unsubstituted indolyl, benzofuranyl, or benzothienyl group.

56. The method of claim 55, wherein B is a substituted or unsubstituted indolyl.

57. The method of claim 54, wherein B is a substituted or unsubstituted pyrrolopyridazinyl, pyrrolopyrimidinyl, or pyrrolopyrazinyl.

58. The method of any one of claims 54 to 57, wherein B is one or two independently fluorine, chlorine, C_1-3Alkyl radical, C_1-3Haloalkyl, -CN, -OH, C_1-3Alkoxy and C_1-3Substituted by a substituent of hydroxyalkyl.

59. The method of any one of claims 54-58, wherein R^1aAnd R^1bEach independently of the others is hydrogen, F, -Cl, -OH, -CN, -CH₃、-CF₃、-CHF₂、-CH₂F or spirocyclopropyl.

60. The method of any one of claims 54 to 59, wherein n is 3.

61. The method of any one of claims 54 to 60, wherein:

is a formula

62. The method of any one of claims 54-61, wherein R^2aAnd R^2bEach is hydrogen.

63. The method of any one of claims 54-62, wherein R^3aAnd R^3bIndependently is hydrogen or-CH₃。

64. The method of any one of claims 54 to 63, wherein the step 1 and step 2 organic solvents are non-polar solvents.

65. The method of any one of claims 54 to 64, wherein the step 2 catalyst is a redox active metal catalyst.

66. The process of any one of claims 54 to 65, wherein the step 3 organic solvent is a polar aprotic solvent.

67. The method of any one of claims 54 to 66, wherein step 3 further comprises an acid catalyst.

68. The method of any one of claims 54-67, wherein the compound of formula (I) is:

including stereoisomers thereof.

69. The method of any one of claims 54-68, wherein the compound of formula (II) is:

including stereoisomers thereof.

70. The method of any one of claims 54-69, wherein the compound of formula (III) is:

wherein X is-NH-, -N-C₁-C₃Unsubstituted alkyl, -O-or-S-.

71. The method of claim 70, wherein the compound of formula (III) is:

72. the method of any one of claims 54-71, wherein the compound of formula (IV) is:

or a salt thereof, including stereoisomers thereof.

73. The method of any one of claims 54 to 72, wherein:

the compound of formula (I) is

The compound of formula (II) is

The compound of the formula (III) is And is

The compound of formula (IV) is

74. A process for preparing a compound of formula (VIII) or a salt thereof, comprising:

(a) reacting a reaction mixture comprising a compound of formula (IV), a compound of formula (V), or a compound of formula (X) and an organic solvent according to the following step 1 to form a compound of formula (VI)

Wherein

B is substituted or unsubstituted indolyl, benzofuranyl, benzothienyl, azaindolyl, indazolyl, benzimidazolyl, pyrrolopyridyl, furopyridyl, thienopyridyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, thienopyridazinyl, thienopyrimidinyl, thienopyrazinyl, furopyridazinyl, furopyrimidinyl, or furopyrazinyl;

R^1aand R^1bEach independently of the others is hydrogen, fluorine, chlorine, -OH, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Hydroxyalkyl, and-CN, C_3-6Cycloalkyl or C_3-6A spiro-cycloalkyl group,

n is an integer of 2 or 3,

R^2aand R^2bEach independently of the others hydrogen, halogen, -OH, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Hydroxyalkyl, -CN, C_3-6Cycloalkyl or C_3-6A spiro-cycloalkyl group,

R^3aand R^3bIndependently of one another is hydrogen, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy, -CN, C _3-6Cycloalkyl radical, C_3-6Heterocycloalkyl, phenyl, C_3-6Heteroaryl or C_3-6A spiro-cycloalkyl group,

j is phenyl or pyridyl;

each R⁴Independently hydrogen, halogen or C_1-3An alkyl group, a carboxyl group,

s is an integer of 0 to 2,

LG is a leaving group and is a hydroxyl group,

LG and CHO are in the para position relative to each other on J of the compound of formula (V),

PG is an aldehyde protecting group, and PG is an aldehyde protecting group,

LG and CH-PG are in the para position relative to each other on J of the compound of formula (X), and

each asterisk independently represents a chiral center, wherein when R^3aAnd R^3bAt different times, with R^3aAnd R^3bThe carbon of (a) is a chiral center; and

(b) reacting a reaction mixture comprising a compound of formula (VI), an organic solvent, and a compound of formula (VII) or a salt thereof according to the following step 2 to form a compound of formula (VIII) or a salt thereof

Wherein

G is C_1-3An alkyl group, a carboxyl group,

p is 0 or 1, and p is,

e is substituted or unsubstituted azetidinyl or pyrrolidinyl,

each R⁵Independently hydrogen, halogen, -OH, -CN, C_1-5Alkoxy or C_1-5A hydroxyalkyl group,

v is an integer of 1 to 5, and

R⁶is halogen or-CN;

R¹⁰is hydrogen or C_1-3An alkyl group.

75. The method of claim 74, wherein B is a substituted or unsubstituted indolyl, benzofuranyl, or benzothienyl group.

76. The method of claim 75, wherein B is a substituted or unsubstituted indolyl.

77. The method of claim 74 which is a substituted or unsubstituted pyrrolopyridazinyl, pyrrolopyrimidinyl or pyrrolopyrazinyl group.

78. The method of any one of claims 74-77, wherein B is one or two independently fluoro, chloro, C_1-3Alkyl radical, C_1-3Haloalkyl, -CN, -OH, C_1-3Alkoxy or C_1-3Substituted by a substituent of hydroxyalkyl.

79. The method of any one of claims 74-78, wherein R^1aAnd R^1bEach independently is hydrogen, -F, -Cl, -OH, -CN, -CH₃、-CF₃、-CHF₂、-CH₂F or spirocyclopropyl.

80. The method of any one of claims 74-79, wherein n is 3.

81. The method of any one of claims 74-80, wherein:

is a formula

82. The method of any one of claims 74-81, wherein R^2aAnd R^2bEach is hydrogen.

83. The method of any one of claims 74-82, wherein R^3aAnd R^3bIndependently is hydrogen or-CH₃。

84. The method of any one of claims 74-83, wherein each R⁴Is fluorine.

85. The method of any one of claims 74-84, wherein n is 2.

86. The method of any one of claims 74-85, wherein the leaving group is bromine.

87. The method of any one of claims 74-86, wherein p is 0.

88. The method of any one of claims 74-87, wherein E is azetidinyl of the structure:

89. the method of any one of claims 74-88, wherein each R⁵Is hydrogen.

90. The method of any one of claims 74 to 89, wherein v is 3.

91. The method of any one of claims 74-90The method of (1), wherein R⁶Is fluorine.

92. The process of any one of claims 74-91, wherein the compound of formula (VII) is a salt of an acid.

93. The process of any one of claims 74 to 92, wherein the step 1 organic solvent is a polar protic solvent, a non-polar solvent, or a combination thereof.

94. The method of any one of claims 74-93, wherein step 1 further comprises an acid catalyst.

95. The method of any one of claims 74-94, wherein the step 2 organic solvent is a polar aprotic solvent.

96. The method of any one of claims 74-95, wherein step 2 further comprises a transition metal catalyst.

97. The method of any one of claims 74-96, wherein the compound of formula (IV) is:

or a salt thereof, including stereoisomers thereof.

98. The method of any one of claims 74-97, wherein the compound of formula (V) is:

Or a salt thereof.

99. The method of any one of claims 74-98, wherein the compound of formula (X) is:

100. the method of any one of claims 74-99, wherein the compound of formula (VI) is:

or a salt thereof, including stereoisomers thereof.

101. The method of any one of claims 74-100, wherein the compound of formula (VII) is:

or a salt thereof.

102. The method of any one of claims 74-101, wherein the compound of formula (VIII) is:

or a pharmaceutically acceptable salt thereof, including stereoisomers thereof.

103. The method of claim 102, further comprising contacting the compound of formula (VIII) with (2R-3R) -tartaric acid in the presence of an organic solvent.

104. The method of any one of claims 74-103, wherein the compound of formula (VIII) is:

or a pharmaceutically acceptable salt thereof.

105. The method of claim 104, wherein the compound of formula (VIII) is:

106. the process of any one of claims 74 to 105, further comprising crystallizing the compound of formula (VIII) as its tartrate salt.

107. A process for preparing a compound of formula (VIII) or a salt thereof, the process comprising reacting a reaction mixture comprising a compound of formula (IX) or a compound of formula (XI), a compound of formula (IV) and an organic solvent according to the following step 1 to form the compound of formula (VIII) or a salt thereof

Wherein

B is substituted or unsubstituted indolyl, benzofuranyl, benzothienyl, azaindolyl, indazolyl, benzimidazolyl, pyrrolopyridyl, furopyridyl, thienopyridyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, thienopyridazinyl, thienopyrimidinyl, thienopyrazinyl, furopyridazinyl, furopyrimidinyl, or furopyrazinyl;

R^1aand R^1bEach independently of the others hydrogen, halogen, -OH, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Hydroxyalkyl and-CN, C_3-6Cycloalkyl or C_3-6Spiro cycloalkyl;

n is an integer of 2 or 3;

R^2aand R^2bEach independently of the others hydrogen, halogen, -OH, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Hydroxyalkyl, -CN, C_3-6Cycloalkyl or C_3-6Spiro cycloalkyl;

R^3aand R^3bIndependently hydrogen, halogen, -OH, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Hydroxyalkyl, -CN, C_3-6Cycloalkyl or C_3-6Spiro cycloalkyl;

j is phenyl or pyridyl;

each R⁴Independently hydrogen, halogen or C_1-3An alkyl group;

s is an integer of 0 to 2;

g is C_1-3An alkyl group;

p is 0 or 1;

e is substituted or unsubstituted azetidinyl or pyrrolidinyl;

each R⁵Independently hydrogen, halogen, -OH, -CN, C _1-5Alkoxy or C_1-5A hydroxyalkyl group;

v is an integer from 1 to 5;

R⁶is halogen or-CN;

R¹⁰is H or C_1-3An alkyl group;

the CHO moiety and the nitrogen atom linking J and G are in the para position relative to each other on J on said compound of formula (IX);

PG is an aldehyde protecting group, and PG is an aldehyde protecting group,

CH-PG and the nitrogen atom linking J and G are in the para position relative to each other on J on said compound of formula (XI); and is

Each asterisk independently represents a chiral center, wherein when R^3aAnd R^3bAt different times, with R^3aAnd R^3bThe carbon of (a) is a chiral center.

108. The method of claim 107, wherein B is a substituted or unsubstituted indolyl, benzofuranyl, or benzothienyl.

109. The method of claim 108, wherein B is a substituted or unsubstituted indolyl.

110. The method of claim 107, wherein B is a substituted or unsubstituted pyrrolopyridazinyl, pyrrolopyrimidinyl, or pyrrolopyrazinyl.

111. The method of any one of claims 107 to 110Wherein B is independently one or two of fluorine, chlorine, C_1-3Alkyl radical, C_1-3Haloalkyl, -CN, -OH, C_1-3Alkoxy or C_1-3Substituted by a substituent of hydroxyalkyl.

112. The method of any one of claims 107-111, wherein R^1aAnd R^1bEach independently of the others is hydrogen, F, -Cl, -OH, -CN, -CH ₃、-CF₃、-CHF₂、-CH₂F or spirocyclopropyl.

113. The method of any one of claims 107-112, wherein n is 3.

114. The method of any one of claims 107 to 113, wherein:

is a formula

115. The method of any one of claims 107-114, wherein R^2aAnd R^2bEach is hydrogen.

116. The method of any one of claims 107-115, wherein R^3aAnd R^3bIndependently is hydrogen or-CH₃。

117. The method of any one of claims 107-116, wherein J is phenyl.

118. The process of any one of claims 107 to 117, wherein E is azetidinyl of the structure:

119. the method of any one of claims 107-118, wherein each R⁴Are both fluorine.

120. The method of any one of claims 107-119, wherein s is 2.

121. The method of any one of claims 107-120, wherein p is 0.

122. The method of any one of claims 107-121, wherein each R is⁵Is hydrogen.

123. The method of any one of claims 107 to 122, wherein v is 3.

124. The method of any one of claims 107-123, wherein R⁶Is fluorine.

125. The process of any one of claims 107 to 124, wherein the organic solvent is a polar protic solvent.

126. The method of any one of claims 107-125, wherein the compound of formula (IV) is:

or a salt thereof, including stereoisomers thereof.

127. The method of any one of claims 107-126, wherein the compound of formula (IX) is:

or a salt thereof.

128. The method of any one of claims 107-127, wherein the compound of formula (XI) is:

or a salt thereof.

129. The method of any one of claims 107-128, wherein the compound of formula (VIII) is:

or a pharmaceutically acceptable salt thereof, including stereoisomers thereof.

130. The process of any one of claims 107 to 129, further comprising contacting the compound of formula (VIII) with (2R-3R) -tartaric acid in the presence of an organic solvent.

131. The method of any one of claims 107-130, wherein the compound of formula (VIII) is:

or a pharmaceutically acceptable salt thereof.

132. The method of claim 131, wherein the compound of formula (VIII) is:

133. the process of any one of claims 107 to 132, further comprising crystallizing the compound of formula (VIII) as its tartrate salt.

134. A process for preparing a compound of formula (IX) or a salt thereof, the process comprising:

(1) Reacting a reaction mixture comprising a compound of formula (X), a compound of formula (VII) or a salt thereof, an organic solvent and a catalyst according to the following step 1 to form a compound of formula (XI)

Wherein

J is phenyl or pyridyl;

each R⁴Independently hydrogen, halogen or C_1-3An alkyl group, a carboxyl group,

s is an integer of 0 to 2,

LG is a leaving group and is a hydroxyl group,

PG is an aldehyde protecting group, and PG is an aldehyde protecting group,

LG and CH-PG are in para positions relative to each other on J,

g is C_1-3An alkyl group, a carboxyl group,

p is 0 or 1, and p is,

e is substituted or unsubstituted azetidinyl or pyrrolidinyl,

each R⁵Independently hydrogen, halogen, -OH, -CN, C_1-5Alkoxy or C_1-5A hydroxyalkyl group,

v is an integer of 1 to 5 and,

R⁶is a halogen or a-CN group,and is

R¹⁰Is hydrogen or C₁-C₃An alkyl group; and

(2) deprotecting the compound of formula (XI) according to step 2 below to form the compound of formula (IX)

135. The method of claim 134, wherein J is phenyl.

136. The method of claim 134 or claim 135, wherein each R is⁴Is fluorine.

137. The method of any one of claims 134 to 136, wherein s is 2.

138. The process of any one of claims 134 to 137, wherein the leaving group is bromine.

139. The method of any one of claims 134 to 138, wherein p is 0.

140. The process of any one of claims 134 to 139, wherein E is azetidinyl of the structure:

141. the method of any one of claims 134 to 140, wherein each R is⁵Is hydrogen.

142. The method of any one of claims 134 to 141, wherein v is 3.

143.The method of any one of claims 134 to 142, wherein R⁶Is fluorine.

144. The process of any one of claims 134 to 143, wherein the compound of formula (VII) is a salt of an acid.

145. The process of any one of claims 134 to 144, wherein the aldehyde protecting group is a trialkyl orthoformate.

146. The process of any one of claims 134 to 145, wherein the step 1 organic solvent is a non-polar solvent.

147. The process of any one of claims 134 to 146, wherein the step 1 catalyst is a transition metal catalyst.

148. The process of any one of claims 134 to 147, wherein the step 2 organic solvent is a non-polar solvent.

149. The process of any one of claims 134 to 148 wherein the compound of formula (XI) is deprotected by contact with an acid.

150. The method of any one of claims 134 to 149, wherein the compound of formula (IX) is:

Or a salt thereof.

151. A process for preparing a compound of formula (III) or a salt thereof, the process comprising:

(1) reacting a reaction mixture comprising a compound of formula (XII), compound B and an organic solvent according to the following step 1 to form the compound of formula (XIII)

Wherein:

b is selected from the group consisting of substituted or unsubstituted indolyl, benzofuranyl, benzothienyl, azaindolyl, indazolyl, benzimidazolyl, pyrrolopyridyl, furopyridyl, thienopyridyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, thienopyridazinyl, thienopyrimidinyl, thienopyrazinyl, furopyridazinyl, furopyrimidinyl, and furopyrazinyl,

R^2aand R^2bEach independently selected from hydrogen, halogen, -OH, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Hydroxyalkyl, -CN, C_3-6Cycloalkyl and C_3-6A spiro-cycloalkyl group,

R^3aand R^3bIndependently selected from hydrogen, halogen, -OH, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Hydroxyalkyl, -CN, C_3-6Cycloalkyl and C_3-6A spiro-cycloalkyl group,

PG is an amine protecting group, and

when R is^3aAnd R^3bAt different times, each asterisk indicates a chiral center; and

(2) deprotecting the compound of formula (XIII) according to the following step 2 to form the compound of formula (III)

152. The method of claim 151, wherein B is substituted or unsubstituted indolyl, benzofuranyl, or benzothienyl.

153. The method of claim 152, wherein B is a substituted or unsubstituted indolyl.

154. The method of claim 151, wherein B is a substituted or unsubstituted pyrrolopyridazinyl, pyrrolopyrimidinyl, or pyrrolopyrazinyl.

155. The method of any one of claims 151 to 154, wherein B is one or two independently selected from fluoro, chloro, C_1-3Alkyl radical, C_1-3Haloalkyl, -CN, -OH, C_1-3Alkoxy and C_1-3Substituted by a substituent of hydroxyalkyl.

156. The method of any one of claims 151-155, wherein R^2aAnd R^2bEach is hydrogen.

157. The method of any one of claims 151-156, wherein R^3aAnd R^3bIndependently selected from hydrogen and-CH₃。

158. The process of any one of claims 151 to 157, wherein the step 1 organic solvent is a non-polar solvent.

159. The process of any one of claims 151 to 158 wherein the step 1 reaction mixture further comprises a catalyst.

160. The process of any one of claims 151 to 159 further comprising preparing the compound of formula (XII), or a salt thereof, the process comprising:

(1) Reacting a reaction mixture comprising a compound of formula (XIV), thionyl chloride and an organic solvent according to the following step 3a to form a compound of formula (XV)

And

(2) reacting a reaction mixture comprising the compound of formula (XV), a catalyst, an oxidant and an organic solvent according to the following step 3a to form the compound of formula (XII)

161. The method of any one of claims 151-160, wherein the compound of formula (III) is:

wherein X is selected from-NH-, -N-C₁-C₃Unsubstituted alkyl, -O-, and-S-.

162. The method of any one of claims 151-161, wherein the compound of formula (III) has the structure:

163. a compound of formula (XVI)

Wherein:

each R⁴Independently selected from hydrogen, halogen and C_1-3An alkyl group;

s is an integer of 0 to 2;

g is C_1-3An alkyl group;

p is 0 or 1;

each R^7aAnd R^7bIndependently selected from hydrogen, halogen, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Hydroxyalkyl and-CN;

each R^8aAnd R^8bIndependently of each otherSelected from hydrogen, halogen, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Hydroxyalkyl and-CN;

R¹⁰is hydrogen or C_1-3An alkyl group;

y is an integer selected from 1 and 2, x is an integer selected from 1 and 2, and the sum of x and y is 2 or 3;

m is substituted or unsubstituted C_1-5An alkyl group;

r is 0 or 1; and is

R⁹Is halogen or-CN.

164. The compound of claim 163, wherein each R⁴Independently selected from hydrogen, fluorine and-CH₃。

165. The compound of claim 163 or claim 164, wherein each R is⁴Is fluorine.

166. The compound of any one of claims 163 to 165, wherein s is 1 or 2.

167. A compound according to any one of claims 163 to 166, wherein p is 0.

168. The compound of any one of claims 163 to 167, wherein R^7a、R^7b、R^8aAnd R^8bEach independently selected from hydrogen, fluorine, -CH₃and-CN.

169. The compound of any one of claims 163 to 168, wherein R^7a、R^7b、R^8aAnd R^8bEach is hydrogen.

170. The compound of any one of claims 163 to 169, wherein M is-CH₂CH₂CH₂-, p is 1, and R⁹Is fluorine.

171. The compound of any one of claims 163 to 170, wherein the compound of formula (XVI) is selected from:

or a salt thereof.

172. A process for preparing a compound having formula (XX):

the method comprises the following steps:

reacting a compound of formula (XXI)

Contacting with a protein transaminase to form a compound of formula (3):

and

contacting the compound of formula (3) with a compound of formula (II) to form a compound of formula (XX)

Wherein

n is 3; and is

R^1aAnd R^1bEach independently selected from hydrogen, halogen, -OH, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Hydroxyalkyl, -CN, C_3-6Cycloalkyl radicals andC_3-6spirocycloalkyl.

173. The method of claim 172, wherein said protein transaminase is selected from the group consisting of an (S) -enantioselective transaminase of SEQ ID No. 1, SEQ ID No. 2, SEQ ID No. 3, and SEQ ID No. 4.

174. The method of claim 171 or claim 172, wherein the compound of formula (XX) has the structure:

175. a process for the preparation of a compound B,

wherein the method comprises the steps of:

176. a process for the preparation of a compound B,

wherein the method comprises the steps of:

177. the process of claim 175 or 176, wherein said process further comprises recrystallization of compound B in methanol and ethanol;

178. the process of claim 175 or 176, wherein said process further comprises recrystallization of compound B in MTBE, water, NaOH, and ethanol;

179. the method of any one of claims 175-178 wherein the indolyl intermediate is synthesized by:

Technical Field

Provided herein are solid forms of 3- ((1R,3R) -1- (2, 6-difluoro-4- ((1- (3-fluoropropyl) azetidin-3-yl) amino) phenyl) -3-methyl-1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b ] indol-2-yl) -2, 2-difluoropropan-1-ol and methods for their use in the treatment of cancer. Also described herein are methods of making fused tricyclic compounds comprising a substituted phenyl or pyridyl moiety.

Background

Fused tricyclic compounds containing substituted phenyl or pyridyl moieties within the scope of the present disclosure are useful as estrogen receptor ("ER") targeting agents.

ER is a ligand-activated transcriptional regulator protein that mediates induction of a variety of biological effects through interaction with endogenous estrogens. Endogenous estrogens include 17 β (beta) -estradiol and estrone. ER has been found to have two isoforms: ER-alpha (alpha) and ER-beta (beta). Estrogens and estrogen receptors are implicated in a number of diseases or conditions, such as breast cancer, lung cancer, ovarian cancer, colon cancer, prostate cancer, endometrial cancer, uterine cancer, and other diseases or conditions. ER- α targeting agents are particularly active in the context of metastatic disease and acquired resistance. ER-alpha targeting agents are disclosed in U.S. publication No. 2016/0175289.

A process for preparing fused tricyclic compounds containing a substituted phenyl or pyridyl moiety is disclosed in U.S. publication No. 2016/0175289. However, there is a need for improved methods of making ER- α targeting agents.

There is significant complexity surrounding the identification and selection of solid forms of pharmaceutical compounds. Differences in the solid form of such compounds can affect physical and chemical properties and may alter the processing, stability, bioavailability, formulation and storage of the pharmaceutical compound. Solid forms and their usefulness as crystalline solids or amorphous solids have no reliable predictability. Crystalline solids may be considered useful, for example, for physical or chemical stability, while amorphous solids may be considered useful, for example, for improved dissolution and increased bioavailability.

Mixtures of crystalline materials result from polymorphism. It is not possible to predict a priori whether a compound exists in a crystalline form, let alone whether a crystalline form can be prepared or isolated. Jones et al, 2006, Pharmaceutical crystals: An empirical Approach to Physical Property engineering, "MRS Bulletin 31: 875-" 879 (it is currently not generally possible to calculate the number of polymorphs that can be predicted to be observed for even the simplest molecules). The number of possible solid forms results in different chemical and physical properties of the pharmaceutical compound and may greatly affect the development, stability and marketing of the product.

The estrogen receptor ("ER") is a ligand-activated transcriptional regulator protein that mediates induction of a variety of biological effects through interaction with endogenous estrogens. Endogenous estrogens include 17 β (beta) -estradiol and estrone. ER has been found to have two isoforms: ER-alpha (alpha) and ER-beta (beta). Estrogens and estrogen receptors are implicated in a number of diseases or conditions, such as breast cancer, lung cancer, ovarian cancer, colon cancer, prostate cancer, endometrial cancer, uterine cancer, and other diseases or conditions. There is a need for new ER- α targeting agents that are active in the context of metastatic disease and acquired resistance. Accordingly, there remains a need for cancer therapies having specific solid forms.

Disclosure of Invention

Solutions to the above problems and other problems in the art are provided herein.

In one aspect, as described herein, provided herein is a compound named 3- ((1R,3R) -1- (2, 6-difluoro-4- ((1- (3-fluoropropyl) azetidin-3-yl) amino) phenyl) -3-methyl-1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b ] indol-2-yl) -2, 2-difluoropropan-1-ol tartrate: and (B) a compound B.

In another aspect, provided herein is a crystalline form of compound B having an X-ray powder diffraction pattern comprising peaks at 19.32, 20.26, 21.63, 23.28, or 24.81 ± 0.1 ° 2 Θ (± 0.1 ° 2 Θ).

In another aspect, provided herein is a crystalline form of compound B having an X-ray powder diffraction pattern comprising peaks at 11.49, 12.54, 19.16, 19.42, or 24.67 ± 0.1 ° 2 Θ (± 0.1 ° 2 Θ).

In another aspect, provided herein is a crystalline form of compound B having an X-ray powder diffraction pattern substantially as shown in figure 10 or figure 14.

In another aspect, provided herein is a crystalline form of compound B having an X-ray powder diffraction pattern comprising peaks at 11.31, 15.70, 16.54, 19.10, or 22.76 ± 0.1 ° 2 Θ.

In another aspect, provided herein is a crystalline form of compound B having an X-ray powder diffraction pattern comprising peaks at 12.52, 15.90, 19.66, 20.65, or 24.99 ± 0.1 ° 2 Θ.

In another aspect, provided herein is a crystalline form of compound B having an X-ray powder diffraction pattern comprising peaks at 11.46, 12.51, 19.29, 19.42, or 20.23 ± 0.1 ° 2 Θ.

In another aspect, provided herein is an amorphous solid comprising compound a.

Also provided herein are pharmaceutical compositions comprising compound B or a crystalline salt thereof. Such compounds and pharmaceutical compositions are useful in methods of treating cancer as set forth herein.

In another aspect, provided herein is a method of preparing a compound of formula (IV) or a salt thereof as set forth herein. The method comprises (1) reacting a reaction mixture comprising a compound of formula (I) as described herein, an organic solvent, and thionyl chloride to form a compound of formula (IIa) as described herein, and (2) reacting a reaction mixture comprising a compound of formula (IIa), a catalyst, an oxidant, and a solvent to form a compound of formula (II) as described herein. The method further comprises reacting a reaction mixture comprising a compound of formula (II) and a compound of formula (III) as described herein in an organic solvent to form a compound of formula (IV) or a salt thereof as described herein.

In another aspect, provided herein is a method of preparing a compound of formula (VIII) as described herein, or a pharmaceutically acceptable salt thereof. The method comprises reacting a reaction mixture comprising a compound of formula (IV) as described herein, a compound of formula (V) as described herein, or a compound of formula (X) as described herein, and an organic solvent to form a compound of formula (VI) as described herein. The process further comprises reacting a reaction mixture comprising a compound of formula (VI), an organic solvent, and a compound of formula (VII) or a salt thereof as described herein to form a compound of formula (VIII) or a salt thereof.

In another aspect, provided herein is a method of preparing a compound of formula (VIII) as described herein, or a pharmaceutically acceptable salt thereof. The method comprises reacting a reaction mixture comprising a compound of formula (IX) as described herein or a compound of formula (X) as described herein, a compound of formula (IV) as described herein, and an organic solvent to form a compound of formula (VIII) as described herein or a salt thereof.

In yet another aspect, provided herein is a method of making a compound of formula (IX) or a salt thereof as described herein. The process comprises reacting a reaction mixture comprising a compound of formula (X) as described herein, a compound of formula (VII) as described herein or a salt thereof, an organic solvent, and a catalyst to form a compound of formula (XI) as described herein or a salt thereof.

In yet another aspect, provided herein is a method of making a compound of formula (III) or a salt thereof as described herein. The process comprises reacting a reaction mixture comprising a compound of formula (XII) as described herein, compound B, and an organic solvent to form a compound of formula (XIII) as described herein.

In yet another aspect, provided herein are compounds of formula (XVI) as described herein.

Further, provided herein is a method of making a compound having formula (XX), wherein the method comprises contacting a compound of formula (XXI) as described herein with a protein transaminase to form a compound of formula (3). Contacting a compound of formula (3) with a compound of formula (II) as described herein to form a compound of formula (XX).

Embodiments of the invention may be more fully understood by reference to the detailed description and examples, which are intended to illustrate non-limiting embodiments.

Drawings

Figure 1 depicts the XRPD pattern of compound B, form a.

Figure 2 depicts the TGA and DSC of compound B form a.

Fig. 3 depicts PLM images of compound B, form a.

Figure 4 depicts the XRPD pattern of compound B, form B.

Figure 5 depicts the TGA and DSC of compound B form B.

FIG. 6 depicts Compound B form B¹³C SSNMR。

FIG. 7 depicts Compound B, form B¹⁹F SSNMR。

Figure 8 depicts a water adsorption/desorption profile for compound B form B.

FIG. 9a depicts an SEM image; figure 9B depicts a PLM image of compound B, form B; figure 9c depicts the Particle Size Distribution (PSD) of compound B form B.

Figure 10 depicts comparative XRPD patterns of compound B form C versus compound B form a and form B. Form C was found to be a mixture of form a and form B.

Figure 11 depicts the TGA and DSC of compound B form C.

Figure 12 depicts an XRPD pattern of compound B form D.

Figure 13 depicts the TGA and DSC of compound B form D.

Figure 14 depicts an XRPD pattern of compound B form E.

Figure 15 depicts the TGA and DSC of compound B form E.

Figure 16 depicts an XRPD pattern of compound B, form F.

Figure 17 depicts a DVS profile for compound B, form F.

Figure 18 depicts DSC of compound B form F.

Figure 19 depicts an XRPD pattern of compound B form G.

Figure 20 depicts the TGA and DSC of compound B form G.

Figure 21 depicts XRPD pattern overlays of compound B, form a, form B, form C, form D, form F and form G.

Fig. 22 depicts XRPD of compressibility properties of compound B form B.

FIG. 23 depicts compressibility properties of Compound B, form B¹⁹F SSNMR。

Figure 24 depicts DSC of compressibility properties of compound B form B.

Fig. 25 depicts the phase transition pathways of compound B forms A, B, D and F.

Fig. 26 depicts the phase transition pathway to obtain form B from compound B, form F.

Figure 27a depicts an XRPD pattern of compound C, form 1; figure 27b depicts the XRPD pattern of compound C form 2.

Figure 28 depicts the TGA and DSC of compound C form 1.

Fig. 29 depicts PLM images of compound C, form 1.

Figure 30 depicts an XRPD pattern of compound D form M.

Figure 31 depicts the TGA and DSC of compound D form M.

Figure 32 depicts an XRPD pattern of an amorphous form of compound a.

Figure 33 depicts TGA and DSC of an amorphous form of compound a.

FIG. 34 depicts cell viability of ER + breast cancer cell lines for Compound B compared to GDC-0810 and GDC-0927.

FIG. 35 depicts the effect of 0.1mg/kg and 1mg/kg of Compound B on tumor volume compared to 100mg/kg of GDC-0927.

Figure 36a depicts a CT scan and figure 36B depicts a FES-PET scan of a breast cancer patient treated with compound B.

Fig. 37a depicts a CT scan and fig. 37B depicts a FES-PET scan of a second breast cancer patient treated with compound B.

Detailed Description

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. See, e.g., Singleton et al, DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY 2 nd edition, J.Wiley & Sons (New York, NY 1994); sambrook et al, Molecular CLONING, A Laboratory Manual, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989). Any methods, devices, and materials similar or equivalent to those described herein can be used in the practice of the present invention.

The following definitions are provided to facilitate understanding of certain terms used frequently herein and are not intended to limit the scope of the present disclosure. All references mentioned herein are incorporated by reference in their entirety.

As used herein, and unless otherwise specified, the terms "about" and "approximately," when referring to a dose, amount, or weight percentage of an ingredient of a composition or dosage form, refer to a dose, amount, or weight percentage that one of ordinary skill in the art would recognize as providing a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percentage. An equivalent dose, amount, or weight percentage can be within 30%, 20%, 15%, 10%, 5%, 1%, or less of the specified dose, amount, or weight percentage.

As used herein, and unless otherwise specified, the terms "about" and "approximately," when referring to a numerical value or range of values (e.g., XRPD peaks) used to characterize a particular solid form described herein, indicate that the value or range of values can deviate from the given values to the extent that one of ordinary skill in the art would recognize as reasonable while still describing the solid form. In one embodiment, the values of the XRPD peak locations may vary by up to ± 0.1 ° 2 θ (or ± 0.05 degrees 2 θ) while still describing that particular XRPD peak.

As used herein, and unless otherwise specified, a crystal that is "pure" is substantially free of other crystalline or amorphous solids or other chemical compounds, and contains less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.01% by weight of one or more other solid forms. Detection of other solid forms can be accomplished by, for example, diffraction analysis, thermal analysis, elemental combustion analysis, and/or spectroscopic analysis. Detection of other chemical compounds can be accomplished by, for example, mass spectrometry, spectroscopic analysis, thermal analysis, elemental combustion analysis, and/or chromatographic analysis.

As used herein, unless otherwise specified, the terms "solvate" and "solvated" refer to a solid form of a material that contains a solvent. The terms "hydrate" and "hydrated" refer to a solvate in which the solvent is water. As used herein, the terms "solvate" and "solvated" may also refer to solvates of salts, co-crystals, or molecular complexes. As used herein, the terms "hydrate" and "hydrated" may also refer to a hydrate of a salt, co-crystal, or molecular complex.

The term "pharmaceutically acceptable" refers to diluents, excipients or carriers in a formulation that are compatible with the other ingredient or ingredients of the formulation and not deleterious to the recipient thereof.

Compound a refers to a compound having the structure:

and is named 3- ((1R,3R) -1- (2, 6-difluoro-4- ((1- (3-fluoropropyl) azetidin-3-yl) amino) phenyl) -3-methyl-1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b ] indol-2-yl) -2, 2-difluoropropan-1-ol, including pharmaceutically acceptable salts thereof. Compound a may be a tartrate salt as described herein (e.g., compound B). Compound a may be a fumarate salt as described herein (e.g., compound C). Compound a can be a malonate salt as described herein (e.g., compound D).

The term "solid form" refers to a physical form in which a liquid or gaseous state is not predominant. The solid form may be a crystalline form or a mixture thereof. In certain embodiments, the solid form may be a liquid crystal. In certain embodiments, the solid form of compound a is form a, form B, form C, form D, form E, form F, form G, form 1 or form 2, an amorphous solid, or a mixture thereof. In one embodiment, the solid form of compound a is a tartrate salt. In another embodiment, the solid form of compound a is a fumarate salt or a mixture thereof. The solid form may be a crystalline form as defined herein.

The term "crystalline form" or "crystalline form" refers to a crystalline solid form. In certain embodiments, the crystalline forms of the compounds described herein can be substantially free of amorphous solids and/or other crystalline forms. In certain embodiments, the crystalline forms of the compounds described herein may contain less than about 1%, less than about 2%, less than about 3%, less than about 4%, less than about 5%, less than about 6%, less than about 7%, less than about 8%, less than about 9%, less than about 10%, less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 35%, less than about 40%, less than about 45%, or less than about 50% by weight of one or more amorphous solids and/or other crystalline forms. In certain embodiments, the crystalline forms described herein are pure. In certain embodiments, a crystalline form of a compound described herein can be about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% pure.

The term "amorphous" or "amorphous solid" refers to a solid form that is substantially non-crystalline as determined by X-ray diffraction. In particular, the term "amorphous solid" describes a disordered solid form, i.e., a solid form lacking long-range crystalline order. In certain embodiments, the amorphous solids of the compounds described herein may be substantially free of other amorphous solids and/or crystalline forms. In certain embodiments, the amorphous solid may be pure. In certain embodiments, an amorphous solid of a compound described herein can be about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% pure.

As used herein, "treating" refers to alleviating, completely or partially, a disorder, disease, or condition, or one or more symptoms associated with a disorder, disease, or condition, or slowing or stopping the further progression or worsening of such symptoms, or alleviating or eradicating one or more causes of the disorder, disease, or condition itself. In one embodiment, the disorder is cancer.

The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound described herein that is capable of treating or preventing a disorder, disease, or condition disclosed herein, or a symptom thereof.

A "patient" or "subject" is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, monkeys, chickens, turkeys, quail or guinea pigs, and the like, in one embodiment mammals, and in another embodiment humans. In one embodiment, the subject is a human having or at risk of having cancer.

As used herein, the terms "moiety" and "substituent" refer to an atom or a group of chemically bonded atoms that is connected to another atom or molecule by one or more chemical bonds, thereby forming part of a molecule.

As used herein, the term "alkyl" refers to an aliphatic straight or branched chain saturated hydrocarbon moiety having from 1 to 20 carbon atoms. In particular embodiments, the alkyl group has 1 to 10 carbon atoms. In particular embodiments, the alkyl group has 1 to 6 carbon atoms. The alkyl group may be optionally independently substituted with one or more substituents described herein.

As used herein, the term "substituted" refers to a compound or moiety wherein at least one hydrogen atom is replaced with another substituent or moiety. Examples of such substituents include, but are not limited to, halogen, -OH, -CN, oxo, alkoxy, alkyl, alkylene, aryl, heteroaryl, haloalkyl, haloalkoxy, cycloalkyl, and heterocycle. For example, the term "haloalkyl" refers to the fact that one or more hydrogen atoms of an alkyl (as defined below) are replaced with one or more halogen atoms (e.g., trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, etc.). In one embodiment, as used herein, substituted may mean that at least one hydrogen atom of a compound or moiety described herein is replaced with a halogen or an alkyl.

As used herein, the term "alkylene" as used herein refers to a straight or branched chain saturated divalent hydrocarbon radical having from one to twelve carbon atoms, in another aspect from one to six carbon atoms, wherein the alkylene radical may be optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.

As used herein, the term "alkoxy" refers to a group of the formula-O-R ', wherein R' is an alkyl group. The alkoxy groups may be optionally independently substituted with one or more substituents described herein. Examples of alkoxy moieties include methoxy, ethoxy, isopropoxy, and tert-butoxy.

As used herein, the term "aryl" refers to a cyclic aromatic hydrocarbon moiety having a monocyclic, bicyclic, or tricyclic aromatic ring of 5 to 16 carbon ring atoms. Bicyclic aryl ring systems include fused bicyclic rings having two fused five-membered aryl rings (represented by 5-5), having five-membered aryl rings and fused six-membered aryl rings (represented by 5-6 and 6-5), and having two fused six-membered aryl rings (represented by 6-6). The aryl group may be optionally substituted as defined herein. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, and the like. The term "aryl" also includes partially hydrogenated derivatives of cyclic aromatic hydrocarbon moieties, provided that at least one ring of the cyclic aromatic hydrocarbon moiety is aromatic, each ring being optionally substituted.

As used herein, the term "heteroaryl" refers to an aromatic heterocyclic mono-, bi-, or tricyclic ring system having 5 to 16 ring atoms, which contains 1, 2, 3, or 4 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon. In some embodiments, the monocyclic heteroaryl ring may be 5-6 membered. Bicyclic heteroaryl ring systems include fused bicyclic rings having two fused five-membered heteroaryl rings (represented as 5-5), having five-membered heteroaryl rings and fused six-membered heteroaryl rings (represented as 5-6 and 6-5), and having two fused six-membered heteroaryl rings (represented as 6-6). Heteroaryl groups may be optionally substituted as defined herein. Examples of heteroaryl moieties include pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, benzothiophenyl, indolyl, azaindolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pyrrolopyridyl, furopyridyl, thienopyridyl, pyrrolopyridazinyl, pyrrolopyrimidyl, pyrrolopyrazinyl, thienopyridazinyl, thienopyrimidinyl, oxadiazolyl, thiadiazolyl, benzothiophenyl, thiadiazolyl, and the like, Thienopyrazinyl, furopyridazinyl, furopyrimidinyl and furopyrazinyl.

As used herein, the terms "halo", "halogen" and "halide", used interchangeably, refer to the substituents fluoro, chloro, bromo or iodo.

The term "haloalkyl" as used herein refers to an alkyl group wherein one or more hydrogen atoms of the alkyl group have been replaced by the same or different halogen atoms, in particular fluorine and/or chlorine atoms. Examples of haloalkyl include mono-, difluoro-or trifluoromethyl, -ethyl or-propyl, for example, 3,3, 3-trifluoropropyl, 2-fluoroethyl, 2,2, 2-trifluoroethyl, fluoromethyl, difluoromethyl or trifluoromethyl.

As used herein, the term "hydroxyalkyl" refers to an alkyl group in which one or more hydrogen atoms of the alkyl group have been replaced with a hydroxyl moiety. Examples include alcohols and glycols.

As used herein, the term "heteroalkyl" refers to a straight or branched chain alkyl group as defined herein having from 2 to 14 carbons, from 2 to 10 carbons, or from 2 to 6 carbons in the chain, one or more of which has been replaced with a heteroatom selected from S, O, P and N. Non-limiting examples of heteroalkyl groups include alkyl ethers, secondary and tertiary alkyl amines, amides, and alkyl sulfides.

As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated carbocyclic moiety having a monocyclic, bicyclic (including bridged bicyclic) or tricyclic ring and having from 3 to 10 carbon atoms in the ring. The cycloalkyl moiety may be optionally substituted with one or more substituents. In particular embodiments, the cycloalkyl group contains 3 to 8 carbon atoms (i.e., (C) ₃-C₈) Cycloalkyl groups). In other particular embodiments, the cycloalkyl group contains 3 to 6 carbon atoms (i.e., (C)₃-C₆) Cycloalkyl groups). Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and partially unsaturated (cycloalkenyl) derivatives thereof (e.g., cyclopentenyl, cyclohexenyl, and cycloheptenyl), bicyclo [3.1.0]Hexyl, bicyclo [3.1.0]Hexenyl, bicyclo [3.1.1]Heptyl and bicyclo [3.1.1]Heptenyl. Cycloalkyl moieties may be linked in a "spirocycloalkyl" manner, such as "spirocyclopropyl":

as used herein, the term "heterocycle" or "heterocyclyl" refers to a 4, 5, 6, and 7 membered monocyclic, 7, 8, 9, and 10 membered bicyclic (including bridged bicyclic) or 10, 11, 12, 13, 14, and 15 membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has one or more (e.g., 1, 2, 3, or 4) heteroatoms selected from oxygen, nitrogen, and sulfur in the ring, with the remaining ring atoms being carbon. In some embodiments, the heterocycle is heterocycloalkyl. In particular embodiments, heterocycle or heterocyclyl refers to a 4, 5, 6, or 7 membered heterocycle. When used in reference to a ring atom of a heterocyclic ring, the nitrogen or sulfur may also be in oxidized form, and the nitrogen may be substituted with one or more (C) ₁-C₆) Alkyl or substituted by a group. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Any heterocyclic ring atom may be optionally substituted with one or more substituents described herein. Examples of such saturated or partially unsaturated heterocycles include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, pyrrolylQuinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazaOxygen nitrogen base, oxygen nitrogen heteroRadical, sulfur nitrogen heteroMesityl, morpholinyl and quinuclidinyl. The term heterocycle also includes groups in which the heterocycle is fused to one or more aryl, heteroaryl or cycloalkyl rings, such as indolinyl, 3H-indolyl, chromanyl, azabicyclo [2.2.1 ] groups]Heptyl, azabicyclo [3.1.0]Hexyl, azabicyclo [3.1.1]Heptyl, octahydroindolyl or tetrahydroquinolyl.

Unless otherwise indicated, the term "hydrogen" or "hydrogen" refers to a hydrogen atom (-H) moiety other than H₂。

As used herein, the term "organic solvent" refers to any of nonaqueous polar aprotic solvents, polar protic solvents, and nonpolar solvents.

As used herein, the term "polar organic solvent" refers to both polar aprotic solvents and polar protic solvents, excluding water.

As used herein, the term "polar aprotic solvent" refers to any polar solvent that does not have proton donating ability. Examples include, but are not limited to, 2-methyltetrahydrofuran, tetrahydrofuran, ethyl acetate, propyl acetate (e.g., isopropyl acetate), acetone, dimethyl sulfoxide, N-dimethylformamide, acetonitrile, N-dimethylacetamide, N-methylpyrrolidone, hexamethylphosphoramide, and propylene carbonate.

As used herein, the term "polar protic solvent" refers to any polar solvent having the ability to donate protons. Examples include, but are not limited to, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, formic acid, nitromethane, and acetic acid. The organic polar protic solvent does not comprise any effective amount of water.

As used herein, the term "non-polar solvent" refers to a solvent that contains bonds between atoms (e.g., carbon and hydrogen) having similar electronegativities such that the charge on the molecule is uniformly distributed. The nonpolar solvent is characterized by having a low dielectric constant. Examples include, but are not limited to, pentane, hexane, heptane, cyclopentane, methyl tert-butyl ether (MTBE), diethyl ether, toluene, benzene, 1, 4-dioxane, carbon tetrachloride, chloroform, and Dichloromethane (DCM). In some embodiments, the dielectric constant of the non-polar solvent is less than 2, examples of which include, but are not limited to, pentane, hexane, and heptane. DCM exhibits a certain degree of polarity at the bond level (i.e., between carbon and chlorine) compared to other non-polar solvents, but only a small degree of polarity at the molecular level due to symmetry-based polarity elimination.

As used herein, the term "anti-solvent" refers to a solvent in which the referenced compound is poorly soluble and which causes the compound to precipitate or crystallize from solution.

As used herein, the term "acid catalyst" refers to an acid catalyst such as, but not limited toAcids, Lewis acids orLowry catalyst. Non-limiting examples of acid catalysts include acetic acid, glacial acetic acid, trifluoroacetic acid, benzoic acid, pivalic acid, diphenylphosphoric acid, trifluoromethanesulfonic acid, formic acid, tartaric acid, fumaric acid, malonic acid, salicylic acid, p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, naphthalenesulfonic acid, clay-based montmorillonite K-10, and resin-based Amberlyst, and combinations thereof.

As used herein, the term "amine protecting group" refers to any known protecting group that will block or protect an amine function. Amine protecting groups within the scope of the present disclosure include, but are not limited to, 1-chloroethyl carbamate (ACD); 4-methoxybenzenesulphonamide; acetamide (Ac); benzylamine (Bn); benzyloxycarbamate (CBz); formamide; methyl carbamate; trifluoroacetamide; tert-butyloxycarbamate (Boc); p-methoxybenzylcarbonyl (MeOZ); 9-Fluorenylmethoxycarbonyl (FMOC); benzoyl (Bz); p-methoxybenzyl (PMB); 3, 4-Dimethoxybenzyl (DMPM); p-methoxyphenyl (PMP); tosyl (Ts); and trichloroethyl chloroformate (Troc). For a description of amine protecting Groups and their use, see p.g.m.wuts and t.w.greene, Greene's Protective Groups in Organic Synthesis 4 th edition, Wiley-Interscience, New York, 2006.

As used herein, the term "aldehyde protecting group" refers to any known substituent attached to an aldehyde group that will block or protect the carbonyl group of an aldehyde function. Suitable protecting groups for the aldehyde function include, but are not limited to, (a) cyclic acetals and ketals, (b) cyclic mono-or dithio-acetals or ketals or other derivatives such as imines, hydrazones, cyanohydrins, oximes or semicarbazones, for example, dialkyl or diaryl acetals or 1,3 dithianes, (c) cyclic imines such as substituted methylene derivatives or N, N' -dimethylimidazolidines. Some non-limiting examples of aldehyde protecting groups include 1, 3-dithiane, 1, 3-dithiolane, diethyl acetal, dimethyl acetal, ethylene glycol acetal, neopentyl glycol acetal, trimethylsilyl cyanohydrin, and trialkyl orthoformates such as triethyl orthoformate. For a description of aldehyde protecting groups and their use, see Wuts and Greene.

As used herein, "leaving group" refers to an atom or group of atoms that is replaced in a chemical reaction with a stable species. Suitable leaving Groups are well known in the art, see, for example, March's Advanced Organic Chemistry,5.sup.th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York:2001 and T.W.Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York,1991, the entire contents of each of which are hereby incorporated by reference. Such leaving groups include, but are not limited to, halogen, alkoxy, sulfonyloxy, optionally substituted alkylsulfonyl, optionally substituted alkenylsulfonyl, optionally substituted arylsulfonyl, and diazo moieties. Examples of some leaving groups include chloro, iodo, bromo, fluoro, methanesulfonyl (mesyl), toluenesulfonyl, trifluoromethanesulfonyl, nitro-phenylsulfonyl (nosyl), and bromo-phenylsulfonyl (brosyl).

"transition metal catalysts" within the scope of the present disclosure include, but are not limited to, palladium, platinum, gold, ruthenium, rhodium, and iridium catalysts. Non-limiting examples of suitable catalysts include: (2-Biphenyl) di-tert-butylphosphine gold (I) ("John Phos"), 2-dicyclohexylphosphino-2 ', 4 ', 6 ' -triisopropylbiphenylylgold (I) ("XPhos AuCl"), 2-dicyclohexylphosphino-2 ', 4 ', 6 ' -triisopropylbiphenylylbis (trifluoromethanesulfonyl) imide gold (I) ("XPhos AuNTf 2"), chloro (2-dicyclohexylphosphino-2 ', 4 ', 6 ' -triisopropyl-1, 1 ' -biphenyl) [2- (2-aminoethyl) phenyl ] palladium (II) ("XPhos Palladicycle"), chloro (2-dicyclohexylphosphino-2 ', 6 ' -dimethoxy-1, 1 ' -biphenyl) [2- (2-aminoethylphenyl) ] palladium (II) -methyl tert-butyl ether adduct ("SPhos Palladicycle t-BuXPhos Palladium (II) phenethylamine chloride ("tBuXPhos Pd G1"), chlorine (2-dicyclohexylphosphino-2 ', 4', 6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] Palladium (II) ("Xphos Pd G2"), chlorine (2-dicyclohexylphosphino-2 ', 6' -dimethoxy-1, 1 '-biphenyl) [2- (2' -amino-1, 1 '-biphenyl) ] Palladium (II) ("SPhos Pd G2"), chlorine (2-dicyclohexylphosphino-2', 6 '-diisopropoxy-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] Palladium (II) ("RuPhos Pd G2"), Chlorine [ (2-dicyclohexylphosphino-2 ', 6 ' -bis (N, N-dimethylamino) -1,1 ' -biphenyl) -2- (2 ' -amino-1, 1 ' -biphenyl) ] palladium (II) ("CPhos-Pd-G2"), [ (2-dicyclohexylphosphino-2 ', 6 ' -bis (N, N-dimethylamino) -1,1 ' -biphenyl) -2- (2 ' -amino-1, 1 ' -biphenyl) ] palladium methanesulfonate (II) ("CPhos-Pd-G3"), [ (2-di-tert-butylphosphino-2 ', 4 ', 6 ' -triisopropyl-1, 1 ' -biphenyl) -2- (2 ' -amino-1, 1 ' -biphenyl) ] palladium (II) methanesulfonate ("tBuXPhos-Pd-G3"), (2-dicyclohexylphosphino-2 ', 6 ' -diisopropoxy-1, 1 ' -biphenyl) [2- (2 ' -amino-1, 1 ' -biphenyl) ] palladium (II) methanesulfonate ("RuPhos-Pd-G3"), (2-dicyclohexylphosphino-2 ', 4 ', 6 ' -triisopropyl-1, 1 ' -biphenyl) [2- (2 ' -amino-1, 1 ' -biphenyl) ] palladium (II) methanesulfonate ("XPhos-Pd-G3"), [ (2-dicyclohexylphosphino-3, 6-dimethoxy-2 ', 4 ', 6 ' -triisopropyl-1, 1 ' -biphenyl) -2- (2 ' -amino-1, 1 ' -biphenyl) ] palladium (II) methanesulfonate ("BrettPhos-Pd-G3"), [ (2- { bis [3, 5-bis (trifluoromethyl) phenyl ] phosphine-3, 6-dimethoxy-2 ', 4 ', 6 ' -triisopropyl-1, 1 ' -biphenyl) -2- (2 ' -amino-1, 1 ' -biphenyl) ] palladium (II) methanesulfonate ("JackiePhos-Pd-G3"), tert-butyl BrettPhos-Pd-G3, [ tert-butyl BrettPhos-Pd (allyl) ] OTf), and combinations thereof.

As used herein, "inorganic acid" refers to acids such as, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and combinations thereof.

As used herein, "organic acid" refers to acids such as, but not limited to: acetic acid; trifluoroacetic acid; phenylacetic acid; propionic acid; stearic acid; lactic acid; ascorbic acid; maleic acid; hydroxymaleic acid; (ii) hydroxyethanesulfonic acid; succinic acid; valeric acid; fumaric acid; malonic acid; pyruvic acid; oxalic acid; glycolic acid; salicylic acid; oleic acid; palmitic acid; lauric acid; pyranosidyl acids such as glucuronic acid or galacturonic acid; alpha-hydroxy acids such as mandelic acid, citric acid or tartaric acid; a cysteine sulfinic acid; amino acids such as aspartic acid, glutaric acid, or glutamic acid; aromatic acids, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid or cinnamic acid; sulfonic acids, such as lauryl sulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid or ethanesulfonic acid; (ii) cysteine sulfonic acid; and combinations thereof.

As used herein, "inorganic base" refers to bases such as, but not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, and combinations thereof.

As used herein, the term "organic base" refers to an organic compound that contains one or more nitrogen atoms and acts as a base. Examples of organic bases include, but are not limited to, tertiary amine bases. Examples of organic bases include, but are not limited to, 1, 8-diazabicyclo [5.4.0] undec-7-ene ("DBU"), N-methylmorpholine (NMM), Diisopropylethylamine (DIPEA), Triethylamine (TEA), tertiary butoxide salts (e.g., sodium, potassium, calcium, or magnesium tert-butoxide).

The compounds of the present disclosure may exist in salt form, which encompasses pharmaceutically acceptable salts and non-pharmaceutically acceptable salts. As used herein, the term "pharmaceutically acceptable salts" refers to those salts that retain the biological effectiveness and properties of the free base or free acid, which are not biologically or otherwise undesirable. In addition to pharmaceutically acceptable salts, the compounds of the present disclosure may be in the form of non-pharmaceutically acceptable salts, which are useful as intermediates in the isolation or purification of the compounds.

Exemplary acid salts of the compounds of the present disclosure include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, gluconate, formate, benzoate, glutamate, mesylate ", ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1, 1' -methylene-bis- (2-hydroxy-3-naphthoate)) salts. Pharmaceutically acceptable salts may involve the introduction of another molecule such as an acetate, succinate or other counterion. The counterion can be any organic or inorganic moiety that will stabilize the charge on the parent compound. In addition, a pharmaceutically acceptable salt may have more than one charged atom in its structure. The case where the plurality of charged atoms are part of a pharmaceutically acceptable salt can have a plurality of counterions. Thus, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counterions.

Exemplary base salts of the compounds of the present disclosure include, but are not limited to, inorganic salts formed from sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum cations. Organic salts formed from cations, including primary, secondary and tertiary amines; substituted amines, including naturally occurring substituted amines; a cyclic amine; a basic ion exchange resin; isopropylamine; trimethylamine; diethylamine; trimethylamine; tripropylamine; ethanolamine; 2-diethylaminoethanol; tromethamine; dicyclohexylamine; lysine; arginine; (ii) histidine; caffeine; procaine; hydrabamine (hydrabamine); choline; betaine; ethylene diamine; (ii) glucosamine; (ii) methylglucamine; theobromine; a purine; piperazine; piperidine; n-ethylpiperidine; and a polyamine resin.

The compounds of the present disclosure may also be solvated, i.e., hydrated. Solvation may be achieved during the manufacturing process or may occur as a result of the hygroscopic nature of the initially anhydrous compound. As used herein, "solvate" refers to an association or complex of one or more solvent molecules with a compound of the present invention. Non-limiting examples of solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate (EtOAc), acetic acid (AcOH), and ethanolamine.

Compounds having the same molecular formula but differing in the nature or order of bonding of their atoms or the arrangement of their atoms in space are referred to as "isomers". Isomers whose atoms are arranged differently in space are referred to as "stereoisomers". Diastereomers are stereoisomers that have opposite configurations at one or more chiral centers, which are not enantiomers. Stereoisomers with one or more asymmetric centers that are non-superimposable mirror images of each other are referred to as "enantiomers". When a compound has an asymmetric center, for example, if a carbon atom is bonded to four different groups, there may be a pair of enantiomers. Enantiomers can be characterized by the absolute configuration of one or more of their asymmetric centers and described by the R-and S-order rules of Cahn, Ingold, and Prelog or designated as dextrorotatory or levorotatory (i.e., the (+) or (-) isomers, respectively) in a manner in which the molecule rotates the plane of polarized light. The chiral compounds may exist as individual enantiomers or as mixtures thereof. Mixtures containing equal proportions of enantiomers are referred to as "racemic mixtures". In certain embodiments, the compounds are enriched in at least about 90% by weight of a single diastereomer or enantiomer. In other embodiments, the compound is enriched in at least about 95%, 98%, or 99% by weight of a single diastereomer or enantiomer.

Certain compounds of the present disclosure have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, regioisomers and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present disclosure.

The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention (including but not limited to diastereomers, enantiomers, and atropisomers, and mixtures thereof, such as racemic mixtures) form part of the invention. In some cases, stereochemistry has not been determined or has been assigned temporarily. Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule about one or more of its chiral centers. The sign of the rotation of the compound to plane polarized light is specified with the prefixes d and l or (+) and (-) where (-) or l means that the compound is left-handed. Compounds with (+) or d prefixes are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Particular stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric mixtures. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur where there is no stereoselectivity or stereospecificity in the chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, which are not optically active. Enantiomers can be separated from racemic mixtures by chiral separation methods, such as Supercritical Fluid Chromatography (SFC). In determining stereochemistry as from x-ray crystallographic data, the assignment of configuration at chiral centers in separated enantiomers may be temporary.

As used herein, "substantially" means at least 90%, at least 95%, at least 98%, or at least 99%.

In the description herein, a depicted structure will be referred to if there is a difference between the structure being depicted and the name given to the structure. In addition, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold wedges or dashed lines, the structure or portion of the structure is to be understood as encompassing all stereoisomers of it. However, in some cases where more than one chiral center is present, structures and names may be represented as single enantiomers to help describe relative stereochemistry.

Unless otherwise indicated, the term "compound of the formula" or "compound of formula" or "compounds of the formula" or "compounds of formula" refers to any compound selected from the class of compounds as defined by the formula (including any pharmaceutically acceptable salt of any such compound, if not otherwise specified).

In one aspect, provided herein is a method of preparing a compound of formula (IV):

or a salt thereof, wherein the process comprises the steps of:

(a) reacting a reaction mixture comprising a compound of formula (I), an organic solvent and thionyl chloride according to the following step 1 to form a compound of formula (IIa), and reacting a reaction mixture comprising a compound of formula (IIa), a catalyst, an oxidant and a solvent according to the following step 2 to form a compound of formula (II)

Wherein

R^1aAnd R^1bEach independently of the others is hydrogen, halogen, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy, -CN, C_3-6Cycloalkyl or C_3-6Spirocycloalkyl radicals, and

n is an integer of 2 or 3; and

(b) reacting a reaction mixture comprising a compound of formula (II) and a compound of formula (III) in an organic solvent according to the following step 3 to form a compound of formula (IV) or a salt thereof

Wherein B is a substituted or unsubstituted indolyl, benzofuranyl, benzothienyl, indazolyl, azaindolyl, benzimidazolyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, thienopyridazinyl, thienopyrimidinyl, thienopyrazinyl, furopyridazinyl, furopyrimidinyl, or furopyrazinyl group,

R^2aand R^2bEach independently of the others hydrogen, halogen, -OH, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Hydroxyalkyl, -CN, C_3-6Cycloalkyl or C_3-6A spiro-cycloalkyl group,

R^3aand R^3bIndependently of one another is hydrogen, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Hydroxyalkyl, -CN, C_3-6Cycloalkyl radical, C_3-6Heterocycloalkyl, phenyl, C_3-6Heteroaryl or C_3-6Spirocycloalkyl radicals, and

when R is^3aAnd R^3bAt the same time, the asterisks indicate the chiral centers.

In one embodiment, B is substituted indolyl, benzofuranyl, benzothienyl, indazolyl, azaindolyl, benzimidazolyl, pyrrolopyridyl, furopyridyl, thienopyridyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, thienopyridazinyl, thienopyrimidinyl, thienopyrazinyl, furopyridazinyl, furopyrimidinyl, or furopyrazinyl.

In another embodiment, B is unsubstituted indolyl, benzofuranyl, benzothienyl, indazolyl, azaindolyl, benzimidazolyl, pyrrolopyridyl, furopyridyl, thienopyridyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, thienopyridazinyl, thienopyrimidinyl, thienopyrazinyl, furopyridazinyl, furopyrimidinyl, or furopyrazinyl.

In one embodiment, B is a substituted or unsubstituted indolyl, benzofuranyl, or benzothienyl group. In another embodiment, B is substituted with one or more halogen or C as described herein_1-3Indolyl, benzofuranyl or benzothienyl substituted by alkyl. In yet another embodiment, B is a substituted or unsubstituted pyrrolopyridazinyl, pyrrolopyrimidinyl, or pyrrolopyrazinyl. In another embodiment, B is substituted with one or more halogen or C as described herein_1-3Alkyl-substituted pyrrolopyridazinyl, pyrrolopyrimidinyl or pyrrolopyrazinyl. In yet another embodiment, B is a substituted or unsubstituted indolyl group. In a preferred embodiment, B is unsubstituted indolyl. In one embodiment, B is substituted indolyl (e.g., substituted with one or more halogen or C as described herein) _1-3Alkyl substituted). In another preferred embodiment, B is a substituted indolyl group comprising a substitution with at least one moiety selected from the group consisting of methyl, Cl, and F. In yet another embodiment, B is benzofuranyl or a substituted benzofuranyl comprising a substitution with at least one moiety selected from methyl, Cl, and Fl.

B may suitably be selected from one or two independently of each other from fluorine, chlorine, C_1-3Alkyl radical, C_1-3Haloalkyl, -CN, -OH, C_1-3Alkoxy and C_1-3Substituted by a substituent of hydroxyalkyl. In one embodiment, B is indolyl substituted with halo (e.g., F or Cl).

In one embodiment, R^1aAnd R^1bEach independently of the others is hydrogen, halogen, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy, -CN or C_3-6A cycloalkyl group. In another embodiment, R^1aAnd R^1bEach independently is hydrogen, -F, -Cl, -OH, -CN, -CH₃、-CF₃、-CHF₂、-CH₂F or spirocyclopropyl. In one embodiment, R^1aAnd R^1bIndependently isF or hydrogen. In a preferred embodiment, R^1aAnd R^1bEach independently is hydrogen, -F or-CH₃. In another preferred embodiment, R^1aAnd R^1bEach independently hydrogen, -F or cyclopropyl. In one embodiment, n is 3.

In one embodiment:

Is a formula

R^2aAnd R^2bEach independently of the others hydrogen, halogen, -OH, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Hydroxyalkyl, -CN or C_3-6A cycloalkyl group. In some embodiments, R^2aAnd R^2bEach is hydrogen. In one embodiment, R^1aAnd R^1bEach independently is-F or CH₃And R is^2aAnd R^2bEach independently hydrogen. In one embodiment, B is indolyl, benzofuranyl, benzothienyl, or thiophenyl, and R is^1aAnd R^1bEach independently is-F or CH₃And R is^2aAnd R^2bEach independently hydrogen.

R^3aAnd R^3bEach independently is hydrogen, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Hydroxyalkyl, -CN, C_3-6Cycloalkyl radical, C_3-6Heterocycloalkyl, phenyl or C_3-6A heteroaryl group. In one embodiment, R^3aAnd R^3bEach independently is hydrogen or-CH₃。

When R is^3aAnd R^3bAt the same time, the asterisks in formula (IV) indicate the chiral centers. Thus, in some embodiments, R^3aAnd R^3bIs different from and is hydrogen or-CH₃。

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

including stereoisomers thereof.

In one particular embodiment, the compound of formula (I) is:

in another embodiment, the compound of formula (I) is:

including stereoisomers thereof.

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

including stereoisomers thereof.

In a particular embodiment, formula (II) is:

in some particular embodiments, the compound of formula (II) is:

including stereoisomers thereof.

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

including stereoisomers thereof, wherein X is-NH-, -N-C₁-C₃Unsubstituted alkyl, -O-or-S-.

In one particular embodiment, the compound of formula (III) is:

in another particular embodiment, the compound of formula (III) is:

in one embodiment, the compound of formula (IV) is:

or a salt thereof, including stereoisomers thereof; and wherein the asterisks indicate the chiral centers.

In a particular embodiment, formula (IV) is:

in another particular embodiment, formula (IV) is:

in one particular embodiment, the compound of formula (I) is:

the compounds of formula (II) are:

the compound of formula (III) is

And is

The compound of formula (IV) is

In step 1, a reaction mixture comprising a compound of formula (I), an organic solvent, and thionyl chloride is reacted to form a compound of formula (IIa). In one embodiment, the compound of formula (I) is compound I. In one embodiment, the organic solvent is a non-polar solvent or a polar solvent. In one embodiment, the solvent is non-polar. Non-limiting examples of suitable non-polar solvents include pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1, 4-dioxane, chloroform, diethyl ether, dichloromethane ("DCM"), and combinations thereof. In one embodiment, the solvent is DCM. In one embodiment, the concentration of formula (I) in the solvent may suitably be about 25g/L, about 50g/L, about 100g/L, about 150g/L, about 200g/L, about 250g/L and up to a concentration near saturation at the reaction temperature, and ranges established by these concentrations, such as about 100g/L to about 250 g/L. The equivalent ratio of thionyl chloride to compound of formula (I) is suitably about 1:1, about 1.1:1, about 1.2:1, about 1.3:1, about 1.5:1 or about 2:1, and ranges established by these ratios, such as about 1.1:1 to about 1.5: 1. In one embodiment, the reaction temperature is below the reflux temperature of the reaction mixture. In one embodiment, the reaction is carried out under reflux. For example, where the solvent is DCM, the reaction temperature may suitably be from about 25 ℃ to about 40 ℃. The reaction time is not critical, and the reaction generally continues until the conversion of formula (I) to formula (IIa) is substantially complete as determined by chromatography (e.g., TLC, GC, or HPLC).

After the reaction is complete, the reaction mixture may be quenched. In some such embodiments, the reaction mixture may be quenched with cold water. In such embodiments, the phase may be separated into an aqueous phase and an organic phase comprising the compound of formula (IIa). The aqueous phase may be extracted one or more times with an organic solvent to recover additional compound of formula (IIa).

In step 2, a reaction mixture comprising a compound of formula (IIa), a catalyst, an oxidant, and a solvent is reacted to form a compound of formula (II). In one embodiment, the organic phase comprising formula (IIa) or the combined organic phase from step 1 is used as the source of formula (IIa) of step 2. In one embodiment, the catalyst is a redox active metal catalyst. Non-limiting examples of suitable catalysts include NiCl₂、RuCl₃、CoCl₂、FeCl₃、FeCl₂And MnCl₂. Non-limiting examples of suitable oxidizing agents include NaIO₄NaOCl and Oxone. Suitable organic solvents include non-polar and polar solvents as discussed elsewhere herein. Typically, the oxidizing agent is in equivalent excess relative to the compound of formula (IIa), for example, the ratio of oxidizing agent to compound of formula (IIa) can be 1.1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, or 5: 1. Step 2 the reaction mixture may further comprise water. In such embodiments, the volume ratio of water to organic solvent used in the step 1 reaction mixture may be about 9:1, about 5:1, about 3:1, about 2:1, about 1:2, about 1:3, about 1:5, or about 1:9, and ranges constructed therefrom, such as from about 2:1 to about 1: 2. The reaction temperature of step 2 may suitably be about 25 ℃, about 15 ℃, about 5 ℃, about 0 ℃, about-5 ℃ or about-10 ℃, and ranges constructed therefrom, such as from about-10 ℃ to about 10 ℃. In one embodiment, one or more organic phases comprising formula (IIa), the catalyst and water are hydrated and cooled to the reaction temperature. Then while maintaining the temperature near the reaction temperature The oxidizing agent is added over a period of time.

After completion of the reaction, the reaction mixture of step 2 can be separated into an aqueous phase and an organic phase comprising the compound of formula (II) in solution. In some optional embodiments, the reaction mixture may be filtered, such as by a filter aid (e.g., diatomaceous earth), prior to phase separation. The aqueous phase may be extracted one or more times with an organic solvent to recover additional compound of formula (II).

In another embodiment, one or more of the organic phases of step 2 may be post-treated by methods known to those skilled in the art. For example, the organic phase may be treated with a base such as Na₂SO₃Washing with an aqueous solution of (1). The organic phase may optionally be further dried, e.g. with an aqueous salt solution and/or by addition of a solid drying agent such as CaCl₂、MgSO₄Or Na₂SO₄. The solid desiccant may suitably be removed by filtration. In one embodiment, a solution of the compound of formula (II) may be used for subsequent reactions. In one embodiment, the compound of formula (II) may be isolated from the solution by methods known in the art, such as by distillation, concentration, precipitation (e.g., by addition of an anti-solvent or pH adjustment), and/or crystallization. In some such embodiments, the one or more organic phases may be concentrated by distillation or stripping to reduce volume, such as by at least 25%, 50%, 100%, or more. The compound of formula (II) may then be precipitated/crystallized from solution by addition of an anti-solvent, followed by optional further concentration. In one embodiment, the antisolvent is C _4-8A non-ionic solvent such as pentane, hexane or heptane. The solids of the compound of formula (II) can be collected by methods known in the art, such as filtration or centrifugation. The solid may be dried, such as under partial vacuum, to yield a solid compound of formula (II). The yields of steps 1 and 2 from the compound of formula (I) to the compound of formula (II) are at least 60%, at least 70% or at least 75%. In one embodiment, the compound of formula (II) is compound 2.

In step 3, a reaction mixture comprising a compound of formula (II), a compound of formula (III) and an organic solvent is reacted to form a compound of formula (IV). In one embodiment, the organic solvent is a polar aprotic solvent. Non-limiting examples of suitable solvents include tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile ("ACN"), dimethyl sulfoxide, nitromethane, and propylene carbonate. In one embodiment, the solvent is ACN. The molar ratio of compound of formula (II) to compound of formula (III) is suitably about 1:1, about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1 or greater, and ranges established by these ratios, such as between 1:1 and 1.3: 1. The concentration of the compound of formula (II) in the solvent is suitably about 10g/L, about 25g/L, about 50g/L, about 75g/L, about 100g/L, about 125g/L, about 150g/L and up to a concentration near saturation at the reaction temperature, and ranges established by these concentrations, such as from about 50g/L to about 150 g/L. The acid catalyst may be an acid catalyst as described elsewhere herein. In some embodiments, the acid catalyst is sulfuric acid, p-toluenesulfonic acid (p-TsOH), or methanesulfonic acid, or a combination thereof. In one embodiment, the acid catalyst is p-toluenesulfonic acid. The equivalent ratio of acid catalyst to compound of formula (II) is suitably about 0.75:1, about 0.9:1, about 1:1, about 1.05:1, about 1.1:1, about 1.2:1, about 1.3:1, 1.4:1, about 1.5:1, or greater, and ranges constructed therefrom, such as from about 1:1 to about 1.2: 1. In one embodiment, the compound of formula (III) is compound 3.

In some step 3 embodiments, the compound of formula (II), the compound of formula (III), the organic solvent, and the base are combined to form a mixture (adjuvant). The base may suitably be a mild base, non-limiting examples of which include potassium tert-butoxide, trimethylamine, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, ammonium hydroxide, and combinations thereof. The mixture may be heated with agitation to a reaction temperature, typically a temperature of from 2 ℃ to about 30 ℃ below reflux temperature to reflux temperature, and for a time sufficient to substantially complete the formation of the reaction product comprising the compound of formula (III). Where an ACN solvent is used, the reaction temperature is suitably about 65 ℃, about 70 ℃, about 75 ℃ or about 80 ℃. The reaction product mixture may then be cooled, such as to less than 50 ℃, less than 40 ℃, or less than 30 ℃, and optionally filtered to remove solid impurities. The solid may optionally be washed with a solvent to recover additional reaction product. An acid (e.g., p-TsOH) and water are then added. The volume ratio of organic solvent to water can be 25:1, 15:1, 10:1, 5:1, 2:1, or 1:1, and ranges constructed therefrom, such as about 15:1 to about 5: 1. The admixture may be heated with agitation to a reaction temperature, typically a temperature of from 2 ℃ to about 20 ℃ below reflux temperature to reflux temperature, and for a sufficient time to substantially complete formation of the compound of formula (IV) as determined by chromatography (e.g., TLC, GC, or HPLC). After the reaction is complete, the reaction mixture can be quenched, such as with cold water (e.g., below 10 ℃ or below 5 ℃). The pH of the quenched reaction mixture can then be adjusted to greater than 7, such as about pH 8, about pH 9, about pH 10, or about pH 11, with a base. In one embodiment, the base is an aqueous base such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, or ammonium hydroxide.

After completion of the reaction, the reaction mixture of step 3 may be separated into an aqueous phase and an organic phase comprising the compound of formula (IV) in solution. In some optional embodiments, the reaction mixture may be filtered, such as by a filter aid (e.g., diatomaceous earth), prior to phase separation. The aqueous phase may be extracted one or more times with an organic solvent to recover additional compound of formula (IV). In one embodiment, the solvent is aprotic. In a particular embodiment, the extraction solvent is suitably isopropyl acetate ("i-PrOAc").

In some embodiments, one or more of the organic phases of step 3 can be post-treated by, for example, washing the organic phase with water. The organic phase may optionally be dried, e.g. with an aqueous salt solution and/or by addition of a solid drying agent such as CaCl₂、MgSO₄Or Na₂SO₄. The solid desiccant may suitably be removed by filtration and the collected desiccant may optionally be washed with a solvent to recover the compound of formula (IV) therefrom. In such embodiments, the one or more organic phases may be concentrated by distillation or stripping under partial vacuum to form a residue of the compound of formula (IV). The residue of the compound of formula (IV) may then be dissolved in an organic solvent at a temperature below the reflux temperature. The anti-solvent may then be added to the solution of the compound of formula (IV) while cooling to, e.g., less than about 10 ℃, as described elsewhere herein Said non-polar organic solvent to precipitate/crystallize the compound of formula (IV) from solution. The solid of the compound of formula (IV) may be collected by methods known in the art, such as filtration or centrifugation, and optionally washed with an anti-solvent. The solid may be dried, such as under partial vacuum, to yield a solid compound of formula (IV). The yield of step 3 from the compound of formula (II) to the compound of formula (IV) is at least 80%, at least 85%, at least 90%, at least 95%, at least 96% or at least 97%. The compound of formula (IV) has a purity of at least 95%, at least 98% or at least 99%.

One aspect of the present disclosure relates to a process for preparing a compound of formula (VIII):

or a salt thereof, wherein the process comprises the steps of:

(a) reacting a reaction mixture comprising a compound of formula (IV), a compound of formula (V), or a compound of formula (X) and an organic solvent according to the following step 1 to form a compound of formula (VI)

Wherein

B is substituted or unsubstituted indolyl, benzofuranyl, benzothienyl, azaindolyl, indazolyl, benzimidazolyl, pyrrolopyridyl, furopyridyl, thienopyridyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, thienopyridazinyl, thienopyrimidinyl, thienopyrazinyl, furopyridazinyl, furopyrimidinyl, or furopyrazinyl;

R^1aAnd R^1bEach independently of the others is hydrogen, fluorine, chlorine, -OH, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Hydroxyalkyl, and-CN, C_3-6Cycloalkyl or C_3-6A spiro-cycloalkyl group,

n is an integer of 2 or 3,

R^2aand R^2bEach independently of the others hydrogen, halogen, -OH, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Hydroxyalkyl, -CN, C_3-6Cycloalkyl or C_3-6A spiro-cycloalkyl group,

R^3aand R^3bIndependently of one another is hydrogen, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy, -CN, C_3-6Cycloalkyl radical, C_3-6Heterocycloalkyl, phenyl, C_3-6Heteroaryl or C_3-6A spiro-cycloalkyl group,

j is phenyl or pyridyl;

each R⁴Independently hydrogen, halogen or C_1-3An alkyl group, a carboxyl group,

s is an integer of 0 to 2,

LG is a leaving group and is a hydroxyl group,

LG and CHO are in the para position relative to each other on J of the compound of formula (V),

PG is an aldehyde protecting group, and PG is an aldehyde protecting group,

LG and CH-PG are in the para position relative to each other on J of the compound of formula (X), and

each asterisk independently represents a chiral center, wherein when R^3aAnd R^3bAt different times, with R^3aAnd R^3bThe carbon of (a) is a chiral center; and

(b) reacting a reaction mixture comprising a compound of formula (VI), an organic solvent, and a compound of formula (VII) or a salt thereof according to the following step 2 to form a compound of formula (VIII) or a salt thereof

Wherein

G is C_1-3An alkyl group, a carboxyl group,

p is 0 or 1, and p is,

E is substituted or unsubstituted azetidinyl or pyrrolidinyl,

each R⁵Independently hydrogen, halogen, -OH,-CN、C_1-5Alkoxy or C_1-5A hydroxyalkyl group,

v is an integer of 1 to 5 and,

R⁶is halogen or-CN; and is

R¹⁰Is hydrogen or C_1-3An alkyl group.

B、R^1a、R^1b、n、R^2a、R^2b、R^3a、R^3bAnd asterisks (—) are as defined herein.

In a preferred embodiment, J is phenyl. In another embodiment, J is pyridinyl.

In one embodiment, each R is⁴Independently hydrogen or halogen. In a preferred embodiment, each R is⁴Is fluorine. In one embodiment, s is 1 or 2. In one embodiment, s is 2. In a preferred embodiment, each R is⁴Is fluorine and s is 2.

In one embodiment, G is methylene or ethylene.

In one embodiment, p is 0.

In one embodiment, each R is⁵Independently hydrogen, halogen, -OH or-CN. In a preferred embodiment, each R is⁵Is hydrogen. In one embodiment, v is 2. In another embodiment, v is 3. In another embodiment, v is 5. In a preferred embodiment, each R is⁵Is hydrogen and v is 3.

In a preferred embodiment, R⁶Is halogen. In one embodiment, R ⁶Is F. In another embodiment, R⁶is-CN.

In one embodiment, R¹⁰Is hydrogen or methyl. In a preferred embodiment, R¹⁰Is hydrogen.

In one embodiment, E is azetidinyl. In another embodiment, E is pyrrolidinyl.

In one embodiment, E has the structure:

in one embodiment, E is an azetidinyl of the structure:

in one embodiment, E has the structure:

wherein R is⁵Is H, v is 2 or 3, and R⁶Is halogen.

In one embodiment, E is an azetidinyl of the structure:

in one embodiment, formula (VIII) is an acid salt. Such acid salts may be pharmaceutically acceptable salts. In some such embodiments, formula (VIII) is a salt of a pharmaceutically acceptable acid. In some particular embodiments, formula (VIII) is a salt of a pharmaceutically acceptable organic acid. In a preferred embodiment, formula (VIII) is a pharmaceutically acceptable tartrate salt. In one embodiment, the compound of formula (VIII) is compound a as described herein. In another embodiment, the compound of formula (VIII) is compound a (tartrate) of compound a as described herein. In another embodiment, formula (VIII) is a pharmaceutically acceptable fumarate salt. In another embodiment, the compound of formula (VIII) is compound B (fumarate) of compound a as described herein.

In one embodiment, formula (VIII) has any one of the following structures, or is a pharmaceutically acceptable salt thereof:

or a pharmaceutically acceptable salt thereof and including stereoisomers thereof.

In one embodiment, formula (VIII) has the following structure, or is a pharmaceutically acceptable salt thereof:

in one embodiment, formula (VIII) has the following structure:

in one embodiment, formula (VIII) has the following structure:

step 1 of the method of synthesizing a compound of formula (VIII) comprises reacting a reaction mixture comprising a compound of formula (IV), a compound of formula (V), or a compound of formula (X) and an organic solvent to form a compound of formula (VI) as set forth herein. In one embodiment, LG is bromo. In a preferred embodiment, LG and CHO are para to each other on J when reacted with compounds of formula (IV) and formula (V). In a preferred embodiment, LG and CH-PG are para to each other on J when reacting formula (IV) with a compound of formula (X).

The compounds of formula (IV) are as described herein.

In one embodiment, the compound of formula (V) is any one of the following compounds, or a salt thereof:

Or a salt thereof.

In some embodiments, formula (X) corresponds to any of the structures of formula (V) or salts thereof described above, but wherein the aldehyde (-CHO) is a protected moiety of the structure-CH-PG, wherein PG is an aldehyde protecting group as defined elsewhere herein.

In some embodiments, formula (VI) has any one of the following structures:

or a salt thereof, including stereoisomers thereof.

In step 2 of the synthesis of the compound of formula (VIII) set forth herein, the compound of formula (VII) may have any one of the following structures:

or a salt thereof.

In one embodiment, the salt is an ethane-disulfonate (e.g., a salt of ethane-1, 2-disulfonate).

In one embodiment, the compound of formula (VII) has the structure

Compound (7) may be prepared according to the examples provided herein, as for example 4 or example 4 a.

In one embodiment, compound 7 is prepared according to the following scheme:

in step 1, a reaction mixture comprising a compound of formula (IV), a compound of formula (V) or a compound of formula (X), and an organic solvent is reacted to form a compound of formula (VI). In one embodiment, the organic solvent is a polar protic solvent, a non-polar solvent, a polar aprotic solvent, or a combination thereof, as described elsewhere herein. In some non-limiting embodiments, the solvent is toluene. In one embodiment, the solvent is acetonitrile, methyl ethyl ketone, or methyl tetrahydrofuran. In one embodiment, the reaction mixture of step 1 further comprises an acid catalyst as described elsewhere herein. In some such non-limiting embodiments, the acid catalyst is acetic acid. The molar ratio of compound (IV) to compound (V) or compound (X) is from about 0.95:1 to about 1.05:1, in a stoichiometric amount, or in some embodiments a slight molar excess of compound (V) or compound (X). The acid catalyst is typically present in stoichiometric excess, e.g., in an equivalent ratio to the compound of formula (IV) of about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1, about 1.6:1, about 1.7:1, about 1.8:1, about 2:1, or higher, and ranges constructed therefrom, e.g., from about 1.2:1 to about 1.8: 1.

In some step 1 embodiments, the reaction mixture may be heated with agitation to a reaction temperature of from 2 ℃ below reflux temperature to about 30 ℃ to reflux temperature and for a sufficient time to substantially complete the reaction to the compound of formula (VI) as determined by chromatography (e.g., TLC, GC, or HPLC). In the case of using a toluene solvent, the reaction temperature is suitably about 65 ℃, about 70 ℃, about 75 ℃, or about 80 ℃. The reaction product mixture may then be cooled and optionally diluted with additional solvent. The reaction product mixture may then be quenched with an aqueous base such as those described elsewhere herein. The step 1 reaction product mixture organic phase comprising the compound of formula (VI) may then be isolated and in some embodiments worked up by washing with water and/or aqueous salt solution as described elsewhere herein by methods known in the art, followed by isolation of the product as a solid. In one embodiment, the reaction product mixture may be treated with activated carbon, followed by filtration and optionally washing of the activated carbon filter cake with a solvent. As described elsewhere herein: (i) the one or more organic phases containing the compound of formula (VI) may be concentrated by distillation or stripping to reduce the volume, such as by at least 25%, 50%, 100% or more; and (ii) the compound of formula (IV) may then be precipitated/crystallized from solution by addition of an anti-solvent, followed by optional further concentration.

In some other step 1 embodiments, the reaction mixture of step 1 is heated at reflux for a period of time to substantially complete the reaction as determined by chromatography (e.g., TLC, GC, or HPLC). The reaction mixture may then be cooled and the pH adjusted with an aqueous base such as a base to a pH at which the compound of formula (VI) precipitates from solution.

In any of the various step 1 embodiments, the solid of the compound of formula (VI) may be collected by methods known in the art, such as filtration or centrifugation. The solid may be dried, such as under partial vacuum, to yield a solid compound of formula (VI). The yields of steps 1 and 2 from the compound of formula (V) to the compound of formula (VI) are at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%.

In step 2, a reaction mixture comprising a compound of formula (VI), a compound of formula (VII), and an organic solvent is reacted to form a compound of formula (VIII). In some embodiments, the organic solvent is a polar aprotic solvent as described elsewhere herein. In some non-limiting embodiments, the solvent is CAN. The reaction mixture of step 2 may further comprise a base, such as an organic base. Non-limiting examples of organic bases include DBU, NMM, DIPEA, and TEA. In some such embodiments, the base is DBU. The reaction mixture of step 2 may further comprise a catalyst, such as a transition metal catalyst. In some embodiments, the catalyst is a Pd catalyst. The molar ratio of compound (VII) to compound (VI) is about 0.95:1, about 1:1, about 1.05:1, about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, or about 1.5:1, and ranges constructed therefrom, such as from about 1:1 to about 1.4: 1. The base is typically present in stoichiometric excess, e.g., in an equivalent ratio to the compound of formula (VI) of about 1.1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, or about 8:1, and ranges constructed therefrom, e.g., from about 3:1 to about 7: 1. The reaction mixture may be heated to the reaction temperature, typically from a temperature of 2 ℃ to about 30 ℃ below reflux temperature to reflux temperature, with agitation, and for a sufficient time to substantially complete the reaction as determined by chromatography (e.g., TLC, GC, or HPLC). In the case of using a CAN solvent, the reaction temperature is suitably about 65 ℃, about 70 ℃, about 75 ℃, or about 80 ℃.

After completion of the reaction, the product mixture may be suitably cooled and optionally diluted with an organic solvent. In one embodiment, the reaction product mixture is diluted with a non-polar solvent as described elsewhere herein. One non-limiting example of a suitable non-polar solvent is MTBE. The reaction product mixture of step 2 can be worked up by methods known to those skilled in the art, including water washing and brine washing. In some such non-limiting embodiments, the post-treatment may include washing with an aqueous solution of ammonium chloride, brine, and water. In some embodiments, the reaction product mixture of step 2 may be contacted with a metal scavenger known in the art, such as, but not limited to, siliaamets thiol. The reaction product mixture may then be filtered to remove solids before isolating the compound of formula (VIII) therefrom.

In some embodiments, the reaction product mixture of step 2 may be concentrated, such as by vacuum distillation or stripping, and diluted with an organic solvent, such as an alcohol (e.g., ethanol), such as in a solvent exchange step. An acid may then be added to the diluted solution of the compound of formula (VIII) followed by cooling to crystallize the compound of formula (VIII) as an acid salt. In some particular embodiments, the acid is tartaric acid and the compound of formula (VIII) is the tartrate salt. In some such embodiments, the acid is (2R-3R) -tartaric acid (L- (+) -tartaric acid). In another aspect, the acid is (2S-3S) -tartaric acid (D- (-) -tartaric acid). In some such embodiments, the solvent comprises an organic solvent. The crystalline material may be collected by centrifugation or filtration, optionally washed with a solvent, and optionally dried.

In some other embodiments, the compound of formula (VIII) may be isolated from the reaction product mixture of step 2 using methods described elsewhere herein, including: (i) distillation, concentration, precipitation (e.g., by addition of an anti-solvent or pH adjustment), and/or crystallization; (ii) collecting the solid by centrifugation or filtration; (iii) optionally washing the collected solids; and (iv) drying.

The compound of formula (VIII) in free base or acid salt form is in step 2 yield of at least 80%, at least 85%, or at least 90%.

Another aspect of the present disclosure relates to a process for preparing a compound of formula (VIII), or a salt thereof, wherein the compound of formula (VIII) is as described elsewhere herein. The process for preparing formula (VIII) according to this embodiment comprises the reaction step 1 as depicted below:

B、R^1a、R^1b、n、R^2a、R^2b、R^3a、R^3b、R⁴、s、J、R⁵、v、R⁶、R¹⁰g, p, E, PG and asterisks are each as described elsewhere herein. The CHO moiety and the nitrogen atom linking J and G are in para position on J relative to each other. The CH-PG moiety and the nitrogen atom linking J and G are in a para position relative to each other on J.

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

or a salt thereof.

In a preferred embodiment, the compound of formula (IX) is compound (8 a). In some embodiments, formula (XI) corresponds to any of the structures of formula (IX) above or a salt thereof, but wherein the aldehyde (-CHO) is a protected moiety of the structure-CH-PG, wherein PG is an aldehyde protecting group as defined elsewhere herein.

In step 1, a reaction mixture comprising a compound of formula (IX) or formula (XI), a compound of formula (IV) and an organic solvent is reacted to form a compound of formula (VIII) or a salt thereof. In one embodiment, the organic solvent is a polar solvent, or a polar protic solvent. The reaction mixture of step 1 also contains an acid catalyst as described elsewhere herein. In a particular embodiment, the acid catalyst is tartaric acid or fumaric acid. In one embodiment, the acid catalyst is tartaric acid. In another embodiment, the acid catalyst is fumaric acid. Non-limiting examples of suitable solvents include n-butanol, isopropyl alcohol, n-propanol, isopropanol, ethanol, methanol, and combinations thereof. In some particular embodiments, the solvent is ethanol. In one embodiment, the concentration of formula (IX) in the solvent may suitably be about 25g/L, about 50g/L, about 100g/L, about 150g/L, about 200g/L, about 250g/L and up to a concentration near saturation at the reaction temperature, and ranges established by such concentrations, such as about 100g/L to about 250 g/L. The molar ratio of formula (IX) or formula (XI) to formula (IV) is suitably about 0.25:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 0.95:1, about 1:1, about 1.05:1, about 1.1:1, or about 1.2:1, and ranges established by these ratios, such as about 0.95:1 to about 1.05: 1. In one embodiment, formula (IX) or formulae (XI) and (IV) are present in approximately stoichiometric amounts. In one embodiment, the reaction temperature is below the reflux temperature of the reaction mixture. In some other embodiments, the reaction is carried out at reflux. For example, when the solvent is ethanol, the reaction temperature may suitably be from about 50 ℃ to about 75 ℃. The reaction time is not critical, and the reaction is typically continued until the conversion of formula (IX) or formula (XI) to formula (VIII) is substantially complete as determined by chromatography (e.g., TLC, GC, or HPLC).

In one embodiment, formula (VIII) may be formed as a salt of an acid. Suitable acids include inorganic acids and inorganic acids as described elsewhere herein. In one embodiment, the acid is an organic acid. In a preferred embodiment, the acid is tartaric acid. In another embodiment, the acid is fumaric acid. In one embodiment, the free base of formula (VIII) may be dissolved in a suitable solvent such as a polar protic solvent (e.g., an alcohol such as methanol or ethanol) at elevated temperature, followed by addition of the acid. Typically, the acid is in stoichiometric excess compared to the compound of formula (VIII). In some such embodiments, the solution temperature and/or the concentration of formula (VIII) is adjusted to maintain the concentration below saturation to avoid precipitation and/or crystallization of formula (VIII). After addition of the acid, the solution may optionally be seeded with a crystalline salt of formula (VIII) of the acid. In any of the various embodiments, the solution is cooled with stirring to form a crystalline salt of formula (VIII). The salt can then be collected by methods known in the art, such as by filtration or centrifugation. In one embodiment, the salt is collected by filtration. The collected salt of formula (VIII) may optionally be washed, e.g. with a dissolving solvent, and then dried, e.g. under partial vacuum.

In a particular embodiment, the reaction mixture of step 1 as described above for the synthesis of the compound of formula (VIII) comprises tartaric acid as an acid catalyst, crystalline tartaric acid of formula (VIII) and an alcohol-containing solvent (e.g. ethanol); diluting the reaction product mixture of step 1 with an alcohol-containing solvent; and cooling the resulting slurry with stirring to form crystalline tartaric acid of formula (VIII). In another embodiment, the reaction mixture of step 1 comprises fumaric acid as an acid catalyst, crystalline fumaric acid of formula (VIII), and a solvent. The compound of formula (VIII) as the tartrate salt has a step 1 yield of at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. In such embodiments, the reaction scheme for step 1 is as follows:

another aspect of the present disclosure relates to a process for preparing a compound of formula (IX) or a salt thereof. The process for the preparation of the compound of formula (IX) comprises two reaction steps depicted below:

R⁴、s、LG、PG、R⁵、v、R⁶、R¹⁰g, p, J and E are as described elsewhere herein.

Aldehyde protecting groups are defined herein and non-limiting examples include 1, 3-dithiane, 1, 3-dithiolane, diethyl acetal, dimethyl acetal, ethylene glycol acetal, neopentyl glycol acetal, trimethylsilyl cyanohydrin, and triethyl orthoformate.

In step 1, a reaction mixture comprising a compound of formula (X), a compound of formula (VII) or a salt thereof, an organic solvent, and a catalyst is reacted to form a compound of formula (XI). In one embodiment, the solvent is a non-polar solvent as described elsewhere herein. Non-limiting examples of suitable solvents include pentane, hexane, heptane, cyclopentane, MTBE, diethyl ether, toluene, 2-methyltetrahydrofuran (2-MeTHF), benzene, 1, 4-dioxane, carbon tetrachloride, chloroform, dichloromethane, and combinations thereof. In some examples, the solvent is toluene. In one embodiment, the catalyst is a transition metal catalyst as described herein. In one embodiment, non-limiting examples of transition metal catalysts include palladium, platinum, gold, ruthenium, rhodium, and iridium catalysts. Non-limiting examples of suitable catalysts include John Phos, XPhos AuCl, XPhos AuNTf2, XPhos Palladacycle, SPhos Palladacycle, tBuXPhos Pd G1, Xphos Pd G2, SPhos Pd G2, RuPhos Pd G2, CPhos-Pd-G2, CPhos-Pd-G3, tBuXPhos-Pd-G3, RuPhos-Pd-G3, XPhos-Pd-G3, BretPhos-Pd-G3, Jackie Phos-Pd-G3, t-butyl Bretphos-Pd-G3, [ t-butyl-Pd (allyl) ] OTf), and combinations thereof. In some embodiments, the catalyst is BrettPhos-Pd-G3. In some embodiments, the reaction mixture of step 1 further comprises an organic base as described elsewhere herein. In some such embodiments, the base is a tert-butoxide salt such as sodium tert-butoxide or potassium tert-butoxide. The molar ratio of compound of formula (VII) to compound of formula (X) is suitably about 1:1, about 1.1:1, about 1.2:1, about 1.3:1, about 1.5:1, or about 2:1, and ranges established by these ratios, such as about 1.1:1 to about 1.5: 1.

In some step 1 embodiments, the reaction mixture may be heated with agitation to a reaction temperature of from 2 ℃ below reflux temperature to about 30 ℃ to reflux temperature and for a sufficient time to substantially complete the reaction to the compound of formula (XI) as determined by chromatography (e.g., TLC, GC, or HPLC). In the case of using a toluene solvent, the reaction temperature is suitably about 50 ℃, about 55 ℃, about 60 ℃, about 65 ℃, about 70 ℃, about 75 ℃, or about 80 ℃. The reaction time is not critical, and the reaction generally continues until the conversion of formula (VII) and (X) to formula (XI) is substantially complete as determined by chromatography (e.g., TLC, GC, or HPLC). After the reaction is complete, the reaction product mixture may be suitably quenched. In some embodiments, the reaction of step 1 may be quenched with water. Upon quenching the reaction with water, the organic phase comprising the compound of formula (XI) in solution can be separated off and optionally washed at least once with water. In some embodiments, the reaction product mixture of step 1 may be contacted with a metal scavenger known in the art, such as, but not limited to, siliaamets thiol. The reaction product mixture may then be filtered to remove solids.

In step 2, the compound of formula (XI) is deprotected by combining a solution of compound (XI) in an organic solvent (e.g., toluene) with an acid and water to form the compound of formula (IX). The acid is typically present in an equivalent excess, e.g., in an equivalent ratio of acid to compound (XI) of 1.01:1, 1.05:1, 1.1:1, 1.15:1, 1.2:1, or higher. In one embodiment, the deprotection temperature is not strictly limited and may suitably be room temperature. After deprotection, the organic and aqueous phases (comprising the compound of formula (IX)) are separated. The organic phase may optionally be washed with water. The one or more aqueous phases may be treated with a base, such as an inorganic base (e.g., NaOH or KOH), and combined with seed crystals of the compound of formula (IX). The base may be added in a suitable equivalent excess. A slurry of the crystalline compound of formula (IX) is formed and optionally cooled. The solid of the compound of formula (IX) may be collected by methods known in the art, such as filtration or centrifugation. The solid may be dried, such as under partial vacuum, to yield a solid compound of formula (IX). The yields of steps 1 and 2 from the compound of formula (XI) to the compound of formula (IX) are at least 65%, at least 70%, at least 75%, at least 80% or at least 85%.

One aspect of the present disclosure relates to a process for preparing a compound of formula (III) or a salt thereof. The process for the preparation of the compound of formula (III) comprises two reaction steps depicted as follows:

(1) Reacting a reaction mixture comprising a compound of formula (XII), compound B and an organic solvent according to the following step 1 to form a compound of formula (XIII)

Wherein PG is an amine protecting group; and

(2) deprotection of a compound of formula (XIII) according to step 2 below to form a compound of formula (III)

Wherein R is^2a、R^2b、R^3a、R^3bB and asterisks as described elsewhere herein.

Non-limiting examples of amine protecting groups include ACD, Ac, Bn, CBz, trifluoroacetamide, Boc, MeOZ, FMOC, Bz, PMB, DMPM, PMP, Ts, and Troc. In one embodiment, PG is Boc.

In one embodiment, the compound of formula (III) has the structure as described herein

Or a salt thereof.

In some other embodiments, the compound of formula (III) has the structure

Or a salt thereof, as described elsewhere herein.

In step 1, a reaction mixture comprising a compound of formula (XII), B and an organic solvent is reacted to form a compound of formula (XIII). In one embodiment, the organic solvent is a non-polar solvent or a polar solvent. In one embodiment, the solvent is non-polar. Non-limiting examples of suitable solvents include pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1, 4-dioxane, chloroform, diethyl ether, DCM, and combinations thereof. In one embodiment, the solvent is DCM. In some embodiments, the concentration of B in the solvent may suitably be about 10g/L, about 25g/L, about 50g/L, about 75g/L, about 100g/L, about 125g/L, about 150g/L, about 175g/L, or about 200g/L and up to a concentration near saturation at the reaction temperature, and ranges established by these concentrations, such as from about 25g/L to about 125 g/L. The equivalent ratio of B to the compound of formula (XII) is about 0.75:1, about 0.9:1, about 1:1, about 1.25:1, about 1.5:1, about 1.75:1 or about 2:1, and ranges thereof, such as from about 1.25:1 to about 1.75: 1. The reaction mixture of step 1 may further comprise a suitable alkylating agent. Non-limiting examples of alkylating agents include alkyl lithium (e.g., methyllithium) and organic magnesium halide compounds such as methyl magnesium chloride (e.g., in THF). The equivalent ratio of B to alkylating agent is suitably about 0.75:1, about 0.8:1, about 0.85:1, about 0.9:1, about 0.95:1, about 1:1, about 1.05:1, about 1.1:1, about 1.15:2, about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1 or higher, and ranges constructed therefrom, such as from about 1.1 to about 1.3: 1. In one embodiment, the reaction mixture further comprises an alkylation catalyst. In some such embodiments, the catalyst is a transition metal catalyst. In some such embodiments, the transition metal is copper. In a particular embodiment, the catalyst is suitably a transition metal halide, such as a copper (I) halide (e.g., CuCl). In one embodiment, the reaction temperature is about 25 ℃, about 20 ℃, about 15 ℃, about 10 ℃, about 5 ℃, about 0 ℃, about-5 ℃, about-10 ℃, about-15 ℃, about-20 ℃, about-25 ℃, about-30 ℃, about-35 ℃, about-40 ℃, about-45 ℃, or about-50 ℃, and ranges constructed therefrom, such as from about-20 ℃ to about 0 ℃. In one embodiment, the reaction time is not critical, and the reaction is typically continued until the conversion of B and the compound of formula (XII) to the compound of formula (XIII) is substantially complete as determined by chromatography (e.g., TLC, GC, or HPLC).

After the reaction is complete, the reaction can be quenched, such as by addition of an aqueous acid solution. In one embodiment, the acid may be an organic acid as described elsewhere herein, one non-limiting example of which is citric acid. The organic phase comprising the compound of formula (XIII) may then be worked up to dry the compound. In some such embodiments, the quenched reaction product mixture can be separated into an aqueous phase and an organic phase comprising the compound of formula (XIII). The aqueous phase may be washed one or more times with an organic solvent, such as the solvent used to form the reaction mixture (e.g., two washes, each with one volume of solvent compared to the volume of the reaction mixture). The organic phases can be combined and washed one or more times with brine (e.g., two washes with one volume of brine per volume of reaction mixture). The washed organic phase can then be combined with activated carbon and a solid desiccant (e.g., Na) with agitation₂SO₄). Any activated carbon and solid desiccant can be removed by filtration or centrifugation. Any collected solid may then optionally be washed with additional solvent to recover the compound of formula (XIII) therefrom.

In one embodiment, a solution of the compound of formula (XIII) may be used as the starting material for step 2. In one embodiment, a solid compound of formula (XIII) may be prepared. In such embodiments, the collected solution of the compound of formula (XIII) in the organic solvent may be concentrated under partial vacuum to form a crude compound of formula (XIII). Alternatively, a solid compound of formula (XIII) may be precipitated/crystallized from solution by addition of an anti-solvent such as a non-polar solvent (e.g. 2 volumes of heptane compared to the volume of solvent in the reaction mixture). The solids can be collected by filtration or centrifugation and the collected solids can be washed with an anti-solvent. The solid may be dried under partial vacuum at a temperature below 40 ℃ to provide the finished product of the compound of formula (XIII). The yield of compound of formula (XIII) based on compound (XII) is typically at least 50%, at least 55%, at least 60%, or at least 65%. Purity is at least 90%, at least 95%, at least 98% or at least 99% according to HPLC (area percentage).

In some step 1 embodiments, compound B, the metal catalyst, and the alkylating agent are combined in a first volume of solvent at the reaction temperature indicated above. The volume of solvent is suitably from about 30% to about 80% of the total volume of solvent used in step 1. Thereafter, a solution of the compound of formula (XII) in the remaining solvent is added at the reaction temperature over a period of time to form a reaction mixture. The reaction mixture is then maintained at a temperature and for a time to substantially complete formation of the compound of formula (XIII), and then the solution of the compound of formula (XIII) or the dried compound of formula (XIII) is quenched and worked up.

In step 2, the compound of formula (XIII) is deprotected to form the compound of formula (III). In any of the various embodiments, a solution of the compound of formula (XIII) is deprotected, suitably by addition of an acid. In one embodiment, the solid compound of formula (XIII) is dissolved in a polar protic solvent (such as methanol, ethanol or isopropanol) as described elsewhere herein. The concentration of the compound of formula (XIII) in the solvent is about 25g/L, about 50g/L, about 75g/L, about 100g/L, about 125g/L, about 150g/L, about 175g/L, or about 200g/L, and ranges constructed therefrom, such as from about 50g/L to about 150 g/L. The temperature of addition of the acid is not strictly limited.

In some step 2 embodiments, the acid is an inorganic acid as described elsewhere herein. One non-limiting example of a suitable mineral acid is HCl. In one embodiment, the equivalent ratio of acid to compound of formula (XIII) is about 1.5:1, about 2.5:1, about 5:1, about 7.5:1, about 10:1, about 12.5:1, or about 15:1, and ranges constructed therefrom, such as about 5:1 to about 15: 1. After addition of the acid, the solution is kept at a temperature with stirring until the deprotection of the compound of formula (XIII) to form the compound of formula (III) is substantially complete. In one embodiment, a solvent exchange may be performed from a polar protic solvent to a non-polar solvent (as described elsewhere herein) or a polar aprotic solvent (as described elsewhere herein). In some such embodiments, a solution of the compound of formula (III) may be concentrated under partial vacuum and extracted with a non-polar or polar aprotic solvent. In some such embodiments, the extraction solvent is DCM. After extraction, the pH of the aqueous phase can be adjusted to strongly basic (i.e., above pH 11) with a suitable base such as aqueous sodium hydroxide. After basification, the aqueous phase may then be further extracted at least once with an extraction solvent. The organic phase or phases may then be dried, such as with brine and/or with a solid desiccant, and then filtered to remove any solids. The collected solids may optionally be washed to recover additional compound of formula (III). The solid compound can be isolated from the solution in the organic solvent by methods known in the art. For example, the solution can be concentrated to dryness under partial vacuum. Alternatively, the solution may be concentrated and then the anti-solvent added to form solid compound (III), which may be collected by filtration or centrifugation, washed and dried. The yield of compound of formula (III) based on compound (XIII) is typically at least 85%, at least 90%, at least 95%, or at least 97%. Purity is at least 90%, at least 95%, or at least 96% according to HPLC (area percent).

In some other step 2 embodiments, the acid is an organic acid as described elsewhere herein. Non-limiting examples of suitable organic acids include sulfonic acid and camphorsulfonic acid (CSA) (e.g., L- (-) -CSA). In the case of CSA, the equivalent ratio of CSA to compound of formula (XIII) is about 1.5:1, about 2:1, about 2.5:1, about 5:1, about 7.5:1, or about 10:1, and ranges constructed therefrom, such as from about 2:1 to about 4: 1. After addition of the acid, the solution may be heated with stirring and maintained at an elevated temperature (e.g., about 35 ℃ to about 60 ℃) to complete deprotection and form a salt of the compound of formula (XIII). The acid salt solution/suspension may then be cooled, e.g., to below about 5 ℃, to form a suspension of the acid salt of the compound of formula (XIII). The salt can be collected by filtration or centrifugation and optionally washed with a solvent. The salt can then be dried under partial vacuum to yield a solid salt of the compound of formula (XIII), such as an L- (-) -CSA salt thereof. The salt yield of the compound of formula (III) based on the compound of formula (XIIII) is typically at least 85%, at least 90%, at least 92% or at least 95%. Purity is at least 90%, at least 95%, at least 96%, or at least 97% according to HPLC (area percentage). The salt of the compound of formula (XIII) may be dissolved in water and the pH adjusted to above 13, e.g. about 14, with a strong base to form a suspension comprising a solid free base of the compound of formula (III). The solid material may be collected by filtration or centrifugation and optionally washed with chilled water. The solid may then be dried under partial vacuum to yield the dried free base of the compound of formula (III). The yield of compound of formula (III) based on compound (XIII) is typically at least 80%, at least 85%, or at least 90%. Purity is at least 90%, at least 95%, at least 96%, or at least 97% according to HPLC (area percentage).

In one embodiment, the compound of formula (VIII) as prepared herein is further recrystallized. In one embodiment, the recrystallization comprises recrystallizing the compound of formula (VIII) in a two-step process. The process comprises heating a slurry comprising a compound of formula (VIII) in a methanol/ethanol mixture, distilling with methanol, and cooling the mixture. In one embodiment, the methanol/ethanol mixture is a 95:5, 90:10, 85:15, or 80:20 methanol/ethanol mixture. In another embodiment, the ethanol/methanol mixture is a 90:10 mixture of methanol/ethanol. The mixture can be heated at a temperature > about 50 ℃, for example, about 55 ℃, 60 ℃, or 65 ℃. Cooling may be reduced to about room temperature. In one embodiment, cooling is to about 20 ℃, 25 ℃, or 30 ℃. The solution may be filtered and dried.

In another embodiment, the recrystallization comprises recrystallizing the compound of formula (VIII) from MTBE. To the slurry containing the compound of formula (VIII) in MTBE is added a base such as NaOH or KOH. The mixture is stirred, optionally filtered and distilled with ethanol, for example at 15 ℃, 20 ℃, 25 ℃ or 30 ℃.

In some embodiments of the process for preparing a compound of formula (III) or a salt thereof, the process further comprises preparing a compound of formula (XII) or a salt thereof.

The process for the preparation of the compound of formula (XII) comprises the reaction steps 3a and 3b depicted below:

(1) reacting a reaction mixture comprising a compound of formula (XIV), thionyl chloride and an organic solvent according to the following step 3a to form a compound of formula (XV)

And

(2) reacting a reaction mixture comprising a compound of formula (XV), a catalyst, an oxidant and an organic solvent according to the following step 3b to form a compound of formula (XII)

R^2a、R^2b、R^3a、R^3bAnd nitrogen protecting group PG is as defined herein.

In step 3a, a reaction mixture comprising a compound of formula (XIV), thionyl chloride and an organic solvent is reacted to form a compound of formula (XV). In one embodiment, the organic solvent is a non-polar solvent or a polar solvent as described elsewhere herein. In one embodiment, the solvent is non-polar as described elsewhere herein. Non-limiting examples of suitable solvents include pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1, 4-dioxane, chloroform, diethyl ether, DCM, and combinations thereof. In some particular embodiments, the solvent is DCM. In one embodiment, the concentration of the compound of formula (XIV) in the solvent may suitably be about 10g/L, about 25g/L, about 50g/L, about 75g/L, about 100g/L, about 125g/L, about 150g/L, about 175g/L, or about 200g/L and up to a concentration near saturation at the reaction temperature, and ranges established by these concentrations, such as from about 25g/L to about 125 g/L. The equivalent ratio of thionyl chloride to compound of formula (XIV) is about 1:1, about 1.25:1, about 1.5:1, about 1.75:1, about 2:1, about 2.25:1, or about 2.5:1, and ranges thereof, such as from about 1.25:1 to about 1.75: 1. In one embodiment, the reaction temperature is about 10 ℃, about 5 ℃, about 0 ℃, about-5 ℃, or about-10 ℃, and ranges constructed therefrom, such as from about-5 ℃ to about 5 ℃. In one embodiment, the reaction time is not strictly limited, and the reaction generally continues until the conversion of the compound of formula (XIV) is substantially complete as determined by chromatography (e.g., TLC, GC, or HPLC). The reaction mixture of step 3a may further comprise a base, one non-limiting example of which is imidazole. In such embodiments, the equivalent ratio of the thiolating agent to thionyl chloride may be about 1:1, about 2:1, about 3:1, or about 4: 1. The reaction mixture of step 3a may further comprise a base, such as an organic base as described elsewhere herein. In some such embodiments, the base can be TEA. In such embodiments, the equivalent ratio of base to compound of formula (XIV) is about 1.25:1, about 1.5:1, about 1.75:1, about 2:1, about 2.25:1, about 2.5:1, about 3:1, about 3.5:1, or about 4:1, and ranges constructed therefrom, such as from about 1.5:1 to about 2.5: 1.

In some particular step 3a embodiments, a solution of a base (e.g., imidazole) in a solvent is formed, to which thionyl chloride is added with stirring while maintaining the reaction temperature. The compound of formula (XIV) in the solvent may then be added with stirring while maintaining the reaction temperature, followed by the addition of the base with stirring while maintaining the reaction temperature. The reaction mixture is then maintained at the reaction temperature with stirring until the conversion of the compound of formula (XIV) to form a reaction product mixture comprising the compound of formula (XV) is substantially complete.

In any of the various step 3a embodiments, the reaction product mixture may be worked up by methods known to those skilled in the art. For example, the reaction mixture of step 3a can be quenched with chilled water (e.g., 0.25 to 2 volumes of water per volume of organic solvent in the reaction product mixture of step 3 a). The organic phase comprising the compound of formula (XV) in solution can be separated off and the separated aqueous phase can be extracted with an organic solvent to recover further compound of formula (XV). The organic phases may be combined and washed with aqueous acid, aqueous base and brine. One non-limiting example of an aqueous acid solution is a solution of a weak acid such as citric acid. One non-limiting example of a base solution is a solution of a weak base such as sodium bicarbonate.

In step 3b, the reaction mixture comprising formula (XV) in solution in an organic solvent is combined with a catalyst and an oxidant and reacted to form a reaction product mixture comprising a compound of formula (XII). In one embodiment, the catalyst is a redox active metal catalyst as described elsewhere herein. Non-limiting examples of suitable catalysts include NiCl₂、RuCl₃、CoCl₂、FeCl₃、FeCl₂And MnCl₂. Non-limiting examples of suitable oxidizing agents include NaIO₄NaOCl and Oxone. In some embodiments, the reaction mixture further comprises water. The volume ratio of water to organic solvent is suitably about 0.25:1, about 0.5:1, about 0.75:1, about 1:1, about 1.25:1, about 1.50:1, about 1.75:1, about 2:1, or about 2.5:1, and ranges constructed therefrom, such as about 0.5:1 to about 1.5: 1. The reaction temperature is suitably from about 5 ℃ to about 50 ℃. The reaction mixture is maintained at the reaction temperature with stirring until the conversion of the compound of formula (XV) to form a reaction product mixture comprising the compound of formula (XII) is substantially complete as determined by chromatography (e.g., TLC, GC, or HPLC).

The reaction product mixture of step 3b can be worked up by methods known to the person skilled in the art. For example, the organic phase comprising the compound of formula (XII) in solution may be separated and the aqueous phase optionally filtered, and then extracted with an organic solvent to recover the compound of formula (XII). The one or more organic phases may optionally be washed with a reducing agent (e.g., sodium thiosulfate) and with brine. The organic phase or phases may be dried with a solid drying agent (e.g., sodium sulfate) and then filtered to remove solids and optionally washed with an organic solvent. The solid compound of formula (XII) is isolated from the solution in organic solvent by methods known in the art. For example, the solution can be concentrated to dryness under partial vacuum. Alternatively, the solution may be concentrated, and then an antisolvent is added to form solid compound (XII), which may be collected by filtration or centrifugation, washed, and dried. The yield of the compound of formula (XII) based on compound (XIV) is typically at least 85%, at least 90%, or at least 92%. Purity is at least 95%, at least 98%, or at least 99% according to HPLC (area percent).

Stereospecific transaminases can be used to produce chiral primary amines via asymmetric transamination of prochiral ketones or kinetic resolution of racemic amines. Transamination is a reaction equilibrium consisting of a pair of amines and ketones (donor and acceptor) and the reaction conditions applied shift this equilibrium towards the chiral target amine. In one such aspect, the amine donor is alanine or 2-propylamine. In one embodiment, the amine acceptor is pyruvate or acetone.

Accordingly, also provided herein is a process for preparing a compound of formula (XX), or a salt thereof, wherein the conversion of a chiral tryptamine comprises the use of an enzymatic conversion:

the method of preparing the compound of formula (XX) comprises reacting a compound of formula (XXI)

Contacting with a protein transaminase to form a compound of formula (3):

the method further comprises the presence of one or more amine donors. In one embodiment, the amine donor is alanine or isopropylamine.

The contacting described above can be carried out in a mixed aqueous organic solvent system. For example, the transaminase reaction can be carried out in an aqueous buffer with an organic cosolvent such as cyclohexane, methylcyclohexane, isooctane, DMSO, acetonitrile or acetone. Such co-solvents may be present at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, or 50 vol/vol%.

In some cases, the mixed organic/aqueous solvent system (micro-aqueous reaction system) may comprise one or more organic solvents that comprise a small amount of an aqueous buffer. In one embodiment, the contacting is carried out in TBME, dibutyl ether, CPME, toluene, ethyl acetate, butyl acetate, isopropyl acetate, butyl butyrate, ethyl butyrate, or isobutyl acetate comprising less than 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 vol/vol% of an aqueous buffer. When carried out in an organic solvent, the transaminase can be immobilized to a solid support.

In another embodiment, the conversion of compound (XXI) to compound (3) is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% or more. In another aspect, the conversion is above 90%. In another embodiment, the conversion is above 95%.

The reductive amination performed by the transaminase can result in a compound of formula (3) with at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% Enantiomeric Excess (EE). In some cases, the transaminase converts a compound of formula (XXI) to (3) with greater than 99% EE.

In one embodiment, the asymmetric transamination of a compound of formula (XXI) is performed using the following scheme:

contacting a compound of formula (3) with a compound of formula (II) as described herein:

to form a compound of formula (XX).

R^1a、R^1bAnd n is as described elsewhere herein. In one embodiment of the method of the present invention,R^1aand R^1bIndependently fluorine.

In one embodiment, the compound of formula (XX) has the structure:

the protein transaminase can be selected from table 6. In one such aspect, the transaminase is (R) -selective. In one embodiment, the transaminase is TA-P2-A01. In one embodiment, the protein transaminase is a (S) -enantioselective transaminase selected from the group consisting of SEQ ID NO 1, SEQ ID NO 2, SEQ ID NO 3 and SEQ ID NO 4.

Also provided herein are methods for enzymatically synthesizing a compound of formula (3) by kinetic resolution of a racemic amine in the presence of an amine acceptor and a transaminase. The reaction may be carried out under conditions as described herein, for example in a mixed aqueous/organic solvent system as described herein. In one such aspect, the reaction is carried out in an aqueous buffer comprising acetonitrile. Such kinetic resolution can produce the compound of formula (3) with at least 99% EE, requiring more than 50% conversion. Kinetic resolution includes kinetic resolution using a (S) -selective transaminase as described herein. In one embodiment, the transaminase is selected from table 6.

One embodiment of the present disclosure relates to compounds of formula (XVI):

R⁴、s、R¹⁰g and p are as defined herein.

R^7a、R^7b、R^8aAnd R^8bEach independently of the others is hydrogen, halogen, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Hydroxyalkyl or-CN. In one embodiment, R^7a、R^7b、R^8aAnd R^8bIn each case independently of one another are hydrogen, fluorine, -CH₃or-CN. In one embodimentIn the formula, R^7a、R^7b、R^8aAnd R^8bEach is hydrogen.

y is an integer of 1 or 2, x is an integer of 1 or 2, and the sum of x and y is 2 or 3.

M is C_1-5An alkyl group;

r is 0 or 1; and

R⁹is halogen or-CN.

In one embodiment, M is-CH₂CH₂CH₂-, p is 1, R⁹Is fluorine.

In one embodiment, M is-CH₂CH₂CH₂-, p is 1, R⁹is-CN.

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

or a salt thereof.

In a particular embodiment, the compound of formula (XVI) is:

in another aspect, provided herein is a compound having the structure:

in another aspect, provided herein is a process for preparing a compound having the formula:

wherein the process is as set forth in scheme a below and is carried out in accordance with embodiments provided herein.

Scheme A:

BrettPhos Pd G3 ═ palladium (II) methanesulfonate [ (2-bis-cyclohexylphosphino-3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) -2- (2 '-amino-1, 1' -biphenyl ]

In another embodiment, the disclosure is a method of making a compound having the formula:

wherein the process is as set forth in scheme B below and is carried out in accordance with the embodiments provided herein.

Scheme B:

the above synthetic process of compound B (e.g., schemes a and B) may further include recrystallization according to scheme C or D below:

scheme C:

scheme D:

in one embodiment, compounds (3) and (4) as described herein and provided in schemes a and B and optionally scheme C or D above are synthesized as in scheme E below and according to embodiments provided herein.

Scheme E:

also provided herein is a process for preparing a compound of formula (XXIII):

or a salt thereof.

B、R^1a、R^1b、n、R^2a、R^2b、R^3a、R^3b、J、R⁴、s、G、R⁵、v、R⁶E and asterisks are as defined herein.

In one embodiment, the compound of formula (XXIII) is an acid salt. In such embodiments, the compound of formula (VIII) is a salt of an acid. In a preferred embodiment, the compound of formula (XXIII) is a salt of tartaric acid. In some embodiments, the compound of formula (XXIII) is a salt of fumaric acid.

In one embodiment, the compound of formula (XXIII) has any one of the following structures or is a tartrate salt thereof:

In another embodiment, the above compound is a fumarate salt.

In one embodiment, the compound of formula (XXIII) has the following structure, or is a pharmaceutically acceptable salt thereof:

the process for the preparation of the compound of formula (XXIII) comprises two reaction steps as depicted below:

LG is as defined herein.

The variables of formulae (IV), (V), and (VI) are as described herein.

In one embodiment, the compound of formula (XXIV) has any one of the following structures or is a salt thereof:

one embodiment of the present disclosure relates to a process for preparing a compound of formula (XXIII) or a salt thereof, wherein the compound of formula (XXIII) is as described herein. A method of preparing a compound of formula (XXIII) according to the present disclosure includes reaction step 1 as depicted below:

B、R^1a、R^1b、n、R^2a、R^2b、R^3a、R^3b、R⁴、s、J、R⁵、v、R⁶g, p, E and asterisks are each as described elsewhere herein. The CHO moiety and the nitrogen atom linking J and G are in para position on J relative to each other.

In some embodiments, the compound of formula (XXIV) is:

or a salt thereof.

One embodiment of the present disclosure relates to a method for preparing a compound of formula (XXVII) or a salt thereof.

The process for the preparation of the compound of formula (XXVII) comprises two reaction steps as depicted below:

R⁴、s、LG、R⁵、v、R⁶G, p, E and PG are as described herein.

Also provided herein are solid forms of compound a, including pharmaceutically acceptable salts thereof, named 3- ((1R,3R) -1- (2, 6-difluoro-4- ((1- (3-fluoropropyl) azetidin-3-yl) amino) phenyl) -3-methyl-1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b ] indol-2-yl) -2, 2-difluoropropan-1-ol, formulations comprising such solid forms, and methods of using such solid forms:

in one embodiment, provided herein is a solid form of compound a. Compound a may be a free base as described herein in the form of an amorphous solid. In another embodiment, compound a is a crystalline solid as described herein. In another embodiment, compound a is a crystalline tartrate salt having the structure:

in another aspect, provided herein is a crystalline solid form of compound a as the fumarate salt, having the structure:

in another aspect, provided herein is a compound a malonate solid form having the structure:

the solid forms described herein may be crystalline. In another embodiment, the solid form is a one-component solid form. The solid forms described herein may be solvates, hydrates, anhydrates or salts as set forth herein. In one embodiment, the solid form described herein comprises a tartrate salt. In another embodiment, the solid form described herein comprises an anhydrate of compound B. In another embodiment, the solid form described herein comprises a fumarate salt. In yet another embodiment, the solid forms described herein comprise phosphate or other salts.

While not intending to be bound by any particular theory, solid forms may be characterized by physical properties such as, for example, stability, solubility and dissolution rate, density, compressibility, hardness, morphology, lysis, viscosity, solubility, water uptake, electrical properties, thermal behavior, solid state reactivity, physical stability, and chemical stability that affect the particular processes (e.g., yield, filtration, washing, drying, milling, mixing, tableting, flowability, dissolution, formulation, and lyophilization) that make certain solid forms suitable for manufacturing solid dosage forms. Such properties can be determined using specific analytical chemistry techniques, including solid state analysis techniques as described herein (e.g., X-ray diffraction, microscopy, spectroscopy, and thermal analysis).

Solid forms described herein, including salt forms, crystalline forms, and amorphous solids, can be characterized by a variety of methods, including, for example, single crystal X-ray diffraction, X-ray powder diffraction (XRPD), microscopy (e.g., Scanning Electron Microscopy (SEM)), thermal analysis (e.g., Differential Scanning Calorimetry (DSC), dynamic gas adsorption (DVS), thermogravimetric analysis (TGA), and hot stage microscopy), spectroscopy (e.g., infrared, raman, and solid state nuclear magnetic resonance), Ultra High Performance Liquid Chromatography (UHPLC), proton nuclear magnetic resonance spectroscopy.

Techniques for characterizing crystalline forms and amorphous solids include, for example, thermogravimetric analysis (TGA), Differential Scanning Calorimetry (DSC), X-ray powder diffraction (XRPD), single crystal X-ray diffraction, vibrational spectroscopy (e.g., Infrared (IR) and Raman spectroscopy), solid-state and solution Nuclear Magnetic Resonance (NMR) spectroscopy (including¹H NMR and F NMR), Scanning Electron Microscopy (SEM), electron crystallography and quantitation, Particle Size Analysis (PSA), surface area analysis, solubility studies, and dissolution studies.

The purity of the solid forms provided herein can be determined by standard analytical methods such as Thin Layer Chromatography (TLC), gel electrophoresis, gas chromatography, Ultra High Performance Liquid Chromatography (UHPLC), and Mass Spectrometry (MS).

Compound B form a:

in certain embodiments, provided herein is a solid form of compound B referred to as form a. Form a is a crystalline solid form of compound B. In one embodiment, form a is an acetone solvate of compound B. In one embodiment, form a is the crystalline acetone solvate tartrate salt of compound a.

In another embodiment, form a of compound B is obtained by slurrying in acetone, followed by evaporation. Form a can be prepared according to the methods and examples described herein.

In one embodiment, the solid form provided herein (e.g., form a) is the tartrate salt of compound a (i.e., compound B) and is crystalline as indicated by X-ray powder diffraction pattern (XRPD) measurements. In one embodiment, the XRPD of the solid form (e.g., form a) provided herein is substantially as shown in figure 1. In another embodiment, the solid form provided herein (e.g., form a) has one or more characteristic XRPD peaks at about 4.64, 8.26, 9.28, 11.18, 11.49, 11.96, 12.54, 13.77, 14.22, 14.61, 15.09, 15.56, 16.01, 17.35, 18.55, 18.84, 19.32, 19.82, 20.26, 21.34, 21.63, 21.92, 22.52, 22.97, 23.28, 23.54, 23.94, 24.81, or 25.96 ± 0.1 ° 2 Θ, as depicted, for example, in fig. 1 and as can be seen in table 16 herein. In yet another embodiment, a solid form provided herein (e.g., form a) has at least 3, at least 5, at least 7, or at least 10 XPRD peaks at about 4.64, 8.26, 9.28, 11.18, 11.49, 11.96, 12.54, 13.77, 14.22, 14.61, 15.09, 15.56, 16.01, 17.35, 18.55, 18.84, 19.32, 19.82, 20.26, 21.34, 21.63, 21.92, 22.52, 22.97, 23.28, 23.54, 23.94, 24.81, or 25.96 ± 0.1 ° 2 Θ, as depicted, for example, in fig. 1 and as can be seen in table 16 herein. In yet another embodiment, the solid form described herein (e.g., form a) has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty or all of the characteristic XRPD peaks as set forth in table 16.

In yet another embodiment, the solid form provided herein (e.g., form a) has one, two, three, four, five, six, seven, eight, nine, or ten characteristic XRPD peaks at about 12.54, 14.61, 16.01, 19.32, 20.26, 21.63, 23.28, 23.54, 23.94, or 24.81 ± 0.1 ° 2 Θ, as depicted, for example, in fig. 1 and as seen in table 16 herein. In another embodiment, the solid form provided herein (e.g., form a) has one, two, three, four, or five characteristic XRPD peaks at about 19.32, 20.26, 21.63, 23.28, or 24.81 ± 0.1 ° 2 Θ, as depicted, for example, in fig. 1 and as seen in table 16 herein. In another embodiment, the solid form provided herein (e.g., form a) has one, two, three, four, or five characteristic XRPD peaks at about 19.32, 20.26, 21.63, 23.28, or 24.81 ± 0.05 ° 2 Θ, as depicted, for example, in fig. 1 and as seen in table 16 herein.

In one embodiment, described herein is a solid form, such as form a, having a TGA thermogram substantially corresponding to the representative TGA thermogram as depicted in figure 2. In certain embodiments, the crystalline form exhibits a TGA thermogram with a total mass loss of about 7.2% of the total mass of the sample before about 125 ℃.

In another embodiment, described herein is a solid form, such as form a, having a DSC thermogram substantially as depicted in figure 2, including a desolvation event at about 124 ℃ and a melting temperature with an onset temperature of about 164 ℃ and a peak maximum temperature of about 171 ℃.

In another embodiment, described herein is a solid form, such as form a, having a polarized light microimage as depicted in fig. 3.

In yet another embodiment, form a is pure. In certain embodiments, pure form a is substantially free of other solid forms, e.g., amorphous solids. In certain embodiments, form a has a purity of no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about 99.9%.

Compound B form B:

in certain embodiments, provided herein is a solid form of compound B referred to as form B. Form B is a crystalline solid form of compound B. In one embodiment, form B is an anhydrate of compound B. In another embodiment, form B is the anhydrous tartrate salt of compound a.

In one embodiment, form B of compound B is obtained by slurrying compound B in ethyl acetate at room temperature for about 24 hours. In another embodiment, form B of compound B is obtained by slurrying compound B in acetone, water (e.g., 90:10, 95:5, 96:4, 97:3, 99:1 (vol/vol)) at about 50 ℃ for about 6 hours. In yet another embodiment, form B of compound B is obtained by slurrying compound B in ethanol.

In some cases, form B of compound B is obtained by slurrying compound B in a solvent system comprising 95% acetone or more (e.g., 95:5 acetone: water or more). Form B of compound B is then isolated from the slurry by, for example, centrifugation or filtration. In another embodiment, form B of compound B is obtained from form a or form F as described herein. In one embodiment, form a of compound B is reslurried in ethanol (e.g., 100% ethanol) for 10, 12, 16, or 24 hours (e.g., overnight) to obtain form B. In one embodiment, form F is converted to form D as described herein in the presence of water. The mixture can then be slurried in either pure ethanol (at, for example, about 50 ℃) or 95:5 or 97:3 acetone to water (vol/vol) to form B. The mixture may optionally be seeded with crystals in form B.

Form B can be prepared according to the methods and examples described herein. Accordingly, provided herein is a method of making form B, wherein the method comprises slurrying compound B in a solvent system comprising acetone or an aqueous mixture of acetone and water (e.g., 50%, 90%, 95%, 96%, 97%, 98%, and 99% (v/v) acetone). In one embodiment, the solvent system used to crystallize form B comprises 95% acetone or more. In one embodiment, the solvent system for form B comprises 96:4 acetone to water. The mixture can be slurried at room temperature for about 120 hours. The mixture can be filtered and analyzed as described herein (e.g., XRPD). In one embodiment, form B is prepared according to the methods and/or examples set forth herein.

In one embodiment, the solid form provided herein (e.g., form B) is the tartrate salt of compound a and is crystalline as indicated by X-ray powder diffraction pattern (XRPD) measurements. In one embodiment, the XRPD of the solid form (e.g., form B) provided herein is substantially as shown in figure 4. In another embodiment, the solid form provided herein (e.g., form B) has one or more characteristic XRPD peaks at about 7.68, 11.49, 12.54, 14.24, 15.30, 15.55, 16.01, 16.63, 17.37, 18.24, 19.16, 19.42, 19.89, 20.24, 21.81, 22.52, 22.99, 23.25, 23.57, 24.67, 25.07, 25.91 ± 0.1 ° 2 Θ, as depicted, for example, in fig. 4 and as can be seen in table 17 herein. In yet another embodiment, the solid form provided herein (e.g., form B) has at least 3, at least 5, at least 7, or at least 10 characteristic XPRD peaks at about 7.68, 11.49, 12.54, 14.24, 15.30, 15.55, 16.01, 16.63, 17.37, 18.24, 19.16, 19.42, 19.89, 20.24, 21.81, 22.52, 22.99, 23.25, 23.57, 24.67, 25.07, 25.91 ± 0.1 ° 2 Θ, as depicted, for example, in fig. 4 and as seen in table 17 herein. In yet another embodiment, the solid form described herein (e.g., form B) has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or all of the characteristic XRPD peaks as set forth in table 17.

In yet another embodiment, the solid form provided herein (e.g., form B) has one, two, three, four, five, six, seven, eight, nine, or ten characteristic XRPD peaks at about 11.49, 12.54, 15.30, 15.55, 19.16, 19.42, 20.24, 23.25, 24.67, or 25.91 ± 0.1 ° 2 Θ, as depicted, for example, in fig. 4. In yet another embodiment, the solid form provided herein (e.g., form B) has one, two, three, four, or five characteristic XRPD peaks at about 11.49, 12.54, 19.16, 19.42, or 24.67 ± 0.1 ° 2 Θ, as depicted, for example, in fig. 4. In yet another embodiment, the solid form provided herein (e.g., form B) has one, two, three, four, or five characteristic XRPD peaks at about 11.49, 12.54, 19.16, 19.42, or 24.67 ± 0.05 ° 2 Θ, as depicted, for example, in fig. 4.

In one embodiment, described herein is a solid form, such as form B, having a TGA thermogram substantially corresponding to the representative TGA thermogram as depicted in figure 5. In certain embodiments, the crystalline form exhibits a TGA thermogram with a total mass loss of about 3.5% of the total mass of the sample.

In another embodiment, described herein is a solid form, e.g., form B, having a DSC thermogram substantially as depicted in figure 5, including an endothermic event with an onset temperature of about 171 ℃ and a peak maximum temperature of about 179 ℃.

In another embodiment, described herein is a solid form, such as form B, having a structure substantially as depicted in fig. 6 and 7, respectively¹³C and¹⁹f NMR spectrum.

In another embodiment, described herein is a solid form, such as form B, having a water absorption-desorption profile as depicted in fig. 8. Solid forms of compound B, such as form B, absorb about 1.2% (weight/weight) of moisture at up to 90% Relative Humidity (RH) and at about 25 ℃.

In another embodiment, described herein is a solid form, such as form B, having a Scanning Electron Microscope (SEM) image and a PLM image as depicted in fig. 9a and 9B, respectively. The sample contained dense spherical aggregates.

In another embodiment, described herein is a solid form, e.g., form B, having a Particle Size Distribution (PSD) as depicted in fig. 9 c.

In yet another embodiment, the solid form (e.g., form B) remains substantially unchanged after compression as described herein. FIGS. 22, 23 and 24 show XRPD, XRPD of form B of Compound B, ¹⁹F SSNMR and DSC and compare compounds before and after compression as described herein.

In yet another embodiment, form B is substantially pure. In certain embodiments, pure form B is substantially free of other solid forms, e.g., amorphous solids. In certain embodiments, substantially pure form B is substantially free of form a, form D, or form F. In certain embodiments, form B has a purity of no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about 99.9%.

Compound B form C:

in certain embodiments, provided herein is a solid form of compound B referred to as form C. Form C is a crystalline solid form of compound B. In one embodiment, form C is a THF solvate of compound B.

In one embodiment, form C of compound B is obtained by slurrying compound B in THF. The mixture may then be filtered. Form C can be prepared according to the methods and examples described herein.

In one embodiment, the solid form provided herein (e.g., form C) is the tartrate salt of compound a and is substantially crystalline as indicated by X-ray powder diffraction pattern (XRPD) measurements. In one embodiment, the XRPD is substantially as shown in figure 10.

In one embodiment, described herein is a solid form, such as form C, having a TGA thermogram substantially corresponding to the representative TGA thermogram as depicted in figure 11. In certain embodiments, the crystalline form exhibits a TGA thermogram with a total mass loss of about 6.8% of the total mass of the sample.

In another embodiment, described herein is a solid form, e.g., form C, having a DSC thermogram substantially as depicted in figure 11, including an endothermic event with an onset temperature of about 118 ℃ and a peak maximum temperature of about 125 ℃.

In yet another embodiment, form C is pure. In certain embodiments, form C has a purity of no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about 99.9%.

Compound B form D:

in certain embodiments, provided herein is a solid form of compound B, referred to as form D. Form D is a crystalline solid form of compound B. In one embodiment, form D is a hydrate of compound B. In another embodiment, form D is a monohydrate of compound B.

In one embodiment, form D of compound B is obtained by slurrying compound B in 100% ethanol for about 48 hours. The mixture may then be filtered.

In one embodiment, the solid form provided herein (e.g., form D) is the tartrate salt of compound a and is substantially crystalline as indicated by X-ray powder diffraction pattern (XRPD) measurements. In another embodiment, form D is a hydrate of compound B. In one embodiment, the XRPD of the solid form (e.g., form D) provided herein is substantially as shown in figure 12. In another embodiment, the solid form provided herein (e.g., form D) has one or more characteristic XRPD peaks at about 7.32, 10.99, 11.31, 12.18, 13.23, 13.48, 14.11, 14.66, 15.14, 15.70, 16.03, 16.21, 16.54, 17.24, 17.63, 18.11, 18.34, 19.10, 20.20, 20.58, 21.16, 21.47, 21.89, 22.76, 23.33, or 23.56 ± 0.1 ° 2 Θ, as depicted, for example, in fig. 12 and as seen in table 19. In yet another embodiment, the solid form provided herein (e.g., form D) has at least 3, at least 5, at least 7, or at least 10 characteristic XRPD peaks at approximately 7.32, 10.99, 11.31, 12.18, 13.23, 13.48, 14.11, 14.66, 15.14, 15.70, 16.03, 16.21, 16.54, 17.24, 17.63, 18.11, 18.34, 19.10, 20.20, 20.58, 21.16, 21.47, 21.89, 22.76, 23.33, or 23.56 ± 0.1 ° 2 Θ, as depicted in, e.g., fig. 12 and as can be seen in table 19. In yet another embodiment, the solid forms described herein have one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or all of the characteristic XRPD peaks as set forth in table 19.

In yet another embodiment, the solid form provided herein (e.g., form D) has one, two, three, four, five, six, seven, eight, nine, or ten characteristic XRPD peaks at about 11.31, 15.70, 16.54, 19.10, 20.58, 21.16, 21.47, 21.89, 22.76, or 23.33 ± 0.1 ° 2 Θ, as depicted, for example, in fig. 12. In yet another embodiment, the solid form provided herein (e.g., form D) has one, two, three, four, or five characteristic XRPD peaks at about 11.31, 15.70, 16.54, 19.10, or 22.76 ± 0.1 ° 2 Θ, as depicted, for example, in fig. 12. In yet another embodiment, the solid form provided herein (e.g., form D) has one, two, three, four, or five characteristic XRPD peaks at about 11.31, 15.70, 16.54, 19.10, or 22.76 ± 0.05 ° 2 Θ, as depicted, for example, in fig. 12.

In one embodiment, described herein is a solid form, such as form D, having a TGA thermogram substantially corresponding to the representative TGA thermogram as depicted in figure 13. In certain embodiments, the crystalline form exhibits a TGA thermogram with a total mass loss of about 1.4% of the total mass of the sample before about 150 ℃.

In another embodiment, described herein is a solid form, e.g., form D, having a DSC thermogram substantially as depicted in figure 13, including an endothermic event with an onset temperature of about 55 ℃ and a peak maximum temperature of about 82 ℃ followed by a second endothermic event with an onset temperature of about 165 ℃ and a peak maximum temperature of about 172 ℃.

In yet another embodiment, form D is pure. In certain embodiments, form D is substantially free of other solid forms, e.g., amorphous solids. In certain embodiments, form D is substantially free of form a, form B, or form F. In certain embodiments, form D has a purity of no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about 99.9%.

Compound B form E:

in certain embodiments, provided herein is a solid form of compound B referred to as form E. Form E is a solid form of compound B. In one embodiment, form E is a DMSO solvate of compound B.

In one embodiment, form E of compound B is obtained by slurrying compound B in DMSO and adding IPAc for about 24 hours. The mixture may then be filtered. Form E can be prepared according to the methods and examples described herein.

In one embodiment, the solid form provided herein (e.g., form E) is the tartrate salt of compound a and is substantially crystalline as indicated by X-ray powder diffraction pattern (XRPD) measurements. In one embodiment, the XRPD is substantially as shown in figure 14.

In one embodiment, described herein is a solid form, such as form E, having a TGA thermogram substantially corresponding to the representative TGA thermogram as depicted in figure 15. In certain embodiments, the crystalline form exhibits a TGA thermogram with a total mass loss of about 8.3% of the total mass of the sample.

In another embodiment, described herein is a solid form, e.g., form E, having a DSC thermogram substantially as depicted in figure 15, including a first endotherm having an onset temperature of about 126 ℃ and a peak maximum temperature of about 134 ℃ and a second endotherm having an onset temperature of about 143 ℃ and a peak maximum temperature of about 147 ℃.

In yet another embodiment, form E is pure. In certain embodiments, form E is substantially free of other solid forms, e.g., amorphous solids. In certain embodiments, form E has a purity of no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about 99.9%.

Compound B form F:

in certain embodiments, provided herein is a solid form of compound B, referred to as form F. Form F is a crystalline solid form of compound B. In one embodiment, form F is an anhydrate of compound B. In another embodiment, form F is the anhydrous tartrate salt of compound a.

In one embodiment, form F of compound B is obtained by slurrying compound B in 100% ethanol at room temperature or at 50 ℃ for about 8, 10, 12, 15, 20, or 25 hours (e.g., overnight). In another embodiment, form F is obtained by slurrying compound B in ethanol/water (e.g., 65:35 (vol/vol)). Obtaining a slurry of compound B of form F can optionally include seeding with form B as described herein. The slurry can then be filtered to obtain form F. Form F can also be obtained by slurrying in 100% DI water, 1:1 acetone/water, or 100% acetone at room temperature. A slurry of form F in pure solvent can be maintained at room temperature. In one embodiment, form F can be obtained from a 1:1 acetone-water mixture stirred at 5 ℃. In yet another embodiment, form F can be obtained by slurrying compound B in a 95:5 acetone: water and 97:3 acetone: water mixture at 50 ℃ for about 2 hours and cooling to room temperature. Form F can be prepared according to the methods and examples described herein.

In one embodiment, the solid form provided herein (e.g., form F) is the tartrate salt of compound a and is substantially crystalline as indicated by X-ray powder diffraction pattern (XRPD) measurements. In one embodiment, the XRPD of the solid form (e.g., form F) provided herein is substantially as shown in figure 16. In another embodiment, the solid form provided herein (e.g., form F) has one or more characteristic XRPD peaks at about 3.92, 10.54, 11.72, 12.52, 14.22, 15.40, 15.54, 15.90, 16.48, 16.84, 17.29, 18.26, 18.47, 19.39, 19.66, 20.00, 20.50, 20.65, 21.16, 21.28, 21.95, 22.97, 23.49, 23.70, 23.94, 24.31, 24.67, or 24.99 ± 0.1 ° 2 Θ, as depicted, for example, in fig. 16 and as can be seen in table 20 herein. In yet another embodiment, the solid form provided herein (e.g., form F) has at least 3, at least 5, at least 7, or at least 10 characteristic XPRD peaks at about 3.92, 10.54, 11.72, 12.52, 14.22, 15.40, 15.54, 15.90, 16.48, 16.84, 17.29, 18.26, 18.47, 19.39, 19.66, 20.00, 20.50, 20.65, 21.16, 21.28, 21.95, 22.97, 23.49, 23.70, 23.94, 24.31, 24.67, or 24.99 ± 0.1 ° 2 Θ, as depicted, e.g., in fig. 16 and as can be seen in table 20 herein. In yet another embodiment, the solid form described herein (e.g., form F) has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, twenty-five, or all of the characteristic XRPD peaks as set forth in table 20.

In yet another embodiment, the solid form provided herein (e.g., form F) has one, two, three, four, five, six, seven, eight, nine, or ten characteristic XRPD peaks at about 12.52, 15.90, 19.66, 20.65, or 24.99 ± 0.1 ° 2 Θ, as depicted, for example, in fig. 16. In yet another embodiment, the solid form provided herein (e.g., form F) has one, two, three, four, or five characteristic XRPD peaks at about 12.52, 15.90, 19.66, 20.65, or 24.99 ± 0.1 ° 2 Θ, as depicted, for example, in fig. 16. In yet another embodiment, the solid form provided herein (e.g., form F) has one, two, three, four, or five characteristic XRPD peaks at about 12.52, 15.90, 19.66, 20.65, or 24.99 ± 0.05 ° 2 Θ, as depicted, for example, in fig. 16.

In one embodiment, described herein is a solid form, e.g., form F, having a DSV isotherm plot substantially corresponding to the representative DVS isotherm plot as depicted in fig. 17.

In another embodiment, described herein is a solid form, e.g., form F, having a DSC thermogram substantially as depicted in figure 18, including an endothermic event with an onset temperature of about 162 ℃ and a peak maximum temperature of about 167 ℃.

In yet another embodiment, form F is pure. In certain embodiments, pure form F is substantially free of other solid forms, e.g., amorphous solids. In certain embodiments, form F is not less than about 95% pure, not less than about 96% pure, not less than about 97% pure, not less than about 98% pure, not less than about 98.5% pure, not less than about 99% pure, not less than about 99.5% pure, or not less than about 99.9% pure.

Compound B form G

In certain embodiments, provided herein is a solid form of compound B referred to as form G. Form G is a solid form of compound B. In one embodiment, form G is a methanol solvate of compound B. In another embodiment, form F is the methanol solvate tartrate salt of compound a.

In one embodiment, form G of compound B is obtained by slurrying compound B in methanol and slowly evaporating the methanol. The mixture may be filtered. Form G can be prepared according to the methods and examples described herein.

In one embodiment, the solid form provided herein (e.g., form G) is the tartrate salt of compound a and is substantially crystalline as indicated by X-ray powder diffraction pattern (XRPD) measurements. In one embodiment, the XRPD of a solid form (e.g., form G) provided herein is substantially as shown in figure 19. In another embodiment, a solid form provided herein (e.g., form G) has one or more characteristic XRPD peaks at about 7.65, 11.46, 12.51, 15.27, 15.51, 16.00, 17.34, 18.21, 19.11, 19.29, 19.42, 19.84, 20.23, 21.31, 21.57, 21.79, 22.49, 22.97, 23.22, 24.65, 25.04, or 25.88 ± 0.1 ° 2 Θ, as depicted, for example, in fig. 19 and as can be seen in table 21 herein. In yet another embodiment, a solid form provided herein (e.g., form G) has at least 3, at least 5, at least 7, or at least 10 characteristic XPRD peaks at about 7.65, 11.46, 12.51, 15.27, 15.51, 16.00, 17.34, 18.21, 19.11, 19.29, 19.42, 19.84, 20.23, 21.31, 21.57, 21.79, 22.49, 22.97, 23.22, 24.65, 25.04, or 25.88 ± 0.1 ° 2 Θ, as depicted, for example, in fig. 19 and as seen in table 21 herein. In yet another embodiment, the solid form provided herein (e.g., form G) has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, twenty, or all of the characteristic XRPD peaks as set forth in table 21.

In yet another embodiment, the solid form provided herein (e.g., form G) has one, two, three, four, five, six, seven, eight, nine, or ten characteristic XRPD peaks at about 11.46, 12.51, 15.27, 16.00, 19.29, 19.42, 20.23, 22.49, 22.97, or 24.65 ± 0.1 ° 2 Θ, as depicted, for example, in fig. 19. In yet another embodiment, the solid form provided herein (e.g., form G) has one, two, three, four, or five characteristic XRPD peaks at about 11.46, 12.51, 19.29, 19.42, or 20.23 ± 0.1 ° 2 Θ, as depicted, for example, in fig. 19. In yet another embodiment, the solid form provided herein (e.g., form G) has one, two, three, four, or five characteristic XRPD peaks at about 11.46, 12.51, 19.29, 19.42, or 20.23 ± 0.05 ° 2 Θ, as depicted, for example, in fig. 19.

In one embodiment, described herein is a solid form, such as form G, having a TGA thermogram substantially corresponding to the representative TGA thermogram as depicted in figure 20. In certain embodiments, the crystalline form exhibits a TGA thermogram with a total mass loss of about 2% of the total mass of the sample.

In another embodiment, described herein is a solid form, e.g., form G, having a DSC thermogram substantially as depicted in figure 20, including an endothermic event with an onset temperature of about 173 ℃ and a peak maximum temperature of about 178 ℃.

In yet another embodiment, form G is pure. In certain embodiments, pure form G is substantially free of other solid forms, e.g., amorphous solids. In certain embodiments, pure form G is substantially free of form B, form D, or form E. In certain embodiments, form G is not less than about 95% pure, not less than about 96% pure, not less than about 97% pure, not less than about 98% pure, not less than about 98.5% pure, not less than about 99% pure, not less than about 99.5% pure, or not less than about 99.9% pure.

Compound C form 1

In certain embodiments, provided herein is a solid form, designated form 1, of compound C. Form 1 is a crystalline solid form of compound C.

In one embodiment, form 1 of compound C is obtained by slurrying compound C in isoamyl alcohol/water at a ratio of about 3:1 at about 55 ℃ for about 1.5 hours. The liquid of the mixture was then evaporated under a stream of nitrogen and reduced pressure. In another embodiment, form 1 of compound C is obtained by slurrying compound C in ethanol/heptane at room temperature in a ratio of about 3: 8. In yet another embodiment, form 1 of compound C is obtained by slurrying compound C in ethanol/heptane at room temperature in a ratio of about 1: 1. Form 1 can be prepared according to the methods and examples described herein.

In one embodiment, the solid form provided herein (e.g., form 1) is the fumarate salt of compound a and is substantially crystalline as indicated by X-ray powder diffraction pattern (XRPD) measurements. In one embodiment, the XRPD is substantially as shown in figure 27 a. In another embodiment, the solid form provided herein (e.g., form 1) has one or more characteristic XRPD peaks at about 7.58, 10.59, 11.44, 11.84, 12.5, 14.44, 15.45, 15.78, 16.09, 17.55, 18.92, 19.69, 19.86, 20.23, 21.35, 22.04, 23.16, 23.89, 24.23, 24.67, 25.23, or 25.93 ± 0.1 ° 2 Θ, as depicted, for example, in fig. 27a and as can be seen in table 36 herein. In yet another embodiment, the solid form provided herein (e.g., form 1) has at least 3, at least 5, at least 7, or at least 10 characteristic XPRD peaks at about 7.58, 10.59, 11.44, 11.84, 12.5, 14.44, 15.45, 15.78, 16.09, 17.55, 18.92, 19.69, 19.86, 20.23, 21.35, 22.04, 23.16, 23.89, 24.23, 24.67, 25.23, or 25.93 ± 0.1 ° 2 Θ, as depicted, for example, in fig. 27a and as seen in table 36 herein. In yet another embodiment, the solid form described herein (e.g., form 1) has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, twenty or all of the characteristic XRPD peaks as set forth in table 36.

In yet another embodiment, the solid form provided herein (e.g., form 1) has one, two, three, four, five, six, seven, eight, nine, or ten characteristic XRPD peaks at about 10.59, 15.45, 15.78, 16.09, 18.92, 19.69, 19.86, 21.35, 23.16, or 24.23 ± 0.1 ° 2 Θ, as depicted, for example, in fig. 27 a. In yet another embodiment, the solid form provided herein (e.g., form 1) has one, two, three, four, or five characteristic XRPD peaks at about 16.09, 18.92, 19.69, 19.86, or 23.16 ± 0.1 ° 2 Θ, as depicted, for example, in fig. 27 a. In yet another embodiment, the solid form provided herein (e.g., form 1) has one, two, three, four, or five characteristic XRPD peaks at about 16.09, 18.92, 19.69, 19.86, or 23.16 ± 0.05 ° 2 Θ, as depicted, for example, in fig. 27 a.

In one embodiment, described herein is a solid form, e.g., form 1, having a TGA thermogram substantially corresponding to the representative TGA thermogram as depicted in figure 28. In certain embodiments, the crystalline form exhibits a TGA thermogram with a total mass loss of about 2% of the total mass of the sample.

In another embodiment, described herein is a solid form, e.g., form 1, having a DSC thermogram substantially as depicted in figure 28, including an endothermic event with an onset temperature of about 167 ℃ and a peak maximum temperature of about 172 ℃.

In yet another embodiment, form 1 is pure. In certain embodiments, pure form 1 is substantially free of other solid forms, e.g., amorphous solids. In certain embodiments, form 1 has a purity of no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about 99.9%.

In another embodiment, described herein is a solid form, such as form 1, having a PLM image as depicted in fig. 29.

Compound C form 2

In certain embodiments, provided herein is a solid form, designated form 2, of compound C. Form 2 is a crystalline solid form of compound C.

In one embodiment, the solid form provided herein (e.g., form 2) is the fumarate salt of compound a and is substantially crystalline as indicated by X-ray powder diffraction pattern (XRPD) measurements. In one embodiment, the XRPD is substantially as shown in figure 27 b. In another embodiment, the solid form provided herein (e.g., form 2) has one or more characteristic XRPD peaks at about 11.52, 11.87, 15.55, 16.04, 16.51, 17.32, 18.36, 19.00, 19.43, 19.87, 20.24, 21.35, 22.03, 23.23, 23.91, 25.43, or 26.03 ± 0.1 ° 2 Θ, as depicted, for example, in fig. 27b and as can be seen in table 37 herein. In yet another embodiment, a solid form provided herein (e.g., form 2) has at least 3, at least 5, at least 7, or at least 10 characteristic XPRD peaks at about 11.52, 11.87, 15.55, 16.04, 16.51, 17.32, 18.36, 19.00, 19.43, 19.87, 20.24, 21.35, 22.03, 23.23, 23.91, 25.43, or 26.03 ± 0.1 ° 2 Θ, as depicted, for example, in fig. 27b and as seen in table 37 herein. In yet another embodiment, the solid form described herein (e.g., form 1) has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or all of the characteristic XRPD peaks as described in table 37 herein.

In yet another embodiment, the solid form provided herein (e.g., form 1) has one, two, three, four, five, six, seven, eight, nine, or ten characteristic XRPD peaks at about 11.87, 15.55, 16.04, 16.51, 17.32, 19.43, 19.87, 20.24, 23.23, or 23.91 ± 0.1 ° 2 Θ, as depicted, for example, in fig. 27 b. In yet another embodiment, the solid form provided herein (e.g., form 1) has one, two, three, four, or five characteristic XRPD peaks at about 15.55, 19.43, 19.87, 20.24, or 23.23 ± 0.1 ° 2 Θ, as depicted, for example, in fig. 27 b. In yet another embodiment, the solid form provided herein (e.g., form 1) has one, two, three, four, or five characteristic XRPD peaks at about 15.55, 19.43, 19.87, 20.24, or 23.23 ± 0.05 ° 2 Θ, as depicted, for example, in fig. 27 b.

Amorphous form of free base compound A

In certain embodiments, provided herein is an amorphous solid form of free base compound a.

In one embodiment, is an amorphous solid form of the free base compound a, as indicated by X-ray powder diffraction pattern (XRPD) measurements. In one embodiment, the XRPD is substantially as shown in figure 32.

In one embodiment, described herein is an amorphous solid form of free base compound a having a TGA thermogram substantially corresponding to the representative TGA and DSC thermogram as depicted in figure 33. In certain embodiments, the amorphous form exhibits a TGA thermogram with a total mass loss of about 9.3% of the total mass of the sample.

In yet another embodiment, the amorphous solid form of compound a is pure. In certain embodiments, the pure amorphous solid form of compound a is substantially free of other solid forms, e.g., crystalline solids as described herein. In certain embodiments, the purity is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 98.5%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

Pharmaceutical composition

The compounds described herein can be administered, for example, orally, intramuscularly, subcutaneously, intravenously, intradermally, transdermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostaticaly, intrapleurally, intratracheally, intrathecally, intranasally, intravaginally, intrarectally, topically, intratumorally, intraperitoneally, subconjunctival, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularly, intraorbitally, intravitreally (e.g., by intravitreal injection), by eye drops, topically, transdermally, parenterally, by inhalation, by injection, by implantation, by infusion, by local infusion directly into target cells, by catheter, by lavage, in a cream, or in a lipid composition. The compounds described herein may be formulated in pharmaceutical compositions suitable for oral administration as provided herein. In another embodiment, the compounds described herein may be administered intramuscularly.

In one embodiment, the compounds described herein are administered as a pharmaceutical composition capable of oral or parenteral administration to a subject. Pharmaceutical compositions of the compounds described herein can be prepared in oral dosage forms such as, for example, capsules, microcapsules, tablets (coated and uncoated), granules, powders, pills, or suppositories. The compounds described herein may be formulated for topical or parenteral use, wherein the compounds are dissolved or otherwise suspended in a solution suitable for injection, suspension, syrup, cream, ointment, gel, spray, solution, and emulsion.

The pharmaceutical compositions described herein comprise one or more pharmaceutically acceptable excipients, such as, but not limited to: sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or carbonate, cellulose, methylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, hydroxypropyl starch, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol (PEG), starch, sodium bicarbonate, calcium citrate, magnesium stearate, sodium lauryl sulfate, sodium benzoate, sodium bisulfite, methyl paraben, propyl paraben, citric acid, sodium citrate or acetic acid, polyvinylpyrrolidone, aluminum stearate), water, and cocoa butter. The use of such excipients as, for example, diluents, binders, lubricants, and disintegrants is well known in the art.

The pharmaceutical compositions described herein comprise an effective amount of a compound described herein (e.g., compound a, compound B, compound C, compound D, or solid forms thereof). The dosage of a compound described herein can be a measure of the particular amount of the compound (e.g., a standard dosage amount) or can be determined based on, for example, the weight of the patient. In one embodiment, a compound described herein is administered in an amount equivalent to about 0.1, 0.5, 0.75, 1, 2, 3, 4, 5, 10, 15, 20, 30, 50, 75, 100, 200, or 250 mg/kg. In another embodiment, a compound described herein is administered in an amount of about 0.1mg/kg to about 1mg/kg, about 0.5mg/kg to about 2mg/kg, about 1mg/kg to about 5mg/kg, about 3mg/kg to about 10mg/kg, about 8mg/kg to about 15mg/kg, or about 15mg/kg to about 30 mg/kg. In yet another embodiment, a compound described herein is administered in an amount of less than about 100mg/kg, less than about 50mg/kg, less than about 30mg/kg, less than about 10mg/kg, or less than about 1 mg/kg.

In one embodiment, a compound described herein is administered in an amount of about 1, 5, 10, 20, 25, 30, 50, 60, 75, 90, 100, 120, 150, or 250 mg. In another embodiment, a compound described herein is administered in an amount of about 10 mg. In yet another embodiment, a compound described herein is administered in an amount of about 30 mg. In yet another embodiment, a compound described herein is administered in an amount of about 90 mg. In one embodiment, a pharmaceutical composition comprising a compound described herein is administered once daily (QD) in the amounts specified above. The compound may be compound B or a solid form thereof (e.g., form a, form B, form C, form D, form E, form F, or form G). In another embodiment, the compound is a solid form of compound B (e.g., form B, form D, or form F). In one embodiment, the compound is compound C or compound C form 1 or form 2. In another embodiment, the compound is compound D or a solid form described herein.

In another embodiment, a compound described herein is administered in an amount of about 1mg to about 10mg, about 10mg to about 30mg, about 10mg to about 90mg, about 30mg to about 90mg, or about 90mg to about 250 mg. In one embodiment, the compound administered is compound B in an amount of about 1, 10, 30, 50, 90, 100, or 150 mg. The dosage of the compounds described herein may be provided in a single dose (e.g., a single tablet or capsule of a given dosage amount) or in multiple doses administered over a period of time (e.g., 2 or more tablets or capsules equivalent to the dosage amount). The compound can be compound B or a solid form thereof (e.g., form a, form B, form C, form D, form E, form F, or form G). In another embodiment, the compound is a solid form of compound B (e.g., form B, form D, or form F). In one embodiment, the compound is compound C or compound C form 1 or form 2. In another embodiment, the compound is compound D or a solid form described herein.

The pharmaceutical compositions described herein may be administered once daily (QD), twice daily (BID), three times daily (TID), every other day (Q2D), every third day (Q3D), or once weekly. Furthermore, doses of the pharmaceutical compositions provided herein comprising a compound described herein can be administered before (ac), after (pc), or at the time of consumption. In one embodiment, the compound described herein is QD administered for a treatment period (the period of time for which the drug is administered to a patient described herein) followed by a rest period (the period of time for which the drug is not administered to a patient described herein). The rest period may include administration of an anti-cancer agent other than the compounds described herein. In one embodiment, the compounds described herein are formulated for oral administration and QD administration as provided herein for 20-28 days, followed by a rest period of 3-10 days. In another embodiment, the compound is administered QD with no rest period.

Preferably, the compounds described herein are formulated for oral administration. Oral administration can promote patient compliance with a compound (e.g., formulated as a pharmaceutical composition), thereby improving compliance and efficacy. Oral pharmaceutical compositions comprising the compounds described herein include, but are not limited to, tablets (e.g., coated, uncoated and chewable) and capsules (e.g., hard gelatin capsules, soft gelatin capsules, enteric-coated capsules and sustained release capsules). Tablets may be prepared by direct compression, by wet granulation or by dry granulation. Oral pharmaceutical compositions comprising the compounds described herein may be formulated as understood in the art for delayed or extended release. In one embodiment, compound B or a solid form described herein (e.g., form B, form D, or form F) is formulated as a tablet or capsule for oral administration in the amounts set forth herein.

Also provided herein are compounds having the formula:

compounds M1, M2, M3 and M4 may be considered metabolites and/or degradants of compound B (including the solid forms described herein). In certain instances, such compounds may be found in compositions described herein, wherein such compositions have been stored for a given time at a Relative Humidity (RH) of about 50%, 55%, 60%, 65%, 70%, 75%, 80%, or higher. Such compounds may also be found at elevated temperatures of about 30 ℃, 35 ℃, 40 ℃, 45 ℃ or about 50 ℃. In one embodiment, compound M1, M2, M3, or M4 is present in a composition described herein, wherein the composition comprises less than about 30mg of compound B or a solid form thereof. In certain instances, such compounds are present in a composition, wherein the composition comprises an uncoated tablet as described herein.

In certain embodiments, a composition described herein comprising compound B or a solid form of compound B described herein (e.g., form a, form B, form C, form D, form E, form F, or form G) comprises less than 0.01%, 0.02%, 0.03%, 0.04, 0.05, 0.1, 0.15, 0.75, 0.2, 0.225, 0.25, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1% (weight/weight) of one or more of M1, M2, M3, or M4. In one embodiment, the compositions described herein comprise less than about 0.5% (weight/weight) of one or more of M1, M2, M3, or M4.

Methods of treating cancer

The compounds and solid forms described herein can be administered in an effective amount (e.g., an amount as described herein) to treat cancer. It is to be understood that the methods described herein further include treatment with a pharmaceutical composition as described herein comprising a compound described herein (e.g., compound B or a solid form thereof) and one or more pharmaceutically acceptable excipients.

In one embodiment, provided herein is a method of treating cancer by administering to a patient having cancer an effective amount of compound B as described herein. In one embodiment, compound B is in a solid form (e.g., form a, form B, form C, form D, form E, form F, or form G) as described herein.

In another aspect provided herein, compound B form a can be administered as described herein to treat a patient having cancer as set forth herein.

In another aspect provided herein, compound B form B can be administered as described herein to treat a patient having cancer as set forth herein.

In another aspect provided herein, compound B form C can be administered as described herein to treat a patient having cancer as set forth herein.

In another aspect provided herein, compound B form D can be administered as described herein to treat a patient having cancer as set forth herein.

In another aspect provided herein, compound B form E can be administered as described herein to treat a patient having cancer as set forth herein.

In another aspect provided herein, compound B form F can be administered as described herein to treat a patient having cancer as set forth herein.

In another aspect provided herein, compound B form G may be administered as described herein to treat a patient having lung, ovarian, endometrial, prostate, uterine, or breast cancer as set forth herein.

In another aspect provided herein, an amorphous, amorphous form of compound a or compound B can be administered as described herein to treat a patient having lung, ovarian, endometrial, prostate, uterine, or breast cancer as set forth herein.

In another aspect, provided herein is a method of treating lung, ovarian, endometrial, prostate, uterine or breast cancer by administering to a patient suffering from said cancer an effective amount of compound B or a solid form as described herein. In one embodiment, the cancer is ovarian or endometrial cancer. In one embodiment, the cancer is breast cancer. In one embodiment of such a method, compound B is in a solid form (e.g., form a, form B, form C, form D, form E, form F, or form G) as described herein.

In yet another aspect, compound B form a may be administered as described herein to treat a patient having lung cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, or breast cancer as set forth herein.

In yet another aspect, compound B form B may be administered as described herein to treat a patient having lung, ovarian, endometrial, prostate, uterine, or breast cancer as set forth herein.

In yet another aspect, compound B form C may be administered as described herein to treat a patient having lung, ovarian, endometrial, prostate, uterine, or breast cancer as set forth herein.

In yet another aspect, compound B form D may be administered as described herein to treat a patient having lung, ovarian, endometrial, prostate, uterine, or breast cancer as set forth herein.

In yet another aspect, compound B form E may be administered as described herein to treat a patient having lung, ovarian, endometrial, prostate, uterine, or breast cancer as set forth herein.

In yet another aspect, compound B form F may be administered as described herein to treat a patient having lung, ovarian, endometrial, prostate, uterine, or breast cancer as set forth herein.

In yet another aspect, compound B form G may be administered as described herein to treat a patient having lung, ovarian, endometrial, prostate, uterine, or breast cancer as set forth herein.

In yet another aspect, an amorphous, amorphous form of compound a or compound B can be administered as described herein to treat a patient having lung, ovarian, endometrial, prostate, uterine, or breast cancer as set forth herein.

Also provided herein are methods of treating breast cancer in a patient having breast cancer by administering an effective amount of compound B or a solid form of compound B as described herein. In one embodiment, is a method of treating breast cancer in such a patient by administering an effective amount of a solid form of compound B as described herein. In one embodiment, the method comprises treating breast cancer in a patient suffering from breast cancer by administering to the patient an effective amount of compound B, form B, as described herein. In one embodiment, the method comprises treating breast cancer in a patient having breast cancer by administering to the patient an effective amount of pure compound B (e.g., substantially free of other solid forms described herein, e.g., substantially free of form D and/or form F). In another aspect, the method comprises treating breast cancer in a patient suffering from breast cancer by administering to the patient an effective amount of compound B form D as described herein. In another aspect, the method comprises treating breast cancer in a patient suffering from breast cancer by administering to the patient an effective amount of compound B form F as described herein. In yet another aspect, the method comprises treating breast cancer in a patient suffering from breast cancer by administering to the patient an effective amount of compound B form a as described herein. In yet another aspect, the method comprises treating breast cancer in a patient suffering from breast cancer by administering to the patient an effective amount of compound B form C as described herein. In yet another aspect, the method comprises treating breast cancer in a patient suffering from breast cancer by administering to the patient an effective amount of compound B form E as described herein. In yet another aspect, the method comprises treating breast cancer in a patient suffering from breast cancer by administering to the patient an effective amount of compound B form G as described herein. In yet another aspect, the method comprises treating breast cancer in a patient suffering from breast cancer by administering to the patient an effective amount of an amorphous, amorphous form of compound B as described herein.

The compounds described herein (e.g., compound B or a solid form thereof as described herein) can be used in the manufacture of a medicament for treating breast cancer as described herein.

The methods of treating breast cancer provided herein include treatments in which the breast cancer can be hormone receptor positive breast cancer (e.g., ER + breast cancer), HER 2-positive breast cancer, HER 2-negative breast cancer, or Triple Negative Breast Cancer (TNBC).

In one embodiment, the breast cancer is HER 2-negative breast cancer. HER 2-negative breast cancer may be defined herein as, for example, HER2 IHC score of 0 or 1+, or IHC score of 2+ and negative fluorescence, color or silver in situ hybridization assays indicating the absence of HER 2-gene amplification, or HER2/CEP17 ratio < 2.0, or local clinical guidelines. In one embodiment, the breast cancer is ER +/HER 2-breast cancer. As understood in the art, breast cancer may be stage 0, I, II, III, or IV.

In another embodiment, the breast cancer is locally advanced or metastatic breast cancer (mBC).

In one embodiment, compound B or a solid form thereof (e.g., form B, form D, or form F) can be administered as a component of adjuvant therapy. In another embodiment, compound B or a solid form thereof (e.g., form B, form D, or form F) can be administered as a component of neoadjuvant therapy.

The breast cancer patients described herein can be pre-menopausal prior to treatment with a compound or solid form as described herein. The breast cancer patients described herein can be post-menopausal prior to treatment with a compound or solid as described herein.

The methods provided herein comprise administering to a patient an effective amount of compound B or a solid form as described herein in an amount as set forth herein. An effective amount may be, for example, an amount of about 10mg, 30mg, 50mg, 90mg, 100mg, 125mg, or 250 mg. In one embodiment of the methods provided herein, compound B or a solid form described herein is administered orally. In one embodiment, compound B or a solid form thereof is administered in a tablet (e.g., a coated or uncoated tablet). In another embodiment, compound B or a solid form thereof is administered in a capsule. Accordingly, provided herein are compositions suitable for administration to a breast cancer patient, wherein such compositions comprise compound B or a solid form as described herein in an amount of about 10mg, 30mg, 50mg, 90mg, 100mg, 125mg, or 250mg in a tablet or capsule as set forth herein. When administered according to the methods provided herein, compound B or a solid form thereof can be pure as described herein.

The patient of the above method may have previously been treated with one or more anti-cancer agents or radiation therapy. For example, in one embodiment, the patient may have been previously treated with doxorubicin, pegylated liposomal doxorubicin, epirubicin, paclitaxel, albumin-bound paclitaxel, docetaxel, 5-fluorouracil, cyclophosphamide, cisplatin, carboplatin, vinorelbine, capecitabine, gemcitabine, ixabepilone, eribulin, olapanil, methotrexate, anastrozole, exemestane, toremifene, letrozole, tamoxifen, 4-hydroxytamoxifene, raloxifene, droloxifene, trovaxifene, keoxifene (keoxifene), ftutamide, nilutamide, bicalutamide, lapatinib, vinblastine, sertraline, leuprolide, pegfilgrastim, filgrastim, or venetokay (e.g., with 1L, 2L, 3L or more line therapy).

In another embodiment, the patient may have been previously treated with an AKT inhibitor, CDK4/6 inhibitor, PARP inhibitor, or aromatase inhibitor (e.g., with 1L, 2L, 3L, or more line therapy). In one embodiment, the AKT inhibitor is patatinib (GDC-0068). In one embodiment, the CDK4/6 inhibitor is bemaciclib, ribociclib, or palbociclib. In some cases, the patient may have previously used: (1) bemaciclib, ribociclib or palbociclib; (2) patatin; (3) everolimus or fulvestrant; (4) enritumumab, trastuzumab, pertuzumab or astuzumab; or (5) alemtuzumab, bevacizumab, cetuximab, panitumumab, rituximab, tositumomab, or a combination thereof. The patients described herein may have undergone surgery prior to treatment with compound B or a solid form thereof.

In another embodiment, the patient herein may be refractory to one or more anti-cancer therapies. For example, the patients herein may be refractory to aromatase inhibitors. In another example, the patient herein may be refractory to a Selective Estrogen Receptor Degrader (SERD) such as, for example, fulvestrant. In yet another example, the patient may be refractory to one or more endocrine therapies such as clomiphene, toremifene, raloxifene, norgestimate, bazedoxifene, bromparthenone, cyclofenib, lasofoxifene, oxybenzoxifene, acobiprofen, elacestrant, brilanestrant, oxyclomiphene, droloxifene, etastil, or ospemifene. In another embodiment, the patient may be refractory to bemaciclib, anastrozole, exemestane, fulvestrant, goserelin, letrozole, leuprolide, megestrol, palbociclib, tamoxifen, or toremifene. In another example, the patient may be refractory to treatment with emmetrotuzumab, trastuzumab, pertuzumab, astuzumab, pembrolizumab, Devolumab, avizumab, or nivolumab.

The compounds described herein may also be used in methods comprising inhibiting era in a patient. Such methods comprise administering to the patient an amount of a compound described herein (e.g., compound a or compound B, including solid forms thereof as described herein).

Combination therapy

The compounds and solid forms described herein may be administered in combination with one or more anti-cancer agents. As set forth herein, "administering in combination" includes sequential administration (in any order) as well as simultaneous administration of a compound described herein and one or more anti-cancer therapies. Accordingly, provided herein is a method of treating breast cancer in a patient suffering therefrom, such method comprising administering compound B or a solid form as described herein in combination with one or more additional anti-cancer therapies. In one embodiment, the anti-cancer therapy comprises doxorubicin, pegylated liposomal doxorubicin, epirubicin, paclitaxel, albumin-bound paclitaxel, docetaxel, 5-fluorouracil, cyclophosphamide, cisplatin, carboplatin, vinorelbine, capecitabine, gemcitabine, ixabepilone, eribulin, olaparinib, methotrexate, anastrozole, exemestane, toremifene, letrozole, tamoxifen, 4-hydroxytamoxifene, raloxifene, droloxifene, trovaxifene, keoxifene (keoxifene), ftutamide, nilutamide, bicalutamide, lapatinib, vinblastine, goserelin, leuprolide, pefilgrastim, filgrastim, or vinatork.

In one embodiment, provided herein is a pharmaceutical composition prepared by combining doxorubicin, pegylated liposomal doxorubicin, epirubicin, paclitaxel, albumin-bound paclitaxel, docetaxel, 5-fluorouracil, cyclophosphamide, cisplatin, carboplatin, vinorelbine, capecitabine, gemcitabine, ixabepilone, eribulin, olaparib, methotrexate, anastrozole, a method of treating breast cancer in a patient suffering from breast cancer by administering in combination exemestane, toremifene, letrozole, tamoxifen, 4-hydroxytamoxifene, raloxifene, droloxifene, troxifene, keoxifene, ftutamide, nilutamide, bicalutamide, lapatinib, vinblastine, goserelin, leuprorelin, pefilgrastim, filgrastim or venetock an effective amount of compound B or a solid form as described herein.

In another aspect, provided herein is a method of treating breast cancer in a patient suffering from breast cancer by administering an effective amount of compound B or a solid form as described herein in combination with paclitaxel, albumin-bound paclitaxel, methotrexate, anastrozole, exemestane, toremifene, letrozole, tamoxifen, 4-hydroxytamoxifene, raloxifene, droloxifene, troloxifene, keoxifene, or venetock. In yet another aspect, provided herein is a method of treating breast cancer in a patient suffering from breast cancer by administering an effective amount of compound B or a solid form as described herein in combination with fulvestrant, paclitaxel, albumin-bound paclitaxel, clomiphene, toremifene, raloxifene, norgestimate, bazedoxifene, bromphenyelene, cyclofenib, lasofoxifene, oxymetaxifene, acobiprofen, elaestrant, brilanestrant, oxyclomiphene, droloxifene, etastil, or ospemifene.

In yet another aspect, provided herein is a method of treating breast cancer in a patient having breast cancer by administering an effective amount of compound B or a solid form as described herein in combination with a CDK4/6 inhibitor, a PARP inhibitor or an aromatase inhibitor.

In a further aspect, provided herein is a method of treating breast cancer in a patient having breast cancer as described herein, wherein the method comprises administering an effective amount of compound B or a solid form as described herein in combination with a CDK4/6 inhibitor, wherein the CDK4/6 inhibitor is bemaciclib, ribociclib or palbociclib. In a preferred embodiment, the method comprises administering compound B or a solid form as described herein in combination with palbociclib. In yet another embodiment, the method comprises administering compound B or a solid form as described herein in combination with bemaciclib or ribociclib. In another aspect, provided herein is a kit comprising (i) a unit dosage form of compound B or a solid form thereof; (ii) a CDK4/6 inhibitor (e.g., palbociclib) in a second unit dosage form; and a container holding each dosage form.

The dose of bemaciclib may be 50mg to 500mg per day or 150mg to 450mg per day and may be administered daily in a 28 day cycle or less than 28 days per 28 day cycle such as 21 days per 28 day cycle or 14 days per 28 day cycle or 7 days per 28 day cycle. In one embodiment, when administered orally, the bmaxinib is administered once a day or preferably twice a day. In the case of twice daily administration, the doses may be separated by 4 hours, 8 hours, or 12 hours. In certain embodiments, the bemaciclib is administered orally at 150mg twice daily, wherein each dose is administered about 12 hours apart. In certain embodiments, the dose of bemaciclib is administered according to the pharmaceutical instructions.

The dose of ribociclib may be 200mg to 1,000mg per day or 250mg to 750mg per day and may be administered daily for a period of 28 days or less than 28 days per 28 day period such as 21 days per 28 day period or 14 days per 28 day period or 7 days per 28 day period. In one embodiment, when administered orally, the ribociclib is administered once a day. In certain embodiments, the dose of ribociclib is administered according to the instructions for the drug product.

The dose of palbociclib may be 25mg to 250mg daily or 50mg to 125mg daily or 75mg to 100mg daily or 125mg daily. Administration may be daily for a 28 day period or less than 28 days per 28 day period, such as 21 days per 28 day period or 14 days per 28 day period or 7 days per 28 day period. In one embodiment, upon oral administration, palbociclib is administered once a day. In certain embodiments, the dose of palbociclib is administered according to the instructions for the drug product.

In another aspect provided herein, the methods described herein comprise administering an effective amount of compound B or a solid form as described herein in combination with an Aromatase Inhibitor (AI), wherein AI is letrozole, anastrozole, exemestane, or testolactone.

In yet another aspect, provided herein is a method of treating breast cancer in a patient having breast cancer by administering an effective amount of compound B or a solid form as described herein in combination with cancer immunotherapy (e.g., an antibody). In one embodiment, compound B or a solid form as described herein is administered in combination with enrmetuzumab, trastuzumab, pertuzumab, astuzumab, pembrolizumab, tefluzumab, avizumab, or nivolumab, or a combination thereof. In one embodiment, compound B or a solid form as described herein is administered in combination with a cancer immunotherapy comprising a PD-1 or PD-L1 inhibitor, wherein the cancer immunotherapy is atuzumab, pembrolizumab, or nivolumab.

Administration of a compound described herein (e.g., compound B or a solid form as described herein) produces side effects (AE) characterized as grade 2 or lower in a patient. In one embodiment, a patient administered compound B or a solid form as described herein has an AE of grade 2 or less.

Example (b):

the following examples are given by way of illustration and not by way of limitation.

Synthesis of the compounds described herein. All reagents and solvents were purchased from commercial suppliers and used without additional purification. Anhydrous solvent (dichloromethane) was used. The commercial solvent was not further purified.

All reactions were carried out under nitrogen atmosphere in a screw-top vial equipped with a teflon septum.

Teledyne Isco Combiflash with preloaded RediSepRf Gold silica gel columns is used^(R)The Rf instrument performs flash column chromatography.

Unless otherwise indicated, the reported yields are for isolated material and corrected for residual solvent.

By passing¹H NMR、¹³One or more of C NMR, melting point, and HRMS and HPLC analysis characterize the compound (e.g., for confirmation of purity).

Recording on a Bruker 400MHz instrument at ambient temperature¹H and¹³c nuclear magnetic resonance spectroscopy. Unless otherwise indicated, all¹The H NMR spectra were both measured in parts per million (ppm) relative to the residual chloroform signal in deuterated solvents (7.26ppm) or dimethyl sulfoxide (2.50 ppm).¹H NMR data are reported below: chemical shift, multiplicity (br ═ broad letter)No. overlap, s ═ singlet, d ═ doublet, t ═ triplet, q ═ quartet, p ═ quintet, m ═ multiplet), coupling constants and integrals. Unless otherwise indicated, all ¹³C NMR spectra were reported in ppm relative to deuterated chloroform (77.06ppm) or deuterated dimethyl sulfoxide (39.53ppm) and taken at full¹H is obtained by decoupling. HPLC analysis was performed on an Agilent 1260 Infinity HPLC system with a 220nm UV detector using an Ace Super C18 column. Melting points were obtained using a Buchi B-540 melting point apparatus and were not corrected. High Resolution Mass Spectrometry (HRMS) data were obtained on a Thermo Scientific Orbitrap Fusion mass spectrometer.

Examples 1 to 3: and (4) alkylating the indole.

Indole alkylation was performed by the sequence of Boc protection (example 1), sulfonamide formation (example 2) and indole alkylation (example 3).

Example 1: boc protection

Example 1: boc protection general reaction scheme.

Boc protection was performed according to the following general reaction scheme, wherein R_AAnd R_BCorresponding to the various functional groups in the protection reaction of example 1 below, and wherein the asterisks indicate the chiral center:

example 1A: preparation of tert-butyl (S) - (2-hydroxy-1- (4-methoxyphenyl) ethyl) carbamate:

the above general reaction scheme 1 was carried out as follows. Boc was added to a slurry of (S) -2-amino-2- (4-methoxyphenyl) ethane-1-ol hydrochloride (1.04g,5.10mmol,100 mol%) in THF (4.4mL) at room temperature₂O(1.21mL,5.61mmol,110mol％)、NaHCO₃(451mg,5.10mmol,100 mol%) and water (4.4 mL). The solution was stirred at room temperature for 18 h and extracted with iPrOAc (20 mL. times.2). Organic layer is used Washed with brine (20mL), dried (Na)₂SO₄) Filtered and concentrated under reduced pressure to give the product without further purification. Example 1A yields reported are based on¹The residual solvent in H NMR was corrected. The reaction yielded tert-butyl (S) - (2-hydroxy-1- (4-methoxyphenyl) ethyl) carbamate as a white solid (1.36g, 100% yield). mp is 139.0 to 139.9 ℃; FTIR (purity, cm)^-1)3370,2984,2837,1681,1613,1512,1461；¹H NMR(400MHz,CDCl₃):δ7.24-7.20(m,2H),6.92-6.86(m,2H),5.10(d,J＝7.2Hz,1H),4.72(br,1H),3.82(t,J＝5.6Hz,2H),3.80(s,3H),2.35(br,1H),1.43(s,9H)；¹³C NMR(100MHz,CDCl₃):δ159.1,156.2,131.6,127.7,114.2,80.0,66.8,56.4,55.3,28.4。

Example 1B: preparation of (R) - (1-cyclopropyl-2-hydroxyethyl) carbamic acid tert-butyl ester:

the general reaction scheme as in example 1A above was followed with (R) -2-amino-2-cyclopropylethane-1-ol (1.16g,11.5mmol,100 mol%) to give tert-butyl (R) - (1-cyclopropyl-2-hydroxyethyl) carbamate as a white solid (2.31g, 100% yield). mp is 70.0-70.8 ℃; FTIR (purity, cm)^-1)3358,2974,2937,1682,1521,1366；¹H NMR(400MHz,CDCl₃):δ4.80(br,1H),3.80(ddd,J＝10.8,6.8,3.2Hz,1H),3.67(ddd,J＝10.8,6.0,4.8Hz,1H),2.94(dtd,J＝9.6,6.4,3.2Hz,1H),2.81(br,1H),1.45(s,9H),0.85(dtt,J＝9.6,8.0,4.8Hz,1H),0.60-0.47(m,2H),0.44–0.25(m,2H)；¹³C NMR(100MHz,CDCl₃):δ156.6,79.7,66.3,57.9,28.4,13.0,3.3,2.9。

Example 1C: preparation of tert-butyl ((1R,2S) -2-hydroxy-2, 3-dihydro-1H-inden-1-yl) carbamate:

with (1R,2S) -1-amino-2, 3-dihydro-1H-inden-2-ol (5.15g,34.5 m)mol,100 mol%) the general reaction scheme of example 1A above was followed to give tert-butyl ((1R,2S) -2-hydroxy-2, 3-dihydro-1H-inden-1-yl) carbamate as a white solid (8.61g, 100% yield). mp is 67.3-68.4 ℃; FTIR (purity, cm)^-1)3428,3350,2983,2933,1688,1509；¹H NMR(400MHz,CDCl₃):δ7.31-7.26(m,1H),7.26-7.18(m,3H),5.17(br,1H),5.05(br,1H),4.57(ddd,J＝7.2,4.8,2.0Hz,1H),3.12(dd,J＝16.8,5.2Hz,1H),2.91(dd,J＝16.8,2.4Hz,1H),2.31(d,J＝4.8Hz,1H),1.50(s,9H)；¹³C NMR(100MHz,CDCl₃):δ156.3,140.9,139.9,128.2,127.1,125.3,124.5,79.9,73.6,58.9,39.4,28.4。

Example 1D: preparation of (S) - (1- (3-fluorophenyl) -2-hydroxyethyl) carbamic acid tert-butyl ester:

The general reaction scheme as in example 1A above was followed with (S) -2-amino-2- (3-fluorophenyl) ethan-1-ol (1.36g,8.73mmol,100 mol%) to give tert-butyl (S) - (1- (3-fluorophenyl) -2-hydroxyethyl) carbamate as a white solid (2.23g, 100% yield). mp is 106.5-107.9 ℃; FTIR (purity, cm)^-1)3251,3059,2977,2901,1671,1587,1543；¹H NMR(400MHz,CDCl₃):δ7.33(ddd,J＝7.6,7.6,6.0Hz,1H),7.12-7.07(m,1H),7.05-6.95(m,2H),5.24(br,1H),4.77(br,1H),3.93-3.77(m,2H),2.02(br,1H),1.44(s,9H)；¹³C NMR(100MHz,CDCl₃):δ163.0(d,¹J_CF＝246Hz),156.0,142.5,130.2(d,³J_CF＝9Hz),122.2(d,⁴J_CF＝3Hz),114.5(d,²J_CF＝21Hz),113.6(d,²J_CF＝21Hz),80.2,66.2,56.3,28.3；¹⁹F NMR(CDCl₃,376MHz):δ-112.4。

Example 1E: preparation of (S) - (1- (3-fluorophenyl) -2-hydroxyethyl) carbamate

The general reaction scheme as in example 1A above was followed with (S) -2-amino-2- (3- (trifluoromethyl) phenyl) ethane-1-ol hydrochloride (1.00g,4.12mmol,100 mol%) to give (S) - (1- (3-fluorophenyl) -2-hydroxyethyl) carbamate as a white solid (1.26g, 100% yield). mp is 50.3-52.5 ℃; FTIR (purity, cm)^-1)3368,3254,2979,2939,1691,1510,1453,1333；¹H NMR(400MHz,CDCl₃):δ7.59-7.54(m,2H),7.53-7.45(m,2H),5.31(d,J＝6.4Hz,1H),4.83(br,1H),3.92(ddd,J＝11.2,6.8,4.0Hz,1H),3.88-3.79(m,1H),1.94(br,1H),1.43(s,9H)；¹³C NMR(100MHz,CDCl₃):δ156.1,141.1,130.9(q,²J_CF＝32Hz),130.1,129.0,124.3(q,³J_CF＝4Hz),124.1(q,¹J_CF＝270Hz),123.4(q,³J_CF＝4Hz),80.3,65.8,56.3,28.2；¹⁹F NMR(CDCl₃,376MHz):δ-62.6。

Example 2: sulfamate formation

Example 2: general reaction scheme for sulfamate formation

Sulfamate formation is carried out according to the following general reaction scheme, wherein R_AAnd R_BCorresponding to the various functional groups in the reaction of example 2 below, and wherein the asterisks indicate the chiral center:

example 2A: preparation of (R) -4-benzyl-1, 2, 3-thiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide:

the above general reaction scheme 2 was carried out as follows. SOCl was added at-40 deg.C₂(10.9mL,149mmol,250 mol%) in CH ₂Cl₂(60.0mL) to a cold (-40 ℃ C.) solution was added tert-butyl (R) - (1-hydroxy-3-phenylpropan-2-yl) carbamate (15.0g,59.7mmol,100 mol%) In CH₂Cl₂(60.0mL) for 60 minutes. Pyridine (25.3mL,313mmol,525 mol%) was then added to the reaction mixture at-40 ℃ over 30 minutes. The reaction mixture was stirred at-40 ℃ for 2 hours and the solvent was exchanged for CH₂Cl₂the/iPrOAc (1:1) mixture was filtered. The filtrate was washed with saturated brine solution (20mL) and dried (Na)₂SO₄) Filtered and concentrated under reduced pressure. The residue was dissolved in CH at 0 deg.C₃CN (60.0 mL). Adding NaIO to the reaction mixture at 0 deg.C₄(14.0g,65.7mmol,110mol％)、RuCl₃(61.9mg,0.298mmol,0.5 mol%) and water (60.0mL) and stirred for 15 min. The reaction mixture was then warmed to room temperature and stirred at room temperature for 2 hours, extracted with iPrOAc (20mL), and saturated NaHCO₃The solution (15mL), saturated saline solution (15mL) was washed and dried (Na)₂SO₄) Filtering on SiO₂The above is purified by chromatography. The specific gradient used for each sample is included in the characterization data. All yields reported are based on¹The residual solvent in H NMR was corrected. Reaction 2A yielded (R) -4-benzyl-1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide as a white solid (18.7g, 56% yield). Column gradient: 0 to 5% of CH ₃OH/CH₂Cl₂. mp is 134.4-135.0 ℃; FTIR (purity, cm)^-1)3261,2979,2903,1712,1673,1540；¹H NMR(400MHz,CDCl₃):δ7.38-7.20(m,5H),4.49-4.40(m,2H),4.35-4.28(m,1H),3.37(dd,J＝14.0,4.0Hz,1H),2.98-2.87(m,1H),1.56(s,9H)；¹³C NMR(100MHz,CDCl₃):δ148.5,135.2,129.5,129.1,127.5,85.6,68.8,58.6,37.9,28.0。

Example 2B: preparation of (S) -4-phenyl-1, 2, 3-thiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide:

the general reaction scheme as in example 2A above was followed with tert-butyl (S) - (2-hydroxy-1-phenylethyl) carbamate (10.0g,42.1mmol,100 mol%) to give a white solidThe compound (S) -4-phenyl-1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide (5.23g, 42% yield). Column gradient: 0 to 5% of CH₃OH/CH₂Cl₂. mp is 144.3-145.0 ℃; FTIR (purity, cm)^-1)2976,1722,1458,1377；¹H NMR(400MHz,CDCl₃):δ7.44-7.35(m,5H),5.28(dd,J＝6.4,4.0Hz,1H),4.87(dd,J＝9.2,6.4Hz,1H),4.39(dd,J＝9.2,4.4Hz,1H),1.42(s,9H)；¹³C NMR(100MHz,CDCl₃):δ148.3,137.0,129.2,129.1,126.2,85.5,71.8,60.8,27.8。

Example 2C: preparation of (S) -4- (4-methoxyphenyl) -1,2, 3-thiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide:

the general reaction scheme as in example 2A above was followed with tert-butyl (S) - (2-hydroxy-1- (4-methoxyphenyl) ethyl) carbamate (1.45g,5.42mmol,100 mol%) to give the compound tert-butyl (S) -4- (4-methoxyphenyl) -1,2, 3-oxathiazolidine-3-carboxylate 2, 2-dioxide as a white solid (1.05g, 59% yield). Column gradient: 0 to 5% of CH₃OH/CH₂Cl₂. 151.6-153.0 ℃ of mp; FTIR (purity, cm)^-1)2979,2933,2838,1721,1636,1510,1457；¹H NMR(400MHz,CDCl₃):δ7.37-7.32(m,2H),6.95-6.90(m,2H),5.24(dd,J＝6.8,4.4Hz,1H),4.84(dd,J＝9.2,6.8Hz,1H),4.39(dd,J＝9.2,4.4Hz,1H),3.82(s,3H),1.44(s,9H)；¹³C NMR(100MHz,CDCl₃):δ160.2,148.3,128.9,127.7,114.6,85.5,72.0,60.5,55.4,27.9。

Example 2D: preparation of (R) -4-methyl-1, 2, 3-thiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide:

using tert-butyl (R) - (1-hydroxypropan-2-yl) carbamate (5.00g,28.5mmol,100 mol%), the general reaction scheme as in example 2A above was followed To give compound (R) -4-methyl-1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide as a white solid (3.85g, 57% yield). Column gradient: 0 to 5% of CH₃OH/CH₂Cl₂. FTIR (purity, cm)^-1)3245,2982,1719,1402,1329；¹H NMR(400MHz,CDCl₃):δ4.66(dd,J＝9.2,6.0Hz,1H),4.41(qdd,J＝6.4,6.0,2.8Hz,1H),4.19(dd,J＝9.2,2.8Hz,1H),1.54(s,9H),1.50(d,J＝6.4Hz,3H)；¹³C NMR(100MHz,CDCl₃):δ148.5,85.4,71.4,53.8,28.0,18.3。

Example 2E: preparation of (R) -4-isopropyl-1, 2, 3-thiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide:

the general reaction scheme as in example 2A above was followed with tert-butyl (R) - (1-hydroxy-3-methylbutan-2-yl) carbamate (5.00g,24.6mmol,100 mol%) to give the compound (R) -4-isopropyl-1, 2, 3-thiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide as a white solid (3.93g, 60% yield). Column gradient: 0 to 5% of CH₃OH/CH₂Cl₂。mp:104.8-105.8℃；¹H NMR(400MHz,CDCl₃):δ4.55(dd,J＝9.6,6.4Hz,1H),4.38(dd,J＝9.6,2.0Hz,1H),4.17(ddd,J＝6.4,5.2,1.6Hz,1H),2.24(qqd,J＝6.8,6.8,5.2Hz,1H),1.53(s,9H),1.00(d,J＝6.8Hz,3H),0.95(d,J＝6.8Hz,3H)；¹³C NMR(100MHz,CDCl₃):δ149.1,85.3,67.0,62.0,30.0,27.9,18.0,16.4。

Example 2F: preparation of (R) -4-cyclopropyl-1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide:

the general reaction scheme as in example 2A above was followed with tert-butyl (R) - (1-cyclopropyl-2-hydroxyethyl) carbamate (2.31g,11.5mmol,100 mol%) to give (R) -4-cyclopropyl-1, 2, 3-oxathiazolidine-3-Carboxylic acid tert-butyl ester 2, 2-dioxide (1.36g, yield 45%). Column gradient: 0 to 5% of CH₃OH/CH₂Cl₂. mp is 52.7-55.7 ℃; FTIR (purity, cm)^-1)2977,1734,1460,1363；¹H NMR(400MHz,CDCl₃):δ4.64(dd,J＝9.2,6.0Hz,1H),4.40(dd,J＝8.8,2.0Hz,1H),3.77(ddd,J＝9.2,6.0,2.0Hz,1H),1.54(s,9H),1.35-1.23(m,1H),0.74-0.65(m,2H),0.63-0.54(m,1H),0.29-0.20(m,1H)；¹³C NMR(100MHz,CDCl₃):δ148.9,85.3,71.1,61.6,27.9,14.3,4.4,1.7。

Example 2G: preparation of (3aR,8aS) -8,8 a-dihydroindeno [1,2-d ] [1,2,3] oxathiazole-3 (3aH) -carboxylic acid tert-butyl ester 2, 2-dioxide:

The general reaction scheme aS in example 2A above was followed with tert-butyl ((1R,2S) -2-hydroxy-2, 3-dihydro-1H-inden-1-yl) carbamate (9.12g,36.6mmol,100 mol%) to give (3aR,8aS) -8,8 a-dihydroindeno [1,2-d ] aS a white solid][1,2,3]Oxathiazole-3 (3aH) -carboxylic acid tert-butyl ester 2, 2-dioxide (7.50g, 66% yield). Column gradient: 0 to 5% of CH₃OH/CH₂Cl₂. mp is 134.2-135.0 ℃; FTIR (purity, cm)^-1)2988,2937,1732,1462,1375；¹H NMR(400MHz,CDCl₃):δ7.62-7.57(m,1H),7.39-7.24(m,3H),5.71(d,J＝5.6Hz,1H),5.50(dt,J＝6.0,3.2Hz,1H),3.38(d,J＝3.2Hz,1H),1.62(s,9H)；¹³C NMR(100MHz,CDCl₃):δ149.6,138.4,137.9,129.9,128.4,126.2,125.2,85.7,82.2,65.0,36.5,28.0。

Example 2H: preparation of (S) -5-methyl-1, 2, 3-thiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide:

the general reaction scheme as for example 2A above was followed with tert-butyl (S) - (2-hydroxypropyl) carbamate (6.25g,35.7mmol,100 mol%) to give a white colorThe compound (S) -5-methyl-1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide (6.10g, yield 72%) as a solid. Column gradient: 0 to 5% of CH₃OH/CH₂Cl₂. mp is 116.9-118.2 ℃; FTIR (purity, cm)^-1)3370,2956,2938,2837,1681,1512,1461,1366；¹H NMR(400MHz,CDCl₃):δ5.00-4.90(m,1H),4.06(dd,J＝9.6,5.6Hz,1H),3.63(dd,J＝9.6,9.2Hz,1H),1.56(d,J＝6.4Hz,3H),1.53(s,9H)；¹³C NMR(100MHz,CDCl₃):δ148.6,85.3,76.2,51.7,27.9,18.0。

Example 2I: preparation of (S) -4- (3-fluorophenyl) -1,2, 3-thiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide:

the general reaction scheme as in example 2A above was followed with tert-butyl (S) - (1- (3-fluorophenyl) -2-hydroxyethyl) carbamate (1.45g,5.68mmol,100 mol%) to give tert-butyl (S) -4- (3-fluorophenyl) -1,2, 3-thiazolidine-3-carboxylate 2, 2-dioxide as a white solid (0.702g, 39% yield). Column gradient: 0 to 50% iPrOAc/heptane. mp is 112.9-114.3 ℃; FTIR (purity, cm) ^-1)2976,1722,1636,1594,1458；¹H NMR(400MHz,CDCl₃):δ7.44-7.36(m,1H),7.24-7.18(m,1H),7.17-7.11(m,1H),7.11-7.05(m,1H),5.28(dd,J＝6.8,3.6Hz,1H),4.88(dd,J＝9.2,6.8Hz,1H),4.39(dd,J＝9.2,3.6Hz,1H),1.47(s,9H)；¹³C NMR(100MHz,CDCl₃):δ163.2(d,¹J_CF＝246Hz),148.2,139.6(d,³J_CF＝7Hz),131.1(d,³J_CF＝8Hz),121.8(d,⁴J_CF＝3Hz),116.2(d,²J_CF＝21Hz),113.4(d,²J_CF＝22Hz),86.0,71.6,60.2(d,⁴J_CF＝3Hz),27.9；¹⁹F NMR(CDCl₃,376MHz):δ-111.0。

Example 2J: preparation of (S) -4- (3- (trifluoromethyl) phenyl) -1,2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide:

the general reaction scheme as in example 2A above was followed with tert-butyl (S) - (1- (3-fluorophenyl) -2-hydroxyethyl) carbamate (1.00g,3.28mmol,100 mol%) to give tert-butyl (S) -4- (3- (trifluoromethyl) phenyl) -1,2, 3-thiazolidine-3-carboxylate 2, 2-dioxide as a white solid (0.528g, 44% yield). Column gradient: 0 to 50% iPrOAc/heptane. mp is 92.0-92.6 ℃; FTIR (purity, cm)^-1)2989,1720,1463,1373,1325；¹H NMR(400MHz,CDCl₃):δ7.70-7.61(m,3H),7.61-7.55(m,1H),5.35(dd,J＝6.8,4.0Hz,1H),4.92(dd,J＝9.2,6.8Hz,1H),4.41(dd,J＝9.2,3.6Hz,1H),1.46(s,9H)；¹³C NMR(100MHz,CDCl₃):δ148.2,138.2,131.8(q,²J_CF＝32Hz),130.1,129.4,126.1(q,³J_CF＝4Hz),123.7(q,¹J_CF＝270Hz),123.4(q,³J_CF＝4Hz),86.2,71.4,60.2,27.8；¹⁹F NMR(CDCl₃,376MHz):δ-62.8。

Example 2K: preparation of (S) -4-phenyl-1, 2, 3-oxathiazinane-3-carboxylic acid tert-butyl ester 2, 2-dioxide:

the general reaction scheme as in example 2A above was followed with tert-butyl (S) - (3-hydroxy-1-phenylpropyl) carbamate (2.00g,7.96mmol,100 mol%) to give (S) -4-phenyl-1, 2, 3-oxathiazinane-3-carboxylate 2, 2-dioxide as a white solid (1.26g, 51% yield). Column gradient: 0 to 50% of iPrOAc. mp is 128.6-129.9 ℃; FTIR (purity, cm)^-1)2986,1727,1449,1367；¹H NMR(400MHz,DMSO-d₆) (94: 6 mixtures of rotamers) < delta > 7.48-7.35(m,4H),7.35-7.23(m,1H),5.65(dd, J ═ 4.4,4.4Hz,0.94H),5.53(dd, J ═ 11.2,4.4Hz,0.06H),4.70(ddd, J ═ 10.4,7.2,2.8Hz,0.94H),4.51(ddd, J ═ 8.8,4.4,4.4Hz,0.06H),4.40(ddd, J ═ 10.4,10.4,6.8Hz,1H),2.80-2.68(m,1H),2.66-2.56(m,1H),1.41(s,8.46H), 1.12(s,0.54H)；¹³C NMR(100MHz,DMSO-d₆) (rotamers): delta 155.1,143.0,128.4(128.6),127.0(127.3),126.3(125.4),78.1(84.3),73.6(70.9),50.5(60.0),36.0,28.2 (27.4).

Example 3: indole alkylation

Chiral tryptamines are often encountered pharmacologically due to their significant biological activity in the central nervous system. In addition, chiral tryptamine moieties are synthetic precursors to many medically important indole alkaloids and are present in many biologically active natural products and drugs.

In particular, the stereocontrolled synthesis of tetrahydro- β -carboline-containing compounds such as those described herein often relies on a diastereomeric selective Pictet-Spengler reaction, which in turn requires enantiomerically pure tryptamine as starting material. The latter are usually prepared in a non-stereoselective manner via a multistep sequence involving hazardous nitroalkane reagents. Thus, the development of a simple regioselective alkylation process involving readily available unprotected indoles as nucleophiles and chiral amine-derived electrophiles such as chiral aziridines and cyclic sulfamates offers the convenience of conveniently obtaining these valuable chiral scaffolds.

Aziridine electrophiles have been applied to provide C under Lewis acidic conditions ³-selective alkylation; however, this method is only applicable to the synthesis of β -substituted tryptamines, since the substitution occurs preferentially on the more highly substituted carbons. It has been found herein that the combination of a lower order cuprate salt of indole with a chiral cyclic sulfamate successfully provides a practical approach to alpha-and beta-substituted chiral tryptamines with high regioselectivity.

It was found that the reaction with chiral aziridine as electrophile always produced a mixture of alpha-and beta-substituted tryptamines, whereas the reaction with cyclic sulfamate as electrophile clearly reacted to replace the C — O bond.

And shows that when a Grignard reagent is used as the base, it is preferentially at C³Literature on alkylation at position is a priori contrary, the initial attempts resulted in lower than expected yields and poor site selectivity. Without being bound to any particular theoryBound by theory, softer indole nucleophiles were attempted because they are likely to react more preferentially as carbon-centered nucleophiles. Various additives were investigated, including Cu and Zn salts. Interestingly, mixed halide systems such as the combination of MeMgCl with CuBr or CuI, or the combination of MeMgBr with CuCl are far less efficient than chloride-only systems. Other copper salts, e.g. CuCl ₂CuCN, CuTC or Cu (SCN) are also inferior to CuCl.

Catalytic amounts of CuCl are not tolerated and result in significant reductions in yield and selectivity. Clearly, a reversal of regioselectivity was observed when using zinc halide instead of CuCl (see above). This is also true when using MeLi instead of MeMgCl as base, while the use of other grignard reagents is well tolerated. The effect of the reaction temperature was evaluated and it was determined that the metathesis reaction proceeded optimally around-20 ℃. At temperatures below-30 ℃, a significant decrease in regioselectivity is observed, probably due to incomplete cuprate formation.

Cu-mediated indole alkylation is resistant to multiple substitutions both on indole nucleophiles and on cyclic sulfamates, providing C in moderate to good yields and excellent regioselectivity³-alkylated indole products. For example, indoles with electron donating or electron withdrawing substituents participate well in the reaction (exemplary compounds 6b-6g above) and bulky substrates also perform well (exemplary compounds 6h and 6i above).

Azaindoles, on the other hand, appear to be potentially poor substrates. Under standard reaction conditions, 6-azaindole provides only 8% of the alkylation product, albeit with comparable regioselectivity (see, e.g., exemplary compound 6j above). Other azaindoles such as indazole and 7-azaindole fail to produce any desired alkylated products.

Various sulfamates were successfully tested in the reaction. Both aryl-and alkyl-substituted sulfamates, prepared in a two-step sequence from the corresponding amino alcohols, are smoothly converted into the respective alpha-substituted chiral tryptamines. Similarly, 6-membered cyclic sulfamates also participate well in the alkylation reaction, producing homologous tryptamines in good yield and regioselectivity. This alkylation process can also be applied to obtain β -substituted and α, β -disubstituted tryptamines (see exemplary compounds 6s and 6t above). In these cases, addition of an indole nucleophile to the corresponding cyclic sulfamate results in a stereochemical reversal with full stereospecificity at the oxygen-containing carbon. As provided herein, the utility of the alkylation process was demonstrated.

Example 3: general reaction scheme for indole alkylation

Indole alkylation according to the following general reaction scheme, wherein R_AAnd R_BCorresponding to the various functional groups in the reaction of example 3 below, and wherein the asterisks indicate the chiral center:

example 3A: preparation of (R) - (1- (1H-indol-3-yl) -3-phenylpropan-2-yl) carbamic acid tert-butyl ester:

the above general reaction scheme 3 was carried out as follows. Indole (280mg,2.39mmol,150 mol%) and CuCl (193mg,1.95mmol,130 mol%) in CH at 0 deg.C ₂Cl₂MeMgCl (3.0M in THF, 0.65mL,1.95mmol,130 mol%) was added over 10 minutes to a cold (0 ℃ C.) mixture (3.0 mL). The reaction mixture was stirred at 0 ℃ for 1 hour and cooled to-20 ℃. (R) -4-benzyl-1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide (500mg,1.60mmol,100 mol%) in CH was added to the reaction mixture over 30 minutes at-20 deg.C₂Cl₂(2.0 mL). The reaction mixture was stirred at-20 ℃ for 18 h, quenched with 0 ℃ 10% aqueous citric acid (5.0mL), filtered, and quenched with CH₂Cl₂(10.0 mL. times.2) by extraction withWashed with saturated brine (20.0 mL. times.2) and dried (Na)₂SO₄) Filtering on SiO₂The above is purified by chromatography. The specific gradient used for each sample is included in the characterization data. All yields reported are based on¹The residual solvent in H NMR was corrected. Reaction 3A yielded (R) - (1- (1H-indol-3-yl) -3-phenylpropan-2-yl) carbamic acid tert-butyl ester as a white solid (424mg, 76% yield). C³/N¹The ratio was 97: 3. Column gradient: 0 to 50% iPrOAc/heptane. mp is 152.1-153.2 ℃; FTIR (purity, cm)^-1)3418,3402,3376,2974,2911,1684,1522；¹H NMR(400MHz,DMSO-d₆) (85: 15 mixtures of rotamers): δ 10.78(br,1H),7.46(d, J ═ 8.0Hz,1H),7.32(d, J ═ 8.0Hz,1H),7.28-7.21(m,2H),7.19-7.10(m,4H),7.05(ddd, J ═ 8.4,7.2,1.2Hz,1H),6.95(ddd, J ═ 8.0,6.8,1.2Hz,1H),6.76(d, J ═ 8.4Hz,0.85H),6.34(d, J ═ 9.2Hz,0.15H),3.97-3.83(m,1H),2.90-2.65(m,4H),1.29(s,7.65H), 1.35 (s, 1.35H); ¹³C NMR(100MHz,DMSO-d₆) (rotamers): delta 155.1,139.6,136.1,129.0,128.0,127.5,125.8,123.2,120.8,118.3,118.1,111.4,111.3,77.3,52.6,39.9,30.4,28.2 (27.8).

Example 3B: preparation of tert-butyl (S) - (2- (1H-indol-3-yl) -1-phenylethyl) carbamate:

the general reaction according to example 3A was carried out between indole (294mg,2.51mmol,150 mol%) and (S) -4-phenyl-1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide (500mg,1.67mmol,100 mol%) to give tert-butyl (S) - (2- (1H-indol-3-yl) -1-phenylethyl) carbamate as a white solid (398mg, 71% yield). C³/N¹The ratio was 97: 3. Column gradient: 0 to 50% iPrOAc/heptane. mp is 134.6-135.2 ℃; FTIR (purity, cm)^-1)3416,3401,3371,2980,2909,1683,1524；¹H NMR(400MHz,DMSO-d₆) (85: 15 mixture of rotamers): δ 10.74(br,1H),7.54(d, J ═ 7.6Hz,1H),7.41(d, J ═ 8.4Hz,1H),7.38-7.25(m,5H),7.20(dd, J ═ 6.8,7.2Hz, 1H), 1H),7.06(dd,J＝7.6,7.2Hz,1H),7.02(s,1H),6.98(dd,J＝7.6,7.2Hz,1H),4.89-4.74(m,1H),3.08(dd,J＝14.8,8.8Hz,1H),2.99(dd,J＝14.4,6.0Hz,1H),1.31(s,7.65H),1.08(s,1.35H)；¹³C NMR(100MHz,DMSO-d₆):δ155.0,144.5,136.0,128.0,127.3,126.5,126.4,123.2,120.8,118.3,118.2,111.3,111.3,77.6,55.0,32.8,28.2。

Example 3C: preparation of (S) - (tert-butyl 2- (1H-indol-3-yl) -1- (4-methoxyphenyl) ethyl) carbamate:

the general reaction according to example 3A was carried out between indole (264mg,2.25mmol,150 mol%) and (S) -4- (4-methoxyphenyl) -1,2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide (495mg,1.50mmol,100 mol%) to give tert-butyl (S) - (2- (1H-indol-3-yl) -1- (4-methoxyphenyl) ethyl) carbamate as a white solid (378mg, 69% yield). C ³/N¹The ratio was 98: 2. Column gradient: 0 to 50% iPrOAc/heptane. mp is 173.3-176.5 ℃; FTIR (purity, cm)^-1)3402,3326,2979,2925,2904,1690,1611,1506；¹H NMR(400MHz,DMSO-d₆) (85: 15 mixtures of rotamers): δ 10.72(br,1H),7.54(d, J ═ 8.0Hz,1H),7.39-7.28(m,2H),7.24(d, J ═ 8.8Hz,2H),7.05(ddd, J ═ 8.4,7.2,1.2Hz,1H),7.02-6.94(m,2H),6.84(d, J ═ 8.4Hz,2H),4.88-4.57(m,1H),3.72(s,3H),3.06(dd, J ═ 14.8,8.4Hz,1H),2.96(dd, J ═ 14.8,6.4Hz,1H),1.31(s,7.65H),1.11(s, 1.35H);¹³C NMR(100MHz,DMSO-d₆):δ157.9,154.9,136.4,136.0,127.5,127.3,123.2,120.7,118.3,118.1,113.4,111.4,111.2,77.5,55.0,54.4,32.8,28.2。

example 3D: preparation of (R) - (1- (1H-indol-3-yl) propan-2-yl) carbamic acid tert-butyl ester:

in the presence of indole (370mg,3.16mmol,150 mol%) and (R) -4-methyl-1, 2, 3-oxathia-neThe general reaction between oxazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide (500mg,2.11mmol,100 mol%) as in example 3A was carried out to give tert-butyl (R) - (1- (1H-indol-3-yl) propan-2-yl) carbamate as a white solid (406mg, 70% yield). C³/N¹The ratio was 99: 1. Column gradient: 0 to 50% iPrOAc/heptane. mp is 82.2-84.3 ℃; FTIR (purity, cm)^-1)3416,3401,3366,2974,2963,1684,1524；¹H NMR(400MHz,DMSO-d₆):δ10.77(br,1H),7.56(d,J＝7.6Hz,1H),7.33(ddd,J＝8.0,1.2,0.8Hz,1H),7.10(d,J＝2.4Hz,1H),7.05(ddd,J＝8.0,6.8,1.2Hz,1H),6.97(ddd,J＝8.0,6.8,1.2Hz,1H),6.71(d,J＝8.4Hz,1H),3.82-3.66(m,1H),2.87(dd,J＝14.0,6.0Hz,1H),2.65(dd,J＝14.0,7.6Hz,1H),1.38(s,9H),1.01(d,J＝6.8Hz,3H)；¹³C NMR(100MHz,DMSO-d₆):δ155.0,136.1,127.5,123.1,120.7,118.4,118.1,111.6,111.2,77.3,46.8,32.2,28.3,20.1。

Example 3E: preparation of (R) - (1- (1H-indol-3-yl) -3-methylbutan-2-yl) carbamic acid tert-butyl ester:

the general reaction as in example 3A was carried out between indole (331mg,2.83mmol,150 mol%) and (R) -4-isopropyl-1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide (500mg,1.88mmol,100 mol%) to give tert-butyl (R) - (1- (1H-indol-3-yl) -3-methylbutan-2-yl) carbamate as a white solid (335mg, 59% yield). C ³/N¹The ratio was 94: 6. Column gradient: 0 to 50% iPrOAc/heptane. mp is 145.1-146.9 ℃; FTIR (purity, cm)^-1)3417,3402,3362,2978,1686,1526；¹H NMR(400MHz,DMSO-d₆) (85: 15 mixtures of rotamers): δ 10.72(br,1H),7.51(d, J ═ 8.0Hz,1H),7.31(ddd, J ═ 8.0,1.2,0.8Hz,1H),7.07(d, J ═ 2.0Hz,1H),7.04(ddd, J ═ 8.0,6.8,1.2Hz,1H),6.96(ddd, J ═ 8.0,6.8,1.2Hz,1H),6.59(d, J ═ 9.2Hz,0.85H),6.15(d, J ═ 10.0Hz,0.15H),3.64-3.53(m,1H),2.80 (ddl, J ═ 14.8,5.2, 1H),2.68 (ddd, J ═ 8, 1H), 1.65 (ddl, 1H), 1.65 (1.65, 1H), 1.6.6.6.6.8, 1H);¹³C NMR(100MHz,DMSO-d₆):δ155.6,136.1,127.5,122.7,120.7,118.3,118.0,112.0,111.2,77.1,55.6,31.4,28.3,27.1,19.4,17.7。

example 3F: preparation of (S) - (1-cyclopropyl-2- (1H-indol-3-yl) ethyl) carbamic acid tert-butyl ester:

the general reaction according to example 3A was carried out between indole (264mg,2.25mmol,150 mol%) and (R) -4-cyclopropyl-1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide (395mg,1.50mmol,100 mol%) to give tert-butyl (S) - (1-cyclopropyl-2- (1H-indol-3-yl) ethyl) carbamate as a white solid (292mg, 65% yield). C³/N¹The ratio was 99: 1. Column gradient: 0 to 50% iPrOAc/heptane. mp is 128.8-130.5 ℃; FTIR (purity, cm)^-1)3414,3400,3362,2981,2937,1683,1525；¹H NMR(400MHz,DMSO-d₆) (9: 1 mixtures of rotamers): δ 10.73(br,1H),7.52(d, J ═ 7.6Hz,1H),7.31(ddd, J ═ 8.0,1.2,0.8Hz,1H),7.07(d, J ═ 2.4Hz,1H),7.04(ddd, J ═ 8.0,6.8,1.2Hz,1H),6.95(ddd, J ═ 8.0,6.8,1.2Hz,1H),6.66(d, J ═ 8.4Hz,0.9H),6.26(s,0.1H),3.30-3.18(m,1H),2.91(dd, J ═ 14.4,5.6Hz,1H),2.85 (ddl, J ═ 8.4, 1H), 1H, 1.8, 0.8, 1H), 1.18 (m,1H),2.91(dd, 14.4,5.6Hz,1H),2.85 (ddh, 14, 8, 0.8, 1H), 1H, 17.8, 1H, 17-32 (m, 1H); ¹³C NMR(100MHz,DMSO-d₆):δ155.3,136.0,127.7,122.9,120.6,118.4,118.0,111.6,111.2,77.2,54.2,30.4,28.2,16.0,3.0,1.9。

Example 3G: preparation of tert-butyl ((1S,2S) -2- (1H-indol-3-yl) -2, 3-dihydro-1H-inden-1-yl) carbamate:

in the presence of indole (282mg,2.41mmol,150 mol%) and (3aR,8aS) -8,8 a-dihydroindeno [1, 2-d%][1,2,3]Oxathiazole-3 (3aH) -carboxylic acid tert-butyl ester 2, 2-dioxide (500mg,1.61mmol,100 mol%) the procedure of example 3A was carried outThe reaction was general to give tert-butyl ((1S,2S) -2- (1H-indol-3-yl) -2, 3-dihydro-1H-inden-1-yl) carbamate as a white solid (304mg, 54% yield). C³/N¹The ratio was 95: 5. Column gradient: 0 to 50% iPrOAc/heptane. mp is 155.7 to 157.1 ℃; FTIR (purity, cm)^-1)3387,3351,2980,2938,1691,1500；¹H NMR(400MHz,DMSO-d₆) (87: 13 mixtures of rotamers): 10.85(br,1H),7.61(d, J ═ 8.0Hz,1H),7.42-7.32(m,2H),7.30-7.20(m,4H),7.17(dd, J ═ 8.0,4.0Hz,1H),7.07(ddd, J ═ 8.0,6.8,1.2Hz,1H),6.97(ddd, J ═ 8.0,6.8,1.2Hz,1H),5.18(dd, J ═ 9.2,9.2Hz,1H),3.69(dd, J ═ 18.4,9.6Hz,0.87H),3.64-3.53(m,0.13H),3.37(dd, J ═ 15.2,8, 0.4, 9.6Hz,0.87H),3.64-3.53(m,0.13H),3.37 (ddh, 15.2,8, 3.2H, 3.2, 3.83, 13.2H), 3.2H, 13H, 13.2H, 13;¹³C NMR(100MHz,DMSO-d₆) (rotamers): delta 155.9,144.5,141.3,136.6,127.2,127.1,126.4,124.4,123.3,121.7,120.9,119.1,118.2,115.5,111.4,77.7,60.8,44.0,37.2,28.2 (27.7).

Example 3H: preparation of (S) - (2- (1H-indol-3-yl) propyl) carbamic acid tert-butyl ester:

the general reaction as in example 3A was carried out between indole (264mg,2.25mmol,150 mol%) and (S) -5-methyl-1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide (356mg,1.50mmol,100 mol%) to give tert-butyl (S) - (2- (1H-indol-3-yl) propyl) carbamate as a colourless liquid (319mg, 78% yield). C³/N¹The ratio was 93: 7. Column gradient: 0 to 50% iPrOAc/heptane. FTIR (purity, cm)^-1)3412,3327,2971,2930,1685,1508,1456；¹H NMR(400MHz,DMSO-d₆) (9: 1 mixture of rotamers): δ 10.78(br,1H),7.58(d, J ═ 7.6Hz,1H),7.33(ddd, J ═ 8.0,1.2,0.8Hz,1H),7.10(d, J ═ 2.0Hz,1H),7.05(ddd, J ═ 8.0,6.8,1.2Hz,1H),6.96(ddd, J ═ 8.0,6.8,1.2Hz,1H),6.86(dd, J ═ 6.0,6.0Hz,0.9H),6.51(s,0.1H),3.29(ddd, J ═ 13.2,5.6,5.6Hz,1H),3.18-3.05(m,1H),2.97(ddd, 2.8, 8.8, 1H), 1.38 (ddd, 1H), 1H, 1s,8.1H),1.25(d,J＝6.8Hz,3H)；¹³C NMR(100MHz,DMSO-d₆) (rotamers): delta 155.7,136.4,126.6,121.0,120.8,118.6,118.1,117.9,111.4,77.4,46.8,30.9,28.3(28.2),18.4 (18.2).

Example 3I: preparation of (R) - (1- (3-fluorophenyl) -2- (1H-indol-3-yl) ethyl) carbamic acid tert-butyl ester:

the general reaction according to example 3A was carried out between indole (263mg,2.25mmol,150 mol%) and (S) -4- (3-fluorophenyl) -1,2, 3-thiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide (475mg,1.50mmol,100 mol%) to give tert-butyl (R) - (1- (3-fluorophenyl) -2- (1H-indol-3-yl) ethyl) carbamate as a white solid (382mg, 72% yield). C ³/N¹The ratio was 99: 1. Column gradient: 0 to 50% iPrOAc/heptane. mp is 148.6-151.2 ℃; FTIR (purity, cm)^-1)3414,3398,3363,3055,2981,1682,1591,1527；¹H NMR(400MHz,DMSO-d₆) (9: 1 mixture of rotamers): δ 10.75(br,1H),7.53(d, J ═ 7.6Hz,1H),7.44(d, J ═ 8.4Hz,1H),7.37-7.26(m,2H),7.20-7.11(m,2H),7.08-6.93(m,4H),4.85-4.65(m,1H),3.06(dd, J ═ 14.4,8.4Hz,1H),2.98(dd, J ═ 14.4,6.4Hz,1H),1.30(s,8.1H),1.08(s, 0.9H);¹³C NMR(100MHz,DMSO-d₆):δ162.2(d,¹J_CF＝243Hz),155.0,147.5(d,³J_CF＝7Hz),136.0,129.9(d,³J_CF＝8Hz),127.2,123.3,122.6,120.8,118.3,118.2,113.3(d,²J_CF＝21Hz),113.0(d,²J_CF＝21Hz),111.3,111.0,77.8,54.7,32.5,28.2；¹⁹F NMR(DMSO-d₆,376MHz):δ-113.6。

example 3J: preparation of (R) - (2- (1H-indol-3-yl) -1- (3- (trifluoromethyl) phenyl) ethyl) carbamic acid tert-butyl ester:

the general reaction as in example 3A was carried out between indole (176mg,1.50mmol,150 mol%) and (S) -4- (3- (trifluoromethyl) phenyl) -1,2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide (368mg,1.00mmol,100 mol%) to give tert-butyl (R) - (2- (1H-indol-3-yl) -1- (3- (trifluoromethyl) phenyl) ethyl) carbamate as a white solid (320mg, 79% yield). C³/N¹The ratio was 98: 2. Column gradient: 0 to 50% iPrOAc/heptane. mp is 99.3-101.4 ℃; FTIR (purity, cm)^-1)3414,3399,3361,2982,2936,1683,1523；¹H NMR(400MHz,DMSO-d₆) (88: 12 mixtures of rotamers): δ 10.76(br,1H),7.80-7.45(m,6H),7.31(d, J ═ 8.0Hz,1H),7.08-7.00(m,2H),6.96(ddd, J ═ 8.0,7.2,1.2Hz,1H),5.11-4.69(m,1H),3.09(dd, J ═ 14.4,8.4Hz,1H),3.00(dd, J ═ 14.4,6.4Hz,1H),1.30(s,7.9H),1.07(s, 1.1H); ¹³C NMR(100MHz,DMSO-d₆):δ155.1,145.8,136.1,130.8,129.0,128.9(q,²J_CF＝32Hz),127.3,124.4(q,¹J_CF＝270Hz),123.3(q,³J_CF＝4Hz),123.0,122.8(q,³J_CF＝4Hz),120.8,118.3,118.2,111.3,110.8,77.9,55.0,32.5,28.2；¹⁹F NMR(DMSO-d₆,376MHz):δ-61.0。

Example 3K: preparation of tert-butyl (S) - (3- (1H-indol-3-yl) -1-phenylpropyl) carbamate:

the general reaction according to example 3A was carried out between indole (264mg,2.25mmol,150 mol%) and (S) -4-phenyl-1, 2, 3-oxathiazinane-3-carboxylic acid tert-butyl ester 2, 2-dioxide (470mg,1.50mmol,100 mol%) to give tert-butyl (S) - (3- (1H-indol-3-yl) -1-phenylpropyl) carbamate as a white solid (401mg, 73% yield). C³/N¹The ratio was 98: 2. Column gradient: 0 to 50% iPrOAc/heptane. mp is 121.7-123.2 ℃; FTIR (purity, cm)^-1)3390,2979,2929,2859,1681,1507,1457,1364；¹H NMR(400MHz,CDCl₃) (80: 20 mixture of rotamers).: delta.8.04 (br,0.2H),7.96(br,0.8H),7.66(d,J＝8.0Hz,0.2H),7.52(d,J＝8.0Hz,0.8H),7.40-7.22(m,6H),7.22-7.15(m,1H),7.15-7.06(m,1H),7.00(br,1H),4.88(br,0.8H),4.75(br,1H),4.53(br,0.2H),3.52-3.35(m,0.4H),3.32-3.20(m,0.4H),2.87-2.67(m,1.6H),2.16(d,J＝8.8Hz,1.6H),1.42(s,9H)；¹³C NMR(100MHz,DMSO-d₆) Delta 155.4(156.2),143.0,136.4(136.6),128.6,127.3,127.2,126.4,121.8(122.0),121.5(120.8),119.0(119.2),118.7,115.3,111.2(111.3),79.5,54.7(46.7),37.2(31.6),28.4(29.7),21.9 (18.7).

Example 3L: preparation of (R) - (1- (5-methyl-1H-indol-3-yl) -3-phenylpropan-2-yl) carbamic acid tert-butyl ester:

the general reaction as in example 3A was carried out between 5-methyl-1H-indole (295mg,2.25mmol,150 mol%) and (R) -4-benzyl-1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide (470mg,1.50mmol,100 mol%) to give (R) - (1- (5-methyl-1H-indol-3-yl) -3-phenylpropan-2-yl) carbamic acid tert-butyl ester as a white solid (401mg, 73% yield). C ³/N¹The ratio was 92: 8. Column gradient: 0 to 50% iPrOAc/heptane. mp is 123.0-123.8 ℃; FTIR (purity, cm)^-1)3413,3368,2974,2927,1685,1524；¹H NMR(400MHz,DMSO-d₆) (85: 15 mixtures of rotamers): δ 10.63(br,1H),7.30-7.13(m,7H),7.07(d, J ═ 2.0Hz,1H),6.87(dd, J ═ 8.4,1.6Hz,1H),6.74(d, J ═ 8.8Hz,0.85H),6.34(d, J ═ 7.6Hz,0.15H),3.96-3.80(m,1H),2.86-2.64(m,4H),2.36(s,3H),1.30(s,7.65H),1.16(s, 1.35H);¹³C NMR(100MHz,DMSO-d₆) (rotamers). delta. 155.1,139.6,134.5,129.1,128.0,127.7,126.4,125.8,123.2,122.3,117.9,111.0,110.9,77.2,52.7,40.0,30.2,28.2(27.8), 21.3.

Example 3M: preparation of (R) - (1- (7-methyl-1H-indol-3-yl) -3-phenylpropan-2-yl) carbamic acid tert-butyl ester:

the general reaction as in example 3A was carried out between 7-methyl-1H-indole (295mg,2.25mmol,150 mol%) and (R) -4-benzyl-1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide (470mg,1.50mmol,100 mol%) to give (R) - (1- (7-methyl-1H-indol-3-yl) -3-phenylpropan-2-yl) carbamic acid tert-butyl ester as a white solid (371mg, 68% yield). C³/N¹The ratio was 97: 3. Column gradient: 0 to 50% iPrOAc/heptane. mp is 124.4-125.9 ℃; FTIR (purity, cm)^-1)3417,3407,3370,2974,2926,1683,1524；¹H NMR(400MHz,DMSO-d₆) (85: 15 mixture of rotamers): δ 10.75(br d, J ═ 2.0Hz,1H),7.34-7.21(m,3H),7.21-7.09(m,4H),6.90-6.83(m,2H),6.74(d, J ═ 8.8Hz,0.85H),6.34(d, J ═ 7.6Hz,0.15H),3.98-3.84(m,1H),2.91-2.65(m,4H),2.44(s,3H),1.31(s,7.65H),1.14(s, 1.35H); ¹³C NMR(100MHz,DMSO-d₆) (rotamers). delta. 155.2,139.6,135.7,129.0,128.0,127.2,125.8,122.9,121.3,120.3,118.4,115.9,111.9,77.3,52.6,39.9,30.5,28.2(27.8), 16.7.

Example 3N: preparation of (R) - (1- (5-chloro-1H-indol-3-yl) -3-phenylpropan-2-yl) carbamic acid tert-butyl ester:

the general reaction as in example 3A was carried out between 5-chloro-1H-indole (341mg,2.25mmol,150 mol%) and (R) -4-benzyl-1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide (470mg,1.50mmol,100 mol%) to give (R) - (1- (5-chloro-1H-indol-3-yl) -3-phenylpropan-2-yl) carbamic acid tert-butyl ester as a white solid (345mg, 60% yield). C³/N¹The ratio was 96: 4. Column gradient: 0 to 50% iPrOAc/heptane. mp is 70.5-73.9 ℃; FTIR (purity, cm)^-1)3417,3368,2980,2928,1684,1518；¹H NMR(400MHz,DMSO-d₆) (85: 15 mixture of rotamers): δ 10.99(br,1H),7.49(d, J ═ 2.0Hz,1H),7.34(d, J ═ 8.8Hz,1H),7.30-7.22(m,2H),7.22-7.13(m,4H),7.04(dd, J ═ 8.4,2.0Hz,1H),6.77(d, J ═ 8.8Hz,0.85H),6.34(d,J＝8.8Hz,0.15H),3.90-3.76(m,1H),2.83-2.62(m,4H),1.27(s,7.65H),1.10(s,1.35H)；¹³C NMR(100MHz,DMSO-d₆) (rotamers): delta 155.1,139.5,134.6,129.0,128.8,128.0,125.8,125.2,122.9,120.6,117.7,112.8,111.5,77.2,52.9,40.0,30.1,28.2 (27.7).

Example 3O: preparation of (R) - (1-phenyl-3- (5- (trifluoromethyl) -1H-indol-3-yl) propan-2-yl) carbamic acid tert-butyl ester:

The general reaction as in example 3A was carried out between 5- (trifluoromethyl) -1H-indole (417mg,2.25mmol,150 mol%) and (R) -4-benzyl-1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide (470mg,1.50mmol,100 mol%) to give (R) - (1-phenyl-3- (5- (trifluoromethyl) -1H-indol-3-yl) propan-2-yl) carbamic acid tert-butyl ester as a white solid (297mg, 47% yield). C³/N¹The ratio was 96: 4. Column gradient: 0 to 50% iPrOAc/heptane. mp is 130.9-131.8 ℃; FTIR (purity, cm)^-1)3417,3368,2980,2929,1684,1519；¹H NMR(400MHz,DMSO-d₆) (85: 15 mixtures of rotamers): 11.26(br,1H),7.84(s,1H),7.50(d, J ═ 8.4Hz,1H),7.37-7.22(m,4H),7.22-7.10(m,3H),6.80(d, J ═ 8.8Hz,0.85H),6.36(d, J ═ 9.2Hz,0.15H),3.99-3.77(m,1H),2.86(d, J ═ 6.8Hz,2H),2.76(d, J ═ 6.8Hz,2H),1.22(s,7.65H),1.04(s, 1.35H);¹³C NMR(100MHz,DMSO-d₆) (rotamers). delta.155.1 (154.6),139.5,137.6(137.7),129.1,128.0,126.9,125.8,125.7(q,¹J_CF＝269Hz),125.6,119.1(q,²J_CF＝32Hz),117.1(q,³J_CF＝4Hz),116.1(q,³J_CF＝4Hz),112.9,111.9,77.2,53.0(53.7),40.3(41.0),29.9(30.9),28.1(27.6)；¹⁹F NMR(DMSO-d₆,376MHz):δ-58.1。

example 3P: preparation of (R) - (1- (5-methoxy-1H-indol-3-yl) -3-phenylpropan-2-yl) carbamic acid tert-butyl ester:

the general reaction as in example 3A was carried out between 5-methoxy-1H-indole (331mg,2.25mmol,150 mol%) and (R) -4-benzyl-1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide (470mg,1.50mmol,100 mol%) to give (R) - (1- (5-methoxy-1H-indol-3-yl) -3-phenylpropan-2-yl) carbamic acid tert-butyl ester as a white solid (523mg, 92% yield). C ³/N¹The ratio was 97: 3. Column gradient: 0 to 50% iPrOAc/heptane. mp is 123.2-123.9 ℃; FTIR (purity, cm)^-1)3368,2975,2933,1692,1680,1516；¹H NMR(400MHz,DMSO-d₆) (85: 15 mixtures of rotamers): δ 10.60(s,1H),7.32-7.24(m,2H),7.24-7.13(m,4H),7.08(d, J ═ 2.4Hz,1H),6.91(d, J ═ 2.4Hz,0.85H),6.83(br,0.15H),6.77(d, J ═ 8.8Hz,0.85H),6.70(dd, J ═ 8.8,2.4Hz,1H),6.34(d, J ═ 9.2Hz,0.15H),3.94-3.80(m,1H),3.72(s,3H),2.85-2.65(m,4H),1.29(s,7.65H),1.13(s, 1.35H);¹³C NMR(100MHz,DMSO-d₆) (rotamers): delta 155.2,152.9,139.6,131.3,129.1,128.0,127.8,125.8,123.8,111.9,111.3,110.8,100.3,77.3,55.3,52.8,40.2,30.2,28.2 (27.8).

Example 3Q: preparation of (R) - (1-phenyl-3- (5-phenyl-1H-indol-3-yl) propan-2-yl) carbamic acid tert-butyl ester:

the general reaction as in example 3A was carried out between 5-phenyl-1H-indole (435mg,2.25mmol,150 mol%) and (R) -4-benzyl-1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide (470mg,1.50mmol,100 mol%) to give (R) - (1-phenyl-3- (5-phenyl-1H-indol-3-yl) propan-2-yl) carbamic acid tert-butyl ester as a white solid (523mg, 82% yield). C³/N¹The ratio was 97: 3. Column gradient: 0 to 50% iPrOAc/heptane. mp is 68.9-70.8 ℃; FTIR (purity, cm)^-1)3427,3411,3392,3310,2977,2929,1715,1696,1506；¹H NMR(400MHz,DMSO-d₆) (rotating device) 85:15 mixtures of structures δ 10.85(br,1H),7.70(s,1H),7.67-7.60(m,2H),7.48-7.33(m,4H),7.32-7.24(m,3H),7.23-7.15(m,4H),6.80(d, J ═ 8.8Hz,0.85H),6.39(d, J ═ 9.2Hz,0.15H),4.03-3.84(m,1H),2.87(d, J ═ 6.8Hz,2H),2.77(d, J ═ 6.8Hz,2H),1.24(s,7.65H),1.09(s, 1.35H);¹³C NMR(100MHz,DMSO-d₆) (rotamers): delta 155.1,142.0,139.6,135.8,130.7,129.1,128.6,128.1,128.0,126.6,126.0,125.8,124.0,120.1,116.6,112.2,111.6,77.2,53.1,40.4,30.1,28.2 (27.8).

Example 3R: preparation of (R) - (1- (2-methyl-1H-indol-3-yl) -3-phenylpropan-2-yl) carbamic acid tert-butyl ester:

the general reaction as in example 3A was carried out between 2-methyl-1H-indole (295mg,2.25mmol,150 mol%) and (R) -4-benzyl-1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide (470mg,1.50mmol,100 mol%) to give (R) - (1- (2-methyl-1H-indol-3-yl) -3-phenylpropan-2-yl) carbamic acid tert-butyl ester as a white solid (386mg, 71% yield). C³/N¹The ratio was 99: 1. Column gradient: 0 to 50% iPrOAc/heptane. mp is 117.6-119.0 ℃; FTIR (purity, cm)^-1)3440,3385,2984,2930,1684,1524；¹H NMR(400MHz,DMSO-d₆) (83: 17 mixtures of rotamers): δ 10.67(br,1H),7.39(d, J ═ 7.6Hz,0.83H),7.33(d, J ═ 8.0Hz,0.17H),7.28-7.18(m,3H),7.18-7.07(m,3H),6.96(ddd, J ═ 8.0,7.2,1.2Hz,1H),6.90(ddd, J ═ 8.0,8.0,1.2Hz,1H),6.73(d, J ═ 8.8Hz,0.83H),6.30(d, J ═ 8.8Hz,0.17H),3.94-3.74(m,1H),2.85(dd, J ═ 14.0,6.4, 1H), 2.8H, 2.17H, 2.04 (m,1H), 2.47 (s, 27.47H), 2.47 (s, 47H); ¹³C NMR(100MHz,DMSO-d₆) (rotamers): 155.1,139.8,135.2,132.4,128.9,128.7,128.0,125.7,119.8,118.0,117.5,110.2,107.4,77.2,53.4,39.4,29.9,28.2(27.7), 11.4.

Example 3S: preparation of (R) - (1-phenyl-3- (2-phenyl-1H-indol-3-yl) propan-2-yl) carbamic acid tert-butyl ester:

the general reaction as in example 3A was carried out between 2-phenyl-1H-indole (435mg,2.25mmol,150 mol%) and (R) -4-benzyl-1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide (470mg,1.50mmol,100 mol%) to give (R) - (1-phenyl-3- (2-phenyl-1H-indol-3-yl) propan-2-yl) carbamic acid tert-butyl ester as a white solid (324mg, 51% yield). C³/N¹The ratio was 98: 2. Column gradient: 0 to 50% iPrOAc/heptane. mp is 178.5-178.8 ℃; FTIR (purity, cm)^-1)3380,3354,3376,2981,2932,1683,1508；¹H NMR(400MHz,DMSO-d₆) (82: 18 mixture of rotamers): δ 11.14(s,1H),7.69(d, J ═ 7.6Hz,1H),7.60(d, J ═ 7.2Hz,2H),7.44(dd, J ═ 7.2,7.2Hz,2H),7.35(dd, J ═ 7.2,7.2Hz,2H),7.21(dd, J ═ 7.2,7.2Hz,2H),7.17-6.97(m,5H),6.79(d, J ═ 9.2Hz,0.82H),6.38(d, J ═ 9.6Hz,0.18H),4.15-3.90(m,1H),3.06(dd, J ═ 14.0,6.8, 1H),2.96(dd, 4.8, 7.8H), 7.6.6.6.6, 8H), 7.6.6.6H, 7.6.6H, 7.6H, 6H, 7.6H, 1H, 6H, 7.6H, 1H;¹³C NMR(100MHz,DMSO-d₆) (rotamers): delta 155.0,139.5,136.0,134.7,133.0,129.2,128.9,128.6,128.0,127.8,127.1,125.8,121.3,119.2,118.5,111.0,109.2,77.2,53.4,40.2,28.1 (27.6).

Example 3T: preparation of tert-butyl (R) - (1-phenyl-3- (1H-pyrrolo [2,3-c ] pyridin-3-yl) propan-2-yl) carbamate:

in 1H-pyrrolo [2,3-c ]]A general reaction as in example 3A was carried out between pyridine (266mg,2.25mmol,150 mol%) and (R) -4-benzyl-1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide (470mg,1.50mmol,100 mol%) to give (R) - (1-phenyl-3- (1H-pyrrolo [2, 3-c%) as a white solid]Pyridin-3-yl) propan-2-yl) carbamic acid tert-butyl ester (40mg, 8% yield). C³/N¹The ratio was 98: 2. Column gradient: 0 to 50% iPrOAc/heptane. mp is 196.2-197.0 ℃; FTIR (purity, cm)^-1)3360,2978,2931,1685,1625,1524；¹H NMR(400MHz,CDCl₃) (90: 10 mixtures of rotamers). delta.8.56 (br,1H),8.28(s,1H),7.57(d, J ═ 6.4Hz,1H),7.38-7.31(m,2H),7.30-7.25(m,2H),7.25-7.20(m,2H),6.70(br,1H),5.44(br,0.10H),5.24(d, J ═ 5.6Hz,0.90H),4.52(dd, J ═ 13.2,8.4Hz,1H),4.36(dd, J ═ 13.6,4.8Hz,1H),4.26-4.14(m,1H),3.00(dd, J ═ 14.0,7.6, 1H),2.91(dd, 8H), 1H), 11.11.11 (s, 8H).

Example 4

Preparation of azetidinyl-amines

The preparation of the compound of formula (VII) is carried out according to the following general scheme:

R⁵、v、R⁶and R¹⁰As defined herein.

Example 4A:

preparation of 1- (3-fluoropropyl) azetidine-3-aminoethane-1, 2-disulfonate

1- (3-fluoropropyl) azetidin-3-aminoethane-1, 2-disulfonate was prepared according to the following reaction scheme:

azetidin-3-ylcarbamic acid tert-butyl ester hydrochloride (109.7kg,1.0 equiv.) was dissolved in MTBE (793.4kg) and 1-bromo-3-fluoropropane (82.3kg) was added. MTBE (14kg) and water (530kg) were added at 15-25 ℃ followed by LiOH. H₂O (66.0kg), then stirred at 50-60 ℃. After completion of the reaction, the organic phases were separated and then an aqueous solution of 1, 2-ethanedisulfonic acid dihydrate (247.8kg) was combined at 0-5 ℃. The resulting mixture was stirred at 15-20 ℃ for 30 minutes. The aqueous phase was separated and 1, 2-ethanedisulfonic acid dihydrate (56.85kg) was added to the organic phase. The resulting mixture was stirred at 35-40 ℃ for 5 hours until deprotection was complete. MeOH (884.1kg) was then added at 35-40 deg.C, and the mixture was stirredStirring at 35-40 deg.C for 2 hr. After cooling to room temperature, the reaction mixture was stirred for 4 hours. The solid was collected by filtration and washed with aqueous NaOH. The washed solid was dried under reduced pressure at 35-42 ℃ to give 106.8kg of 1- (3-fluoropropyl) azetidin-3-aminoethane-1, 2-disulfonate (yield 63%).¹H NMR(400MHz,DMSO-d₆)δ9.92(s,0.7H),9.63(s,0.3H),8.35(s,3H),4.52(dt,J＝47.1,5.6Hz,2H),4.43-4.08(m,5H),3.36(s,3H),2.74(s,4H),2.06–1.77(m,2H)。

Example 4B:

1- (3-fluoropropyl) azetidin-3-aminoethane-1, 2-disulfonate was prepared via strain-release chemistry.

Preparation of 2, 3-dibromopropane-1-amine hydrobromide (3)

To 1(20.0g,1.0 eq, 50 wt.% in water) was added K at 0 deg.C₂CO₃(29.55g,1.0 equiv.) solution in Water (100mL) and Boc₂A solution of O (93.32g,2.0 equiv.) in EtOAc (100 mL). The reaction mixture was stirred at 20 ℃ for 15 hours. The organic layer was separated and the solvent exchanged to EtOH (100mL) to give a solution of 2 in EtOH. Then adding it to Br at 0 deg.C₂(71.74g, 2.1 equiv.) in EtOH (60mL) in a cold (0 ℃ C.) solution. The reaction mixture was stirred at 20 ℃ for 16 h, filtered, washed with MTBE (60mL) and dried under vacuum at 40 ℃ for 15 h to give 3 as a colourless solid (43.01g, 66%):¹H NMR(400MHz,CD₃OD)δ4.55-4.47(m,1H),4.01(dd,J＝10.9,4.6Hz,1H),3.86(dd,J＝10.9,8.7Hz,1H),3.71(dd,J＝13.9,3.2Hz,1H),3.39–3.33(m,1H)。

preparation of N, N-dibenzylazetidin-3-aminoethane-1, 1-disulfonate.

At 20 ℃ to Bn₂NH (33.12g,1.0 eq.)) To a solution in THF (330mL) was added iPrMgCl. LiCl (1.3M in THF, 130mL,1.0 equiv.) and stirred at 20 ℃ for 5 h to give Bn₂Solution of NMgCl LiCl in THF. A separate reactor was charged with 3(50.0g,1.0 equiv.) in THF (500mL) and cooled to-60 ℃. To the suspension was added n-BuLi (201mL, 2.5M solution in n-hexane, 3.0 equiv.) at-60 ℃ and stirred at-60 ℃ for 2 h to give a solution of 4 in THF. Adding Bn to 4 at-60 deg.C ₂NMgCl. LiCl solution, warmed to 20 ℃ and stirred at 20 ℃ for 12 h to give a solution of 5 in THF. The reaction mixture was cooled to 0 ℃ and Boc was added at 0 ℃₂A solution of O (73.28g,2.0 equiv.) in THF (200mL) was stirred at 20 deg.C for 2 hours, cooled to 0 deg.C, and treated with AcOH (20.16g,2.0 equiv.) in H₂The solution in O (383mL) was quenched. Organic layer with 5% Na₂SO₄(150mL) washed. The aqueous layers were combined and back-extracted with MTBE (100 mL. times.2) to give a solution of 6. To this solution was added a solution of ethane disulfonic acid (40.0g,1.5 eq.) in MeOH (225mL) at 20 deg.C and stirred at 40 deg.C for 20 hours. The slurry was filtered, washed with THF (100mL), and dried under vacuum (40 ℃ C.) for 20 hours to give 7 as a white solid (69.21g, 75% yield):¹H NMR(400MHz,D₂O)δ7.57-7.44(m,10H),4.66(t,J＝8.2Hz,1H),4.36(s,4H),4.10-3.95(m,4H),3.22(s,4H)。MS([M+H]⁺):C₁₇H₂₁N₂calculated 253.17, found 253.00.

Preparation of N, N-dibenzyl-1- (3-fluoropropyl) azetidin-3-amine (8)

To a solution of 7(40.0g,1.0 eq) in MTBE (200mL) and H₂To a solution in O (200mL) were added 1-bromo-3-fluoropropane (17.20g,1.5 equivalents) and LiOH. H₂O (15.18g,4.0 equiv.). The reaction mixture was heated to 55 ℃ and stirred at 55 ℃ for 20 hours, cooled to 20 ℃. The organic layer was separated and washed with 5% Na₂SO₄(120 mL. times.2) washing. Concentration of the MTBE solution under reduced pressure afforded 8 as a white solid (22.3g, 83% yield): ¹H NMR(400MHz,DMSO-d₆)δ7.35-7.22(m,10H),4.45(t,J＝6.0Hz,1H),4.33(t,J＝6.0Hz,1H),3.45-3.39(m,4H),3.28-3.17(m,3H),2.67-2.56(m,2H),2.35(t,J＝7.0Hz,2H),1.64-1.48(m,2H)。MS([M+H]⁺)：C₂₀H₂₆FN₂Calculated 313.21, found 313.10.

Preparation of 1- (3-fluoropropyl) azetidine-3-aminoethane-1, 2-disulfonate

To a solution of 8(2.00g,1.0 eq) in MeOH (20.0mL) at 0 deg.C was added ethane disulfonic acid dihydrate (1.23g,1.0 eq) in H₂Solution in O (10.0 mL). The reaction mixture was heated to 30 ℃ and passed through a carbon column. Pd/C (0.40g,0.20 eq.) was then added to the reaction mixture at 45 ℃ and 40psi H₂Stirring, filtration, concentration to 5mL, addition of MeOH (20.0mL), stirring at 20 ℃ for 3 hours, filtration, washing with MeOH (2mL) gave the title compound as a white solid (1.36g, 93% yield):¹H NMR(400MHz,D₂O)δ4.70-4.57(m,3H),4.57-4.31(m,4H),3.51(t,J＝7.2Hz,2H),3.24(s,4H),2.11-1.97(m,2H)；¹⁹F NMR(376MHz,D₂O)δ-219.59。

example 5

Preparation of (R) -1- (1H-indol-3-yl) propan-2-amine

At-5 to 0 ℃ and N₂To a solution of imidazole (102.8g,1.51mol,1.5 equivalents) in DCM (1.33L) was added SOCl dropwise over 30 minutes₂(179.3g,1.51mol,1.5 equiv.). The reaction mixture was stirred at-5 to 0 ℃ for 0.5 hour. Tert-butyl (R) - (1-hydroxypropan-2-yl) carbamate (Boc-alaninol) (177.7g,1.01mol,1.0 eq)/DCM (1.33L,7.5 vol) was added dropwise over 1 hour at-5 to 0 ℃. The reaction mixture was stirred at-2 to 0 ℃ for 0.5 hour and then gradually at-5 to 0 DEG CTriethylamine (204g,2.02mol,2 eq.) was added dropwise. The resulting mixture was stirred for 0.5 hours or until the N-Boc-alaninol was completely consumed as determined by GC analysis. Water was added to the reaction mixture (1.3L) at 0-20 ℃. The phases were separated and the aqueous phase was extracted with DCM (1.3L). The organic phases were combined and washed successively with 10% by weight of citric acid (1.3L), NaHCO ₃Aqueous (1.3L) and brine (1L). Cooling the organic phase to 0-10 deg.C, adding water (3.1L) and RuCl 3. xH₂O (2.66g) followed by Oxone (927.1g,1.51mol,1.5 eq). The reaction mixture was gradually warmed to 22 ℃ for 3.5 hours or until the aminosulfinate intermediate was completely consumed as determined by GC analysis. The phases were separated and the aqueous phase was filtered through a pad of celite (50g) and washed with DCM (1.3L). The filtrate was extracted with DCM (1.3L), the organic phases were combined and then saturated Na₂S₂O₃(1.3L) and brine (1L. times.2). With Na₂SO₄(50g) The organic phase was dried, then filtered and washed with DCM (200 mL). The filtrate and washings were combined and concentrated in vacuo at 30 ℃ for 1 hour, then further dried under high vacuum, two steps yielding 220g>99% by weight of (R) -4-methyl-1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide, isolated in a yield of 91.8% (corrected).¹H NMR(400MHz,CDCl₃):δ4.66(dd,J＝9.2,6.0Hz,1H),4.41(qdd,J＝6.4,6.0,2.8Hz,1H),4.19(dd,J＝9.2,2.8Hz,1H),1.54(s,9H),1.50(d,J＝6.4Hz,3H)。

The other oxidation reactions were generally carried out as per the above procedure, with changes in oxidant, catalyst and solvent. The results are reported in table 1 below, where "exp." refers to the experimental number, "product" refers to (R) -4-methyl-1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide, "SM" refers to Boc-alaninol starting material, "LC a%" refers to the area percent purity according to liquid chromatography, and "ND" refers to not detected. The reaction temperatures for experiments 1 and 3-9 were 0-25 deg.C and for experiment 2 0-40 deg.C. The reaction time for experiments 1-4 and 7 was 4 hours, for experiments 5 and 6 was 8 hours, and for experiments 8 and 9 was 18 hours.

Table 1: oxidant catalyst conditions and productivity

At-15 ℃ and N₂To a mixture of indole (7.4g,63.2mmol,1.5 equiv.) and CuCl (5.4g,54.7mmol,1.3 equiv.) in DCM (60mL) was added MeMgCl (3.0M in THF, 18.7mL,56mmol,1.33 equiv.) over 10 min. The resulting pale yellow mixture was stirred at-20 ℃ for 10 minutes, then at-10 ℃ and N₂A solution of (R) -4-methyl-1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide (10.0g,42.1mmol,1.0 eq) in DCM (40ml) was added dropwise over 30 minutes. The mixture is stirred at-10 ℃ for 2 hours or until the reaction is complete as judged by TLC (disappearance of (R) -4-methyl-1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide) (PE/EA ═ 5/1) or by GC. The reaction was quenched by the addition of 10% citric acid (100mL) while maintaining the internal temperature<5 ℃ is adopted. The phases were separated and the aqueous phase was extracted with DCM (100 mL. times.2). The organic phases were combined and washed with brine (100 mL. times.2), then activated carbon (5g) and Na were added to the organic phase₂SO₄(10g) In that respect The resulting mixture was stirred at room temperature for 30 minutes and then filtered. The filter cake was washed with DCM (50 mL. times.2). The filtrate and washings were combined and concentrated in vacuo at 30 ℃ to give crude tert-butyl (R) - (1- (1H-indol-3-yl) propan-2-yl) carbamate (16.9g,40.9 LCA%). To the crude tert-butyl (R) - (1- (1H-indol-3-yl) propan-2-yl) carbamate was added heptane (200ml) and the mixture was stirred at room temperature for 1 hour, during which time an off-white solid gradually precipitated. The solid was collected by filtration and the filter cake was washed with heptane (17 mL. times.3). The solid was dried under high vacuum at 25 ℃ to give 7.0g of tert-butyl (R) - (1- (1H-indol-3-yl) propan-2-yl) carbamate (25.5mmol, 97A%, 99 wt%). ¹H NMR(400MHz,DMSO-d₆)δ10.76(s,1H),7.55(d,J＝7.9Hz,1H),7.32(dt,J＝8.1,1.0Hz,1H),7.09(d,J＝2.3Hz,1H),7.05(ddd,J＝8.2,7.0,1.2Hz,1H),6.96(ddd,J＝8.0,6.9,1.1Hz,1H),6.71(d,J＝8.0Hz,1H),3.76-3.69(m,1H),2.86(dd,J＝13.9,5.8Hz,1H),2.64(dd,J＝14.1,7.7Hz,1H),1.37(s,9H),1.00(d,J＝6.6Hz,3H)。

Other indole alkylation reactions were generally carried out in accordance with the procedure above, with varying stoichiometry of the copper catalyst species and the Grignard reagent. The results are reported in table 2 below, where "exp." refers to the experimental number, "CuX" refers to the copper catalyst species, "eq." refers to the equivalent number, "Prod" refers to (R) - (1- (1H-indol-3-yl) propan-2-yl) tert-butyl carbamate, "N1" refers to the byproduct where the indoleamine was alkylated, "BA" refers to the dialkyl byproduct, "AY" refers to the yield reduced according to LC analysis, "a%" refers to the area percent purity according to liquid chromatography, "ND" refers to no detection.

Table 2: indole alkylation reaction conditions and yields

The other indole alkylation reactions were generally carried out as per the above procedure, with the reaction temperature being varied. The results are reported in table 3 below, where "exp." refers to the experimental number, "G temp" refers to the grignard reagent addition temperature (c), "S temp" refers to the sulfamate addition temperature (c), "Prod" refers to t-butyl (R) - (1- (1H-indol-3-yl) propan-2-yl) carbamate, "N1" refers to the byproduct where the indoleamine is alkylated, "BA" refers to the dialkyl byproduct, "AY" refers to the yield as converted from LC analysis, and "a%" refers to the area percent purity as per liquid chromatography.

Table 3: indole alkylation experiments at different temperatures

At 0 ℃ and N₂To a solution of tert-butyl (R) - (1- (1H-indol-3-yl) propan-2-yl) carbamate (0.5g,1.8mmol, 92A%) in MeOH (5mL,10 vol) over 10 min under an atmosphereHCl/MeOH (10M,1.0mL,18mmol) was added dropwise. The resulting solution was stirred at 0 ℃ for 2 hours and then at 25-30 ℃ for 1 hour. The solution was concentrated under vacuum at 30 ℃, diluted with water (10mL), and extracted with DCM (10mL × 2). The pH of the aqueous phase was adjusted to-13 with 1M aqueous NaOH at 0-10 ℃ and then extracted with DCM (20 mL. times.4). With Na₂SO₄(10g) The organic phase was dried. The drying agent was filtered and the filter cake was washed with DCM (10 mL). The filtrate and washings were combined and concentrated under vacuum at 30 ℃ to give 0.31g of crude (R) -1- (1H-indol-3-yl) propan-2-amine with a purity of 95.8 LCA% and 99.2% ee in 97% isolated yield.¹H NMR:400MHz(CDCl₃):δ1.20(d,J＝6,3H),1.56(s,br,2H),2.69(dd,J＝14,8,1H),2.91(dd,J＝14,4,1H),3.30-3.33(m,1H),7.05(s,1H),7.14(t,J＝7,1H),7.22(t,J＝7,1H),7.38(d,J＝8,1H),7.64(d,J＝8,1H),8.27(s,1H)。

Example 6

Preparation of (R) -3- ((1- (1H-indol-3-yl) propan-2-yl) amino) -2, 2-difluoropropan-1-ol

Thionyl chloride (58.4kg,491.4mol,1.2 equiv.) was added to a solution of 2, 2-difluoropropane-1, 3-diol (51kg,90 wt%, 409.5mol,1 equiv.) in DCM (332kg,5 volumes) at 20-25 deg.C over 2 hours. The reaction mixture was heated to 30-35 ℃, stirred for 2 hours, and ice water (255kg) was added to quench the reaction. The phases were separated and the aqueous phase was extracted with DCM. The organic phases were combined and washed with water. To the crude organic phase were added water (255kg) and FeCl ₃(1.6kg) and the two phase mixture was cooled to-3 ℃. Bleaching agent [ NaClO (8.1 wt%), 680kg,1556mol,3.8 equiv ] was then added dropwise at-5 to 1 deg.C over 5 hours]And the reaction mixture was stirred at 0 ℃ for 1 hour. The reaction mixture was filtered through celite. The phases were separated and the aqueous phase was extracted with DCM. The organic phases were combined and washed with Na₂SO₃Washed with brine and then with Na₂SO₄And (5) drying. The drying agent was filtered off and the filtrate was concentrated to about 100L. Adding to the obtained suspensionHeptane (80kg) was added and the mixture was further concentrated to about 100L. The solid was collected by filtration and dried in vacuo to give 52.01kg of 5, 5-difluoro-1, 3, 2-dioxathiane 2, 2-dioxide as off-white crystals (72% yield, obtained in two steps starting from 2, 2-difluoropropane-1, 3-diol).¹H NMR(400MHz,DMSO-d₆)δ5.14(t,J＝10.8Hz,1H)。

Various other catalysts were evaluated for the preparation of 5, 5-difluoro-1, 3, 2-dioxathiahexane 2, 2-dioxide generally following the procedure immediately above. The results are reported in table 4 below, where "exp." refers to the experimental number, "diol" refers to 2, 2-difluoropropane-1, 3-diol, "Prod" refers to 90 wt.% 5, 5-difluoro-1, 3, 2-dioxacyclohexane 2, 2-dioxide, "yield" refers to the yield converted from the analytical results. Each reaction was quenched with 5 volumes of water.

Table 4: conditions for the preparation of 5, 5-difluoro-1, 3, 2-dioxathiane 2, 2-dioxide

In a 2L flask was placed (R) -1- (1H-indol-3-yl) propan-2-amine (99% by weight, 100g,568.2mmol,1 eq.), 5-difluoro-1, 3, 2-dioxacyclohexane 2, 2-dioxide (97.9% by weight, 108g,608mmol,1.07 eq.), K₂CO₃(55g,398mmol,0.7 equiv.) and acetonitrile (1L,10 vol.). The reaction mixture was heated to 80 ℃ and stirred for 4 hours. The reaction was cooled to 35 ℃ and filtered. The filter cake was washed with acetonitrile (100 mL. times.2) and p-TsOH monohydrate (119g,625.6mmol,1.1 equiv.) and water (100mL,1 volume) were added to the combined filtrates. The resulting biphasic mixture was heated to 80 ℃ and stirred for 3 hours. The mixture was then poured into 1L of ice water and heated<Saturated Na at 5 deg.C₂CO₃(350mL) the pH of the mixture was adjusted to 9. The phases were separated and the aqueous phase was extracted with i-PrOAc (500 mL. times.2). Combining the organic phases andwashed with water (500mL) and brine (500 mL. times.2) and then Na₂SO₄(30g) And (5) drying. The drying agent was filtered off and the filter cake was washed with i-PrOAc (100 mL. times.2). The filtrate and washings were combined and concentrated under vacuum at 40 ℃. The residue was dissolved in i-PrOAc (200mL) and heated to 60 ℃. Heptane (800mL) was added dropwise at 60 ℃, and then the resulting mixture was stirred for 10 minutes. The mixture was slowly cooled to 30-35 ℃ over 2 hours, then further cooled to 0 ℃. After stirring for 10 min, the solid was collected by filtration and the filter cake was washed with heptane (100mL × 2). The solid thus obtained was dried under vacuum at 45 ℃ to give (R) -3- ((1- (1H-indol-3-yl) propan-2-yl) amino) -2, 2-difluoropropan-1-ol (155g,99.2 LCA%, 96 wt%, isolated yield 97.6%). ¹H NMR(400MHz,DMSO-d₆)δ10.79(s,1H),7.51(dd,J＝7.9,1.2Hz,1H),7.33(dt,J＝8.2,1.0Hz,1H),7.13(d,J＝2.3Hz,1H),7.05(ddd,J＝8.2,6.9,1.3Hz,1H),6.96(ddd,J＝8.0,6.9,1.2Hz,1H),5.35(t,J＝6.3Hz,1H),3.61(td,J＝13.8,5.2Hz,2H),3.03-2.91(m,3H),2.83(dd,J＝14.0,5.7Hz,1H),2.59(dd,J＝14.0,7.2Hz,1H),1.69(s,1H),0.96(d,J＝6.2Hz,3H)。

Example 7

Preparation of 3- ((1R,3R) -1- (2, 6-difluoro-4- ((1- (3-fluoropropyl) azetidin-3-yl) amino) phenyl) -3-methyl-1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b ] indol-2-yl) -2, 2-difluoropropan-1-ol (2R,3R) -2, 3-dihydroxysuccinate

In step 1, 4-bromo-2, 6-difluorobenzaldehyde (131.79g,596.35mmol), (R) -3- ((1- (1H-indol-3-yl) propan-2-yl) amino) -2, 2-difluoropropan-1-ol (160g,596.35mmol), acetic acid (51.26mL,894.52mmol), and toluene were combined in a flask with stirring. The reaction was heated to 75 ℃ and held overnight, cooled, and then diluted with toluene. The resulting solution was then quenched with aqueous potassium carbonate, washed with brine and water, and treated with activated carbon. After filtration, the solution was concentrated and crystallized from toluene/heptane to give 3- ((1R,3R) -1- (4-bromo) as a pale yellow solid-2, 6-difluorophenyl) -3-methyl-1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b]Indol-2-yl) -2, 2-difluoropropan-1-ol in 81% yield.¹H NMR(400MHz,DMSO-d₆)δ10.59(s,1H),7.45–7.36(m,3H),7.20(d,J＝8.1Hz,1H),7.05–6.92(m,2H),5.29(t,J＝6.1Hz,1H),5.21(s,1H),3.71–3.55(m,1H),3.53–3.38(m,2H),3.17(q,J＝15.2Hz,1H),2.89(ddd,J＝15.3,4.8,1.5Hz,1H),2.71–2.55(m,2H),1.08(d,J＝6.5Hz,3H)。MS([M+H]+)：C₂₁H₁₉BrF₄N₂O calculated 470.06, found 470.80.

Alternatively, 4-bromo-2, 6-difluorobenzaldehyde (67.2g,304mmol), (R) -3- ((1- (1H-indol-3-yl) propan-2-yl) amino) -2, 2-difluoropropan-1-ol (80.0g,298mmol), acetic acid (25.6mL,447mmol) and methanol were combined in a stirred flask. The mixture was refluxed for 24 hours and then cooled. A solid was precipitated from the resulting solution by adding an aqueous solution of potassium carbonate. The resulting slurry was filtered and washed to give 3- ((1R,3R) -1- (4-bromo-2, 6-difluorophenyl) -3-methyl-1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b ] indol-2-yl) -2, 2-difluoropropan-1-ol as a pale yellow solid in 97% yield.

In steps 2 and 3, 3- ((1R,3R) -1- (4-bromo-2, 6-difluorophenyl) -3-methyl-1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b ] was combined in a stirred flask]Indol-2-yl) -2, 2-difluoropropan-1-ol (100g,212.2mmol), 1- (3-fluoropropyl) azetidin-3-aminoethane-1, 2-disulfonate (82.09g,254.6mmol), acetonitrile, DBU (1061mmol,161.5g,159.4mL), followed by Pd-175(5.304mmol,4.144 g). The reaction was heated to 75 ℃ for 2 hours, cooled, concentrated, and then diluted with methyl tert-butyl ether. The resulting solution was worked up with aqueous ammonium chloride, brine and water and then purged with SiliaMetS thiol. After filtration, the solution was concentrated, diluted with ethanol and crystallized with tartaric acid to give 3- ((1R,3R) -1- (2, 6-difluoro-4- ((1- (3-fluoropropyl) azetidin-3-yl) amino) phenyl) -3-methyl-1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b ] as a yellow solid]Indol-2-yl) -2, 2-difluoropropan-1-ol (2R,3R) -2, 3-dihydroxysuccinate in a yield of 90%, followed by filtration and washing.¹H NMR(400MHz,DMSO-d₆)δ10.52(s,1H),7.38(dd,J＝7.5,1.3Hz,1H),7.21–7.16(m,1H),7.02–6.90(m,2H),6.82(d,J＝6.9Hz,1H),6.18–6.08(m,2H),5.07(s,1H),4.53(t,J＝5.8Hz,1H),4.42(t,J＝5.9Hz,1H),4.18(s,2H),4.14–4.05(m,1H),3.93(ddt,J＝9.1,7.0,3.5Hz,2H),3.74–3.60(m,1H),3.51–3.32(m,2H),3.21–3.02(m,3H),2.88–2.73(m,3H),2.70–2.51(m,2H),1.83–1.66(m,2H),1.09–1.05(m,3H)。MS([M+H]+)：C₂₇H₃₁F₅N₄O calculated 522.24, found 523.00.

Example 8

Preparation of 3- ((1R,3R) -1- (2, 6-difluoro-4- ((1- (3-fluoropropyl) azetidin-3-yl) amino) phenyl) -3-methyl-1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b ] indol-2-yl) -2, 2-difluoropropan-1-ol (2R,3R) -2, 3-dihydroxysuccinate

In steps 1-4, 4-bromo-2, 6-difluorobenzaldehyde (75.0g,0.339mol,100 mol%), p-toluenesulfonic acid monohydrate (162mg,0.000849mol,0.250 mol%) and toluene (225mL) were added to the reactor. Triethyl orthoformate (55.4g,62.1mL,0.373mol,110 mol%) was added over 15 minutes at room temperature, the mixture was stirred at room temperature for 1 hour, and then the mixture was distilled to give a toluene solution of 5-bromo-2- (diethoxymethyl) -1, 3-difluorobenzene. To another reactor was added 1- (3-fluoropropyl) azetidin-3-amine 2- (trioxane radical thio) ethane-1-sulfonate (131.3g,0.407mol,120 mol%) and acetonitrile (656 mL). DBU (124.0g,122.8mL,0.814mol,240 mol%) was added over 15 minutes at room temperature, and the mixture was stirred at room temperature for 2 hours, distilled with toluene, and filtered to give a toluene solution of 1- (3-fluoropropyl) azetidin-3-amine, which was added along with NaOtBu (39.14g,0.407mol,120 mol%) to a toluene solution of 5-bromo-2- (diethoxymethyl) -1, 3-difluorobenzene. The mixture was bubbled with Brettphos Pd G3(3.076G,0.00309mol,1.00 mol%), bubbled, heated at 60 ℃ for 18 hours, cooled, quenched with water, and washed twice with water. Silamets Thiol (20.0g) was added and the mixture was heated at 50 ℃ for 2 hours, cooled, and filtered to give A toluene solution of N- (4- (diethoxymethyl) -3, 5-difluorophenyl) -1- (3-fluoropropyl) azetidin-3-amine. Acetic acid (21.4mL,0.373mol,110 mol%) and water (300mL) were added and the mixture was held at room temperature for 2 hours. The aqueous phase was separated, treated with aqueous NaOH (50 wt%, 21.5mL,0.407mol,120 mol%) and seeded with 2, 6-difluoro-4- ((1- (3-fluoropropyl) azetidin-3-yl) amino) benzaldehyde (923mg,0.00339mol,1.00 mol%). The resulting solid was filtered, washed with water, and dried to give 2, 6-difluoro-4- ((1- (3-fluoropropyl) azetidin-3-yl) amino) benzaldehyde as a white solid (77.9g, 84.3% yield).¹H NMR(400MHz,CDCl₃)δ10.05(dd,J＝1.2Hz,1H),6.05-5.97(m,2H),5.03(d,J＝6.4Hz,1H),4.54(t,J＝6.0Hz,1H),4.42(t,J＝6.0Hz,1H),4.14-4.03(m,1H),3.70(td,J＝6.8,1.6Hz,2H),2.99-2.93(m,2H),2.59(t,J＝7.2Hz,2H),1.83-1.66(m,2H)。MS：C₁₃H₁₅F₃N₂O[M+H]⁺The calculated value is 273.1, and the measured value is 273.0.

In step 5, (R) -3- ((1- (1H-indol-3-yl) propan-2-yl) amino) -2, 2-difluoropropan-1-ol (6.60kg,24.60mol,100 mol%), 2, 6-difluoro-4- ((1- (3-fluoropropyl) azetidin-3-yl) amino) benzaldehyde (6.70kg,24.60mol,100 mol%), L-tartaric acid (5.54kg,36.90mol,150 mol%) and ethanol (39.6L) were added to the reactor. The reaction mixture was heated at 70 ℃ for 2 hours, seeded with 3- ((1R,3R) -1- (2, 6-difluoro-4- ((1- (3-fluoropropyl) azetidin-3-yl) amino) phenyl) -3-methyl-1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b ] indol-2-yl) -2, 2-difluoropropan-1-ol (2R,3R) -2, 3-dihydroxysuccinate (0.0827kg,0.123mol,0.5 mol%), stirred at 70 ℃ for 2 days, quenched with ethanol (26.4L), cooled, and the solid collected by filtration. The solid was washed with ethanol and dried in vacuo to give 3- ((1R,3R) -1- (2, 6-difluoro-4- ((1- (3-fluoropropyl) azetidin-3-yl) amino) phenyl) -3-methyl-1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b ] indol-2-yl) -2, 2-difluoropropan-1-ol (2R,3R) -2, 3-dihydroxysuccinate as an off-white solid (12.7kg, 78% yield).

The various acids other than tartaric acid and the comparative example using tartaric acid were evaluated for the step 5 ring closure reaction generally in the same manner as above. The results are reported in table 5 below, where "exp." refers to the experimental number and "Conv" refers to the conversion to the fused tricyclic structure. Tartrate results in a substantial increase in the final yield. In addition, the tartrate salt minimizes the occurrence of by-product oligomers formed during the synthesis, resulting in a higher product purity and a lower degree of epimerization of the final compound product.

Table 5: acids tested for Ring closure reaction of Compound A

Example 9:

and (4) recrystallizing the compound B.

To a 250mL reactor was added crude compound B (4.00g,5.95mmol) in a mixture of MeOH (90.0mL) and EtOH (10.0 mL). The slurry was heated to 60 ℃ and it became homogeneous. Seed crystals of compound B (200mg,0.297mmol,5 mol%) were added to the solution. The slurry was distilled with EtOH, cooled to 25 ℃ over 1 hour, held at 25 ℃ for 1 hour, filtered, and dried to give compound B as an off-white solid (3.83g, 91% yield).

Example 10:

recrystallization of compound B:

example 10A: A30L reactor was charged with crude compound B (1.26kg,1.88mol,100 mol%) and MTBE (6.30L,5.00 mL/g). To the slurry was added a solution of NaOH (154g,3.85mol,205 mol%) in water (6.30L,5.00 mL/g). The reaction mixture was stirred at 20 ℃ for 30 minutes. The top organic layer was washed twice with water (2.53L,2.00mL/g) and passed through a charcoal column and distilled with EtOH to give compound B as a free base solution in EtOH.

Example 10B: A20L reactor was charged with L-tartaric acid (296g,1.97mol,105 mol%), EtOH (2.52L,2.00mL/g) and heated to 70 ℃. A 20% solution of compound B free base was transferred to a 20L reactor. Seed crystals of compound B (25.2g,0.0375mol,2 mol%) were added to the solution. The remaining solution of compound B free base was transferred to a 20L reactor over 1 hour, aged at 70 ℃ for 30 minutes, cooled to 20 ℃ over 5 hours, aged at 20 ℃ for a minimum of 2 hours, filtered, washed three times with EtOH (2.52L,2.00mL/g), and dried to give compound B as an off-white solid (1.12kg, 89%).

Example 11:

as understood in the art, the compounds provided herein are characterized by mass spectrometry and/or NMR techniques. The stereochemistry of the compounds of this example was confirmed unless otherwise indicated.

Compound (M1)

Measured m/z: 672.64.

compound (M2)

Measured m/z: 672.64.

compound (M3)

Measured m/z: 652.63 Compound (M4)

Measured m/z: 540.57 (mixture of stereoisomers).

Example 12:

enzymatic conversion:

screening of the transaminase in kinetic resolution mode of racemic α -methyltryptamine revealed an enzyme with sufficient (R) -enantioselectivity for the asymmetric reductive amination process and sufficient (S) -enantioselectivity for the kinetic resolution process. Exemplary transaminases are listed in table 6.

Table 6: enantioselective Transaminase (TA):

asymmetric reduction was performed using the transaminase TA-P2-A07 in buffer, isopropylamine and a 5g scale organic co-solvent such as DMSO or acetonitrile. After 1 day, compound (XXI) was converted to compound (3) as described herein to an extent of greater than 95%, with an Enantiomeric Excess (EE) of greater than 99%.

Reductive amination was also performed in an organic solvent containing a small amount of buffer and isopropylamine, in which the transaminase TA-P2-A07 was immobilized on a solid support. After 4 weeks, compound (XXI) is converted to compound (3) with a conversion of greater than 95% and greater than 99% EE. Organic solvents allow higher substrate loadings of up to 5% [ weight/weight ].

The kinetic resolution is carried out in the presence of the transaminase ATA12 (1) in whole cells, (2) in cell-free lysates or (3) in crude lyophilizates in pyruvate-containing buffers and organic cosolvents, such as acetonitrile. Enantiomeric excess of > 99% was obtained. A degree of conversion to the compound (3) equal to or higher than 50% is obtained. The undesired enantiomer is depleted by oxidative deamination to the ketone.

Sequence identification of selected TAs:

3FCR Y59F/Y87F/T231G: amino acid (SEQ ID NO:1)

3FCR Y59W/Y87F/T231A: amino acid (SEQ ID NO:2)

3FCR Y59F/S86A/Y87F/Y152F/T231A/I234M/L382M: amino acid (SEQ ID NO:3)

3HMU I264V: amino acid (SEQ ID NO:4)

Bold underlined residues correspond to mutations in the native sequence.

Example 13:

characterization of free base, salt and polymorph of Compound A

Abbreviations:

MIBK methyl isobutyl ketone

ACN acetonitrile

EtOAc ethyl acetate

EtOH ethanol

MTBE methyl tert-butyl ether

IPAc acetic acid isopropyl ester

MeTHF methyl tetrahydrofuran

CPME Cyclopentylmethyl Ether

MeOH methanol

THF tetrahydrofuran

IPA isopropyl alcohol

DMSO dimethyl sulfoxide

DMC dimethyl carbonate

MEK methyl Ethyl Ketone

DCM dichloromethane

And (4) screening a free base polymorphic substance. A 96-well automated High Throughput Screening (HTS) was performed using the Symyx CM2 system (Freeslate inc., CA) to identify potential polymorphic forms of compound a free base. Compound a was dispensed into each well (8 mg/well) using an automatic powder dispensing accessory, then 800 μ l of solvent (neat or a mixture) was added and the slurry was stirred at 50 ℃ for 2 hours. Compound a was initially distributed in a slurry plate using ethyl acetate (for tartrate) or MIBK (for fumarate) to maintain the solid form. The supernatant was filtered from the master plate and distributed to three separate plates for evaporation, precipitated by anti-solvent addition and controlled cooling, from 50 ℃ to 20 ℃ over 8-10 hours. In all cases the residual solvent was evaporated or siphoned off and the solid was examined using polarized light microscopy and XRPD.

Example 14:

and (4) salt screening. Based on the approximate solubility data of the free base and the list of acids required, five solvent systems were used in the screening. Approximately 20mg of the free base amorphous compound was first dispersed in 0.5mL of the selected solvent in a glass vial, and then the corresponding acid was added at a molar charge ratio of 1: 1. Due to the presence of two basic functional groups, an additional molar ratio (acid/free base) of 2:1 was tried for HCl. The mixture was stirred at room temperature overnight. The resulting solid was analyzed by XRPD. The clear solution obtained after stirring was stirred at 5 ℃ for 2 days and then at ACN/H₂0.5mL of H was added to each clear solution in O (19:1, v/v)₂O while adding 0.5mL of n-heptane to each clear solution in the other solvent system, then stirring at 5 ℃ for about 3 days and transferring the final clear solution to slow evaporation at room temperature to determine as many crystalline hits (hits) as possible.

The first round of screening identified crystalline form hits as provided in table 7. Tartrate and fumarate salts were further scaled up to the 50mg-1.5g scale for further characterization. Testing under different solvent systems and conditions allows a) in-depth characterization of the different polymorphic forms obtained as hits in the screening and b) determination of the conditions that inhibit and control the formation of cis-epimers. The epimer content varied between < 1% and 22% in different free base batches.

Table 7: salt screening and crystalline form hits against compound a.

The method comprises the following steps:

ambient X-ray powder diffraction (XRPD). XRPD patterns were acquired using a PANalytical Empyrean powder X-ray diffractometer (PANalytical Inc. (Lelyweg, the netherlands)). The powder samples were packaged in zero background silicon holders and run in reflection mode (Bragg Brentano configuration). The instrument was equipped with a Cu Ka source and the tube voltage and current were 45kV and 40mA, respectively. Data was collected from 3.0 to 40.0 ° 2 θ at ambient temperature using 0.0263 ° steps and a spin speed of 8 seconds. The incident beam path was equipped with a 0.02 ° soller slit, a fixed 1 ° anti-scatter slit, a fixed 10mm incident beam mask and an automatic mode programmable scatter slit. A beam knife for a linear detector is used. The diffracted beam was equipped with a 0.02 ° soller slit, an auto-mode programmable anti-scatter slit, and a nickel K-beta filter. The PIXcel 1D detector was used in scan line detector (1D) mode. Using commercial software (Version 9, Materials Data inc. (liformer, ca)) to analyze the Data.

And (5) water absorption analysis. Approximately 5-6mg of the powder sample was placed in a sample pan of an automatic water absorption analyzer (Q5000SA, TA instruments, N.C. Del.) at 25 ℃ and a nitrogen flow rate of 200 mL/min. The samples were first "dried" at 0% RH for a total of 400 minutes (at 60 ℃ then 25 ℃), then the RH was incremented from 0-90% in 10% increments with a residence time of 200 minutes at each RH. The RH was then decremented by 10% back to 0% RH using the same protocol.

Differential sweepCalorimetry (DSC). Using DSC Q2000 equipped with a cryo-cooling attachment^TM(TA instruments (N.C. Del.) approximately 3-8mg of the powder sample was analyzed. Packaging the samples in non-airtight disks (Tzero)^TMAluminum pan) and heated from 0 ℃ to 200 ℃ typically at 10 ℃/min under a dry nitrogen purge. The instrument was calibrated using sapphire (baseline) and indium (temperature and unit cell constants). Data were analyzed using commercial software (Universal Analysis 2000, version 4.7A, TA Instruments).

Thermogravimetric methods (TGA). In a thermogravimetric analyzer (Discovery TGA, TA instruments), a 3-5mg sample of compound a was heated from room temperature to 350 ℃ in an open aluminum pan under a dry nitrogen purge at a heating rate of 10 ℃/min. Use ofAnd nickel for temperature calibration. For weight calibration, 100mg and 1gm standard weights were used.

Polarized Light Microscopy (PLM). The samples were dispersed in silicone oil and observed under crossed polarizers with a video-enhanced Leica DM 4000B microscope equipped with a high resolution CCD camera and an electric stage (Clemex Technologies Inc. (quebecloguey, canada)) at a magnification of 200X. Micrographs were taken using Clemex Vision PE software (Clemex Technologies Inc. (quebecloguey, canada)).

Scanning Electron Microscopy (SEM). Powder samples were sputter plated on SEM sample stage and then examined using a desktop Phenom SEM (Nanoscience Instruments, Inc. Micrographs were taken at different magnifications.

Particle Size Distribution (PSD). Particle size analysis was performed using a Malvern Mastersizer 2000 instrument equipped with a hydro 2000SM moisture dispersion accessory (Malvern Instruments Ltd. (morvin, england)). Weigh-40 mg of API into a vial and add 1mL of 0.1% Span 85/heptane. The vial was sonicated for 10 seconds, about 0.5mL was added to the sampler at a stirring rate of 1500rpm, and PSD was performed at a 10-20% ambiguity. Since there are a large number of clusters in the sample, which quickly settle out of the suspension, the dispersant was changed to 0.2% Span 85/heptane to stabilize the suspension. 2 external sonications for two 5 minutes were applied to break up clusters and to acquire PLM images before and after sonication. Aliquots were mixed in a sampler for 2 minutes prior to data acquisition to ensure homogeneity. The instrument was rinsed twice with Isopropanol (IPA) and once with heptane and then filled with 0.1% Span 85/heptane for each sample. After the last sample was run, the instrument was rinsed once with IPA. Replicate data have been reported for 5 minutes sonication.

BET surface area analysis. Surface area measurements were made using a Micromeritics ASAP 2460(Micromeritics Instrument Corp., Ga.). 500mg-1g of sample was weighed into an empty ASAP 2460 tube and placed on a Smart VacPrep, degassed for 24 hours at ambient conditions and then exposed to krypton adsorption at 25 ℃ and a dwell pressure of 100 mmHg. 11 point measurements were made over a relative pressure range of 0.050-0.300 and the data was analyzed using Microactive software supplied by the supplier.

Solid state nuclear magnetic resonance spectroscopy (SSNMR). All were performed using a 500Mhz Bruker instrument (Bruker BioSpin GmbH (Carlsuhe, Germany))¹³C (at 8kHz rotation speed) SSNMR experiments. Acquisition using CP/TOSS sequences¹³And C, data. 1-2K scans were collected for signal averaging. A contact time of 2 milliseconds and a cycle delay of 5 seconds were used. The decoupling was performed using a Spinal 64 sequence with a pulse length of 5.3 microseconds. Using 2.9 microseconds¹H90 degree pulse length. All were performed using a 500Mhz Bruker instrument¹⁹F (at 14kHz rotation speed) SSNMR experiments. Acquisition using CP and direct polarization sequence¹⁹And F, data. 64-256K scans were collected for signal averaging. A contact time of 750 microseconds and a cycle delay of 7 seconds were used. Using 3.54 microseconds ¹H90 degree pulse length.

Example 15:

preliminary characterization of compound a free base. Compound a free base was found to be amorphous. The starting material free base compound a was characterized by XRPD, TGA and mDSC prior to screening. As shown by the characterization results in fig. 32 and fig. 33, the compound a starting material was amorphous, ranging to 220 in TGAWeight loss before c was 9.3% and no significant glass transition signal in mDSC. Addition of anti-solvent MeOH/H by shaking₂O (3:20, v/v) and air dried for-7 days to obtain a white solid of the free base compound A.

And (4) screening polymorphic substances. The solubility of free base compound a in 16 solvents at room temperature was estimated (table 8). Polymorph screening experiments were performed using different solution crystallization or solid phase transition methods. The methods used and the crystalline forms determined are summarized in table 9.

Table 8: approximate solubility of free base Compound A

Solvent(s)	Solubility (mg/mL)	Solvent(s)	Solubility (mg/mL)
				Acetone (II)	S＞60.0	MIBK	S＞60.0
2-propanol	S＞60.0	MTBE	S＞60.0
				EtOAc	S＞60.0	IPAc	S＞60.0
ACN	S＞60.0	MeTHF	S＞60.0
				H2O	S＜1.9*	CPME	S＞44.0*
1, 4-dioxane	S＞60.0	N-heptane	S＜2.1*
				EtOH	S＞60.0	Cyclohexane	S＜1.9*
Toluene	S＞60.0	Isobutanol	S＞40.0*

Table 9: summary of polymorphic forms of free base Compound A

The solid vapor diffuses. Solid vapor diffusion experiments were performed using 13 different solvents. For each experiment, approximately 15mg of starting material was weighed into a 3mL vial and then placed into a 20mL vial with 2mL of the corresponding volatile solvent. The 20mL vial was sealed with a cap and left at room temperature for 11 days to allow the solvent vapor to interact with the solid sample. The isolated solid was tested by XRPD. As summarized in table 10, only oil or amorphous material was obtained.

Table 10: summary of solid vapor diffusion experiments

Solvent(s)	End result
		H2O	Amorphous form
DCM	N/A
		EtOH	Oil
MeOH	Oil
		ACN	Oil
THF	N/A
		CHCl3	Oil
Acetone (II)	N/A
		DMF	Oil
EtOAc	N/A
		1, 4-dioxane	N/A
IPA	Oil
		DMSO	Oil

And (3) converting the slurry at room temperature. Slurry conversion experiments were performed in different solvent systems at room temperature. Approximately 40mg of starting material was suspended in 0.3mL of solvent in a 1.5mL glass vial. After stirring, all clear solutions were transferred to 5 ℃ and then slowly evaporated at room temperature for 3 days. The results in summary show that only amorphous, gel or oil is obtained.

Table 11: summary of slurry conversion experiments for free base Compound A

No application of Slow Evaporation

Solid was centrifuged after 4 days stirring at room temperature and analyzed by XRPD

N/A: no solid was obtained

Anti-solvent addition. A total of 15 anti-solvent addition experiments were performed. About 30mg of the starting material was weighed into a 20mL glass vial and dissolved in 0.15mL of the corresponding solvent at room temperature. The anti-solvent was added stepwise until precipitation occurred or the total amount of anti-solvent reached 12mL and the sample was magnetically stirred. The precipitate was isolated for XRPD analysis. If no solids were observed, the clear solution was magnetically stirred at 5 ℃ overnight and then evaporated at room temperature. The results in table 12 show that only amorphous or gel was produced.

Table 12: summary of anti-solvent addition experiments for free base Compound A

The liquid vapor diffuses. Liquid vapor diffusion experiments were performed under 14 conditions (table 13). Approximately 30mg of starting material was weighed into each 3mL glass vial. The corresponding solvent was added to obtain a solution. The vial was sealed into a 20mL glass vial with 3mL of the corresponding anti-solvent and kept at room temperature, allowing the vapor to interact with the solution for about 11 days. The precipitate was isolated for XRPD analysis. The clear solution was transferred to evaporation at room temperature.

Table 13: summary of liquid vapor diffusion experiments for free base Compound A

Slowly evaporate. The slow evaporation experiment was performed under 12 conditions. For each experiment, about 20mg of starting material was weighed into a 3mL glass vial, and the corresponding solvent or solvent mixture was then added to give a clear solution. Subsequently, the vials were covered with parafilm with 3-4 pinholes and kept at 4 ℃ to allow slow evaporation of the solution. Only gels were obtained as summarized in table 14.

Table 14: summary of Slow Evaporation experiments for free base Compound A

Table 15 summarizes the forms obtained via manual screening as described herein.

Table 15: polymorphic forms of Compound B

Example 16:

Characterization of compound B, form a. Compound B form a was prepared on a 200mg scale via solution reactive crystallization in acetone as confirmed by XRPD (fig. 1). As shown in fig. 2a and 2b, a weight loss of about 7.2% before 125 ℃ was observed in the TGA and DSC results showed an endotherm at 124.3 ℃ (onset temperature).¹H NMR showed a molar ratio of 0.98 (acid/free base) and 5.6% acetone was detected (molar ratio to free base 0.69). A heating experiment was performed to further identify form a. No change in form was observed after heating form a to 90 ℃, but the sample became amorphous after heating to 140 ℃. A significant amount of acetone (4.5%) was observed after heating the form a sample to 90 ℃. The form a sample consisted primarily of fine particles and some aggregates (fig. 3). Based on the data collected, compound B, form a, was an acetone solvate and loss of solvent occurred with melting.

Table 16: representative XRPD peaks of compound B form a:

preparation of compound B form a. About 57.5mg tartaric acid was weighed into a 5mL glass vial and 2.0mL acetone was added to give a clear solution. To a 5mL vial, this clear acid solution was added to 2.0mL of a stock solution of the free base in acetone (-100 mg/mL) at a molar ratio of 1:1 and stirred at room temperature. The solution became cloudy by adding about 1mg of compound B form a seed. The sample was stirred overnight and XRPD measurements were then performed as described herein. The profile is consistent with compound B, form a. The suspension was then stirred at room temperature for a further 24 hours and the filter cake was dried at 50 ℃ for 1.5 hours. Yield: 170.4mg, yield 65.3%.

Example 17:

characterization of compound B form B. Compound B form B was prepared on a 200mg scale via reactive crystallization of a solution in EtOAc as confirmed by XRPD (figure 4). As shown in fig. 5a and 5b, a limited weight loss of about 1.3% before 140 ℃ was observed in the TGA and DSC results showed a melting endotherm at 156.7 ℃ (onset temperature). The stoichiometry was found to be 1.08 (acid/free base) and was determined by¹H NMR detected 1.4% EtOAc (molar ratio to free base 0.11). Compound B, form B, was an anhydrate based on the collected characterization data.

Solid state characterization data indicate that form B is substantially crystalline (XRPD) and TGA indicates the presence of some 2% of surface solvent according to the earlier onset of weight loss from room temperature to 100 ℃) and a melting onset temperature of 163 ℃. After a slight endotherm (evaporation of residual solvent), melting at 163 ℃ started. Based on the deduced weight loss curve, the onset of weight loss (2.4% (w/w)) was detected long before 100 ℃, which could be attributed to the surface solvent. The total weight loss, including when melted, was 3.5% (weight/weight). Form B was found to be slightly hygroscopic with a 1.2% (weight/weight) moisture regain at 90% RH, 25 ℃, as shown by the water absorption-desorption graph in fig. 8. ¹³C (FIG. 6) and¹⁹the F SSNMR spectrum (fig. 7) also indicates the formation of form B. SEM (fig. 9a, magnification 500X) and PLM (fig. 9B, magnification 200X) images of compound B show that form B consists of dense spherical aggregates.

Table 17: representative XRPD peaks for Compound B form B

Preliminary stress stability analysis of compound B form B. XRPD pattern of compound a salt (fumarate and tartrate) exposed to 40 ℃/75% RH for one month under open conditions. Under these conditions, the solid form was not altered.

Although no correlation was observed between the epimer content in the range of 0.56-0.72% and the solid state properties of the different salt forms, the SSNMR, XRPD and DSC data indicate the possibility of obtaining a mixture of forms from the fumarate salt and that control of the form of either salt requires extensive downstream work in view of the variability of the structural data and melting point with the crystallization conditions. After one month exposure to 40 ℃/75% RH, the tartrate salt had no 0.18% impurities found in the fumarate salt sample.

Compression analysis of compound B form B. Fig. 22, 23 and 24 show the effect of compression on compound B tartrate form B. A 250mg compact of pure compound B form B was analyzed. Both SSNMR and XRPD (fig. 23 and 22, respectively) showed that the form remained unchanged after compression. After compression is observed ¹⁹F T₁Reduction of relaxation time due to disorder generation, although as from FIG. 23 via compression of Compound B form B¹⁹The F SSNMR spectrum is very slightly visible. Included in Table 18 are as received and compressed Compound B form B¹⁹F T₁The relaxation value. As seen in the DSC thermogram (fig. 24), compression did not affect the melting point of compound B form B. Comparative XRPD collected before and after exposure to accelerated stability conditions of 30 ℃/65% RH and 40 ℃/75% RH for 6 months (open) showed that compound a, form B, remained unchanged after exposure to these conditions.

Table 18: of compound B form B¹⁹F T₁Relaxation time

XRPD of one month stable samples. XRPD of compound B form B exposed to 40 ℃/75% RH for one month shows that compound B form B remains unchanged under stress stability conditions including elevated temperature and humidity.

Preparation of compound B form B. About 58.0mg tartaric acid was weighed into a 5mL glass vial and 2.0mL EtOAc was added. The acid remains undissolved. To this 5mL vial was added about 2.0mL of a stock solution of the free base in EtOAc (. about.100 mg/mL) at a 1:1 molar ratio and the solution was stirred at room temperature. About 1mg of form B seed was added and the solution remained clear. The solution was stirred overnight and sampled by XRPD. The profile is consistent with compound B, form B. The suspension was then stirred at 50 ℃ for a further 2 days. The suspension was centrifuged and the filter cake was dried at 50 ℃ for 2 hours. Yield: 144.5mg, yield 56.1%.

Example 18:

preparation of compound B form C: form C was prepared on a 200mg scale via solution reactive crystallization in THF as confirmed by XRPD (fig. 10). As shown in fig. 11a and 11b, a weight loss of about 6.8% before 130 ℃ was observed in the TGA and DSC showed an endotherm at 118.1 ℃ (onset temperature). The stoichiometric ratio was found to be 1.02 (acid/free base) and 9.7%.

Preparation of compound B form C. To a 3mL glass vial was added about 56.9mg tartaric acid and 1.0mL THF to give a clear solution. The clear acid solution was added to 2.0mL of a stock solution of the free base in THF (-100 mg/mL) at a molar ratio of 1:1 and stirred at room temperature. About 1mg of form C seed was added and the solution became somewhat cloudy. The suspension was stirred overnight and sampled by XRPD. The pattern corresponds to form C. The suspension was stirred at room temperature for a further 24 hours and the filter cake was dried at 50 ℃ for 1.5 hours. The suspension was centrifuged to collect the solid. Yield: 161.4mg, yield 62.7%.

Example 19:

preparation of compound B form D. Via flash evaporation in MeOH/DCM and H at room temperature, respectively₂O-medium pulping gives form D samples. XR for form D is shown in FIG. 12 PD pattern. The TGA and DSC results for the form D sample are provided in fig. 13a and 13b, respectively, and show a 3.5% weight loss before 150 ℃ and an endotherm at 73.0 ℃ before melting/decomposing at 163.9 ℃ (onset temperature). Form D was observed to change to form F after heating to 150 ℃, cooling to 30 ℃ under nitrogen, and then exposure to ambient conditions. By passing¹H NMR did not detect a significant amount of the process solvent MeOH or DCM and further determined the stoichiometric ratio of L-tartaric acid to free base to be 1.0. Form D is a hydrate.

To evaluate the physical stability of form D at different humidities, DVS data were collected at 25 ℃ for the form D samples after equilibration of the samples at ambient humidity (80% RH). A plateau from 20% RH (2.25% water uptake) to 80% RH (2.72% water uptake) was observed during desorption in the DVS test for form D, indicating that dehydration of hydrated form D occurred when the relevant humidity value was less than 20%. Furthermore, form D is likely to be a monohydrate since the theoretical water content of the monohydrate is 2.6%.

Table 19: representative XRPD peaks for Compound B form D

Example 20:

preparation of compound B form E. Form E was obtained via DMSO-mediated crystallization by adding IPAc to the DMSO solution and its XRPD is shown in figure 14. The TGA and DSC curves (fig. 15a and 15b, respectively) show a substantial weight loss of 8.3% before 140 ℃ and an endotherm at 126.3 ℃ before melting/decomposing at 142.6 ℃ (onset temperature). ¹The H NMR spectrum indicated 0.7 equivalents of DMSO (-9.4 wt%) and no significant amount of IPAc was detected. The stoichiometric ratio of L-tartaric acid to free base was determined to be 1.0. Form E is a DMSO solvate.

Example 21:

preparation of compound B form F. Form F was obtained via heating the form D sample to 150 ℃, cooling to 30 ℃ under nitrogen, and exposure to ambient conditions. In FIG. 16, shapes are providedAn XRPD pattern for formula F. DSC analysis (fig. 18) indicated that form F was crystalline with an endothermic peak at 164.2 ℃ (onset temperature).¹H NMR determined the stoichiometric ratio of L-tartaric acid to free base to be 1.0 and no significant solvent signal was detected.

Table 20: representative XRPD peaks for Compound B form F

To further characterize form F, form D was subjected to a variable temperature XRPD (VT-XRPD) under nitrogen blanket, where the temperature was increased to 150 ℃ and decreased back to 30 ℃. Under such conditions, form F is observed after dehydration of the form D sample at elevated temperatures, indicating that form F is an anhydrate.

To evaluate the physical stability of form F at different humidities, Dynamic Vapor Sorption (DVS) data for form F were collected at 25 ℃ after equilibrating the samples at ambient humidity (80% RH). Water uptake of-1.9% was observed before 80% RH, indicating that form F is slightly hygroscopic.

Preparation of compound B form G. Form G was obtained by slow evaporation in MeOH at room temperature. The XRPD of form G is provided in fig. 19. TGA and DSC results are provided in fig. 20a and 20b, respectively, and demonstrate a 3.3% weight loss before 150 ℃ and a melting/decomposition peak at 170.4 ℃ (onset temperature).¹The H NMR spectrum showed 0.49 equivalents of MeOH (equivalent to 3.0 wt%). The stoichiometric ratio of L-tartaric acid to free base was determined to be 1.0. Form G is MeOH solvate.

Table 21: representative XRPD peaks for Compound B form G

Example 22:

and (3) screening polymorphic substances of the L-tartrate. The solubility of compound B form B material was estimated at room temperature in 20 solvents. To a 3mL glass vial was added approximately 2mg of solid. The solvents in tables 6-7 were then added dropwise to the vial until the solids dissolved or a total volume of 1mL was reached. The results in table 22 were used to guide solvent selection in polymorph screening. Polymorph screening experiments were performed using different solution crystallization or solid phase transition methods. The methods employed and the crystalline forms determined are summarized in table 23.

Table 22: solubility of Compound B

Solvent(s)	Solubility (mg/mL)	Solvent(s)	Solubility (mg/mL)
				DMSO	S＞38.0	Anisole	S＜1.9
MeOH	6.7＜S＜20.0	MTBE	S＜2.1
				THF	2.1＜S＜7.0	2-MeTHF	S＜1.9
Acetone (II)	2.1＜S＜7.0	1, 4-dioxane	S＜2.2
				EtOH	S＜1.9	CPME	S＜2.1
IPA	S＜2.1	ACN	S＜2.1
				MEK	S＜2.0	N-heptane	S＜2.0
MIBK	S＜1.9	Toluene	S＜1.9
				EtOAc	S＜1.9	H2O	S＜1.9
IPAc	S＜1.9	DCM	S＜2.0

Table 23: summary of polymorphic forms

Method of producing a composite material	Number of experiments	Separated solid form
			Addition of anti-solvent	14	Form B, D, E
Slurry conversion	34	Form B, D, G
			Slow evaporation	9	Form G
Solid vapor diffusion	11	Form B
			Liquid vapor diffusion	12	Form B, form B + G, form B + D
Slowly cooling	10	N/A
			Total of	84	Form B, D, E, G, B + G, B + D

Example 23:

anti-solvent addition. A total of 14 anti-solvent addition experiments were performed. For each experiment, approximately 15mg of compound B form B was weighed into a 20mL glass vial, followed by the addition of 0.3-1.0mL of the corresponding solvent. The mixture was then magnetically stirred at room temperature at 500RPM to give a clear solution. Subsequently, the corresponding anti-solvent was added to the solution to induce precipitation or until the total amount of anti-solvent reached 10.0 mL. The clear solution was transferred to slurrying at 5 ℃. If no precipitation occurred, the solution was transferred to flash evaporation at room temperature. The solid was isolated for XRPD analysis. The results summarized in table 24 indicate that compound B forms B, D and E were obtained.

Table 24: summary of anti-solvent addition experiments

Solid obtained via stirring at 5 ℃

Solid obtained via flash evaporation at room temperature

N/A: no solid was obtained

Example 24:

slurry conversion at room temperature. Slurry conversion experiments were performed in different solvent systems at room temperature. For each experiment, approximately 20mg of compound B form B was suspended in 0.3mL of the corresponding solvent in a 1.5mL glass vial. After magnetically stirring the suspension at room temperature for 17 days, the remaining solid was isolated for XRPD analysis. The results summarized in table 25 indicate that compound B forms B, D and G were obtained.

Table 25: summary of slurry conversion experiments at room temperature

Sample was heated-cooled after 17 days of stirring.

Example 25:

the slurry is converted at elevated temperature. Slurry conversion experiments were performed at 50 ℃ and 70 ℃ in different solvent systems. For each experiment, approximately 20mg of compound B form B was suspended in 0.3mL of the corresponding solvent in a 1.5mL glass vial. After magnetic stirring of the suspension at 50 ℃ and 70 ℃ for 17 days, the remaining solid was isolated for XRPD analysis. The results summarized in table 26 indicate that compound B, form B, was obtained.

Table 26: summary of slurry conversion experiments at elevated temperatures

Example 26:

slowly evaporate. The slow evaporation experiment was performed under 9 conditions. For each experiment, approximately 15mg of compound B form B was weighed into a 3mL glass vial, and the corresponding solvent or solvent mixture was then added to give a clear solution. Subsequently, the vials were covered with parafilm with 3-4 pinholes and kept at room temperature to allow slow evaporation of the solution. The isolated solid was tested by XRPD. As summarized, compound B, form G, is produced.

Table 27: summary of slow Evaporation experiments

Solvent (volume)	End result
		MeOH	Form G
Acetone (II)	Yellow gel
		EtOH	Yellow gel
2-MeTHF	Yellow gel
		THF	Yellow gel
ACN/MeOH,1:3	Yellow gel
		EtOAc/MeOH,1:3	Form G
DCM/MeOH,1:3	Form G
		anisole/MeOH, 1:3	Yellow gel

Example 27:

the solid vapor diffuses. The solid vapor diffusion experiment was performed using 11 solvents. For each experiment, approximately 15mg of compound B form B was weighed into a 3mL vial and then placed into a 20mL vial with 4mL of the corresponding solvent. The 20mL vial was sealed with a cap and left at room temperature for 14 days to allow the solvent vapor to interact with the solid sample. The isolated solid was tested by XRPD. The results summarized in table 28 indicate that compound B, form B, was obtained.

Table 28: summary of solid vapor diffusion experiments

Solvent(s)	End result
		H2O	Form B
DCM	Form B
		EtOH	Form B
MeOH	Form B
		ACN	Form B
THF	Form B
		CHCl3	Form B
Acetone (II)	Form B
		EtOAc	Form B
1, 4-dioxane	Form B
		IPA	Form B

Example 28:

the liquid vapor diffuses. Twelve liquid vapor diffusion experiments were performed. For each experiment, approximately 15mg of compound B form B was dissolved in 0.5-1.0mL of the corresponding solvent in a 3mL vial to obtain a clear solution. Subsequently, the solution was placed in a 20mL vial with 4mL of the corresponding anti-solvent. The 20mL vial was sealed with a cap and kept at room temperature for sufficient time for the solvent vapor to interact with the solution. The solid was isolated for XRPD analysis. The results summarized in table 29 indicate that a mixture of compound B, form B and form B + G/B + D was obtained.

Table 29: summary of liquid vapor diffusion experiments

N/A: no solid was obtained

Example 29:

and (5) slowly cooling. The slow cooling experiment was performed in 10 solvent systems. For each experiment, approximately 20mg of compound B form B was suspended in 1.0mL of the corresponding solvent in a 3mL glass vial at room temperature. The suspension was transferred to slurrying at 50 ℃ with a magnetic stirrer at 500 RPM. The sample was allowed to equilibrate at 50 ℃ for 2 hours and filtered using a 0.45 μm nylon membrane. The filtrate was then slowly cooled from 50 ℃ to 5 ℃ at a rate of 0.1 ℃/min. The results summarized indicate that no solids were observed.

Table 30: summary of Slow Cooling experiments

Solvent, volume to volume	End result
		MeOH	N/A
EtOH	N/A
		Acetone (II)	N/A
MEK	N/A
		THF	N/A
2-MeTHF	N/A
		H2O	N/A
ACN/DMSO,4:1/	N/A
		toluene/MeOH, 3:1	N/A
EtOAc/MeOH,3:1	N/A

Example 30:

and (4) phase transition. Crystallization of compound B from solvents such as ethyl acetate, ethanol, acetone, or/and aqueous mixtures thereof may result in the formation of one or more of the following forms: anhydrous form B, anhydrous form F, monohydrate form D, and acetone solvate form a. XRPD patterns of these four solid forms are shown in figure 21. Therefore, it is important to know the physical stability of these forms to determine the complete phase transition situation and to control crystallization to obtain the desired form B. Since the melting points of forms F and B are very close (initial temperature 160-. Therefore, equilibrium solubility studies were conducted for 17 hours at 25, 35 and 50 ℃ for both forms in ethanol to determine their thermodynamic stability relationships.

Form F was found to have higher solubility at these three temperatures, confirming that form B is the thermodynamically stable form at 25-50 ℃. The Van't Hoff plots of the solubility of forms B and F as a function of temperature show that the two anhydrates are enantiomerically related with a transition temperature of 19 ℃. Form B was found to be in water activity (a) with respect to hydrate-anhydrate stability_w)a_w<Stable at 0.2(RT), above which hydrate form D is stable. However, form B was found to be a at up to 0.4(RT) in slurry bridging experiments_wThe lower kinetics stabilized for 36 days. This indicates that the water is being fed into the reactor thoughCritical for the conversion of the form of the compound a_wThe values are low, but there is a large kinetic barrier for the conversion from form B to form D.

Slurried and crystallized samples. Form B + form A

A 1:1 mixture of compound B batches comprising (1) a mixture of form a/acetone solvate and form B) and (2) form B) was prepared and added to 100% acetone and an aqueous mixture of acetone and water (90% acetone, 95% acetone, 96% acetone, 97% acetone, 98% acetone and 99% acetone (v/v)). The samples were slurried at room temperature for 120 hours, filtered, and then analyzed by XRPD.

Form F

Form F was slurried in 100% ethanol at room temperature and 50 ℃ overnight. One of the suspensions was inoculated at room temperature as form B and the other was not inoculated. The suspension stirred at 50 ℃ was inoculated with form B. The sample was filtered and analyzed by XRPD. Samples of form F were slurried in 100% DI water, 1:1 acetone/water, and 100% acetone, respectively, at room temperature. A slurry of form F in pure solvent was kept at room temperature to obtain a solution of form F in a 1:1 acetone: water mixture, then stirred at 5 ℃ to cool the crystals/precipitate. After 24 hours, all samples were filtered and analyzed by XRPD. Form F was also slurried in a 95:5 mixture of acetone: water and 97:3 mixture of acetone: water at 50 ℃ for 2 hours, then the slurry was cooled to room temperature, filtered and analyzed by XRPD. Finally, form F was recrystallized from 95:5 acetone/water seeded with form B at 50 ℃.

Form D

Form D was slurried in 100% ethanol at room temperature for 48 hours. The sample was then filtered and analyzed by XRPD.

Results

Development of calorimetric evaluation of purity. Switching from ethanol to acetone/water as the crystallization solvent, the purity was significantly improved, the oligomer content was reduced by 5% (w/w) on average and an acceptable yield was obtained. The oligomer content and yield varied with the slurry solvent composition. An increase in water content increases purity but decreases yield. Melting Point onset temperature and oligomer content for a given solvent composition% The opposite result is consistently shown, indicating that purity is likely to affect melting point, and higher% oligomers depress melting point and vice versa. Based on this observation, several slurry batches obtained from acetone/water were analyzed using DSC, tested for oligomer content by SEC, and a correlation curve was plotted. XRPD data were collected for all these samples to ensure that they were consistent with compound B form B. Purity estimates were made for several batches using exponential fits to the data, including up to 20gm and IPC samples. An R of 0.96 was obtained for a linear fit between the experimental and predicted oligomer content²The value is obtained. Considering that these are solid/powder samples, there is an inherent problem of sample homogeneity, so this higher R²The values provide confidence in the robustness of the correlation determined between the starting melting point and the purity.

Compound B form B was always obtained (slurried or crystallized) from 100% ethanol. Further conditions were carried out including slurrying or crystallization from ethanol/water and slurrying in acetone/water (. gtoreq.95% acetone). Depending on the slurrying and crystallization parameters, several other solid forms of compound B were obtained, namely form F (ethanol/water), form a/acetone solvate (≧ 95% acetone), and mixtures of forms a and B or forms a and F. Under the conditions for obtaining form F, it is presumed that the intermediate hydrate (form D) is formed, since a of the ethanol/water mixture employed for these samples _wValues well above 0.2(RT), where the hydrate is thermodynamically stable. Table 31 shows the crystallization conditions and the forms obtained. Since mixtures of forms are obtained in several cases, a form control strategy is implemented to obtain form B in the final solid phase.

Table 31: crystallization conditions and corresponding solid forms

Since the acetone/water system was most effective in removing oligomers from compound B, a competitive slurry bridging experiment was performed using two different batches of a 1:1 mixture of compound B: one batch was predominantly form a with some form B, while the second batch was slurried in acetone/water mixtures of various compositions at room temperature for 120 hours. Acetone solvates were obtained in a stable form from > 95% acetone, whereas mixtures of form B and form D hydrates were obtained at 90% acetone. Since the desired acetone content is between 96% and 95% (relative to the oligomer level), it is possible to obtain either of forms A, B or D from the final crystallization.

A formal control strategy: conversion of forms a and F to form B. Figure 2b shows the DSC thermogram of form a acetone solvate. The first endotherm at 124 ℃ indicates solvent loss and evaporation, while the second endotherm at 164 ℃ indicates melting of the corresponding anhydrate. XRPD confirmed that the anhydrate was form B when form a was heated to 152 ℃. Form a was reslurried in 100% ethanol overnight to convert to form B. Thus, if the first slurry in acetone/water produces form a or a mixture of forms a and B, depending on the slurry conditions, it is advisable to employ a two-step slurrying process to assist in the form control of compound B to obtain form B. This will ensure that form B will be the final compound B form isolated after the second slurry step, regardless of the change in form during the first slurry.

Unlike acetone solvate, form F obtained from 65:35 ethanol to water crystallization seeded with form B showed only one melting endotherm at 162 ℃. Since the solubility values of forms F and B in ethanol are nearly equal at 25 deg.C (0.23 mg/mL for form B and 0.26mg/mL for form F), the thermodynamic driving force for the conversion of metastable form F to stable form B is small, and thus, the rate of form F → form B conversion is slow even in the presence of form B as a seed. Form F → form B transformation is slow and a mixture of the two forms is obtained after 12 hours, regardless of inoculation or not and temperature.

To facilitate form F → form B conversion in a shorter time scale, a solvate route is employed in which form F is converted to form B via acetone solvate or hydrate formation followed by desolvation thereof to form B. Form F was slurried overnight in pure water, acetone, and a 1:1 acetone water mixture without any seeding. Form F remained unchanged in 100% acetone, but was converted to the hydrate in the presence of water (form D). When the hydrate was slurried in pure ethanol, a mixture of form D and form F was produced, indicating the tendency of the hydrate to desolvate to the metastable anhydrous form. Form F slurried in 95:5 acetone: water and 97:3 acetone: water at 50 ℃ confirmed the presence of form B but incomplete conversion. Recrystallization of form F from 95:5 acetone to water using form B seeds results in complete conversion of form F → form B. Fig. 25 and 26 provide schematic illustrations of the form conversion between forms A, B, D and F.

The thermodynamic relationship between anhydrous form B and form F under slurry competition between anhydrous forms B and F. To determine the thermodynamic stability between forms B and F, competitive slurry experiments were performed at room temperature (25. + -. 3 ℃) and 50 ℃ in an acetone/EtOH/EtOAc solvent system as listed in Table 32. A mixture of forms B and F in equal mass ratios was suspended in a saturated acetone/EtOH/EtOAc solution of form B and then magnetically stirred at the target temperature. After slurrying for about 4-11 days, the remaining solid was isolated for XRPD characterization. Observing the mixture of forms B and F indicates a slow transition between forms B and F.

Table 32: slurry competition conditions for the thermodynamic relationship between Compound B, form B and form F

The thermodynamic stability relationship between anhydrous forms B and F was determined via slurry competition and equilibrium solubility measurements. As a result, a mixture of forms B and F was observed in all slurry competition experiments, indicating a slow transition between forms B and F. Without being bound by any particular theory, the low solubility of form B and form F may be caused by their low solubility in the tested solvent (acetone/EtOH/EtOAc). Therefore, equilibrium solubilities (17 hours) were measured in EtOH at 25 ℃, 35 ℃ and 50 ℃ respectively to determine their thermodynamic stability relationships. Form F showed higher solubility in EtOH at all three temperatures tested compared to form B, indicating that form B is thermodynamically more stable than form F at 25 ℃ to 50 ℃.

Determination of a between Anhydrous form B and hydrated form D via slurry Competition at room temperature under various Water Activity conditions_w. A at 0.6 and 0.8_wForm D was observed after one week in and after 36 days in water. In EtOH (a)_w<0.2) form B was observed after one week. At a_wA mixture of forms D and B was observed after stirring for 36 days at room temperature in the systems at 0.2 and 0.4. To further confirm a temperature at room temperature_wThermodynamic stability relationships between form B and form D in systems of 0.2 and 0.4 were taken and their equilibrium solubilities under the corresponding conditions (24 hours) were taken. In comparison with the sample starting with form B, at a_wLower solubility was observed in the samples starting with form D in both the 0.2 and 0.4 systems (no final limited crystalline form of the solid was examined).

Equilibrium solubility measurements for anhydrous forms B and F. To further determine the thermodynamic stability between forms B and F, equilibrium solubility measurement experiments were performed in EtOH at 25 ℃, 35 ℃ and 50 ℃ respectively. The detailed procedure is summarized as follows: the solids of forms B and F were suspended in 0.4mL EtOH at the target temperature and magnetically stirred for 17 hours (750 rpm). After centrifugation, the filtrate was tested for free base concentration and HPLC purity. The crystal form of the remaining solid was checked by XRPD.

Form F showed higher solubility in EtOH at 25 ℃, 35 ℃ and 50 ℃ compared to form B (table 33). According to XRPD results, no change in form was observed after solubility testing, indicating that form B is likely to be thermodynamically more stable than form F at 25 ℃ to 50 ℃.

Table 33: summary of equilibrium solubility measurements for form B and form F in EtOH

Critical water activity determination between forms B and D. To determine the critical water activity between anhydrous form B and hydrated form D, the slurries were run at room temperature under various water activity conditions as set forth in Table 34Pulp competition. Suspending a mixture of forms B and D in equal mass ratios in saturated EtOH-water of form B (with various a's)_w) In solution and then magnetically stirred at room temperature. After slurrying for about 7-36 days, the remaining solids were separated and subjected to XRPD characterization.

Table 34: forms B and D in each of a_wSummary of slurry Competition under conditions

A at 0.6 and 0.8_wForm D was observed after one week of slurrying and after 36 days in water. In EtOH (a)_w<0.2) form B was observed after one week. Form B was observed after one week of slurrying in EtOH. At a_wA mixture of forms D and B was observed after stirring for 36 days at room temperature in the systems at 0.2 and 0.4.

Solubility measurements for forms B and D. To further confirm a at room temperature at 0.2 and 0.4_wThermodynamic stability relationship between form B and form D under the conditions, equilibrium solubilities under the conditions as listed in table 35 were collected.

Table 35: at a_wSummary of equilibrium solubility measurements for forms B and D in 0.2/0.4 systems

Separately, the solids of anhydrous form B and hydrated form D were suspended in 0.5mL of the target solvent system (a)_w0.2/0.4) and magnetically stirred for 24 hours (750 rpm). The suspension was filtered and the filtrate was tested for the concentration of free base. Lower solubility was observed in samples starting with form D. When a is at room temperature (25. + -. 3 ℃ C.)_wAt ≧ 0.2, hydrated form D appears thermodynamically more stable than anhydrous form B.

Example 31:

malonate form M

A maleate hit with low crystallinity was obtained from the screen: maleate form M. Its XRPD pattern is shown in figure 30. A weight loss of 4.1% before 110 ℃ was observed in TGA and the DSC results showed multiple endotherms (figure 31). The stoichiometry was found to be 0.50 (acid/free base) and determined by¹H NMR detected 6.2% THF (0.58 mole ratio to free base). Maleate form M is a THF solvate due to multiple endotherms and considerable amounts of THF observed, but is not further characterized due to its low crystallinity.

Example 32:

fumarate salt form 1

A crystalline fumarate hit was obtained from the screen: fumarate salt form 1. A weight loss of 0.9% before 150 ℃ was observed in TGA and DSC (figure 28) results showed one melting endotherm at 164.3 ℃ (onset temperature). The stoichiometry was found to be 0.88 (acid/free base) and determined by¹H NMR detected 1.5% EtOAc (molar ratio to free base 0.11).

Preparation of fumarate salt form 1. About 44.7mg fumaric acid was weighed into a 5mL glass vial and 2.0mL EtOAc was added. The acid remains undissolved. To this 5mL vial was added about 2.0mL of a stock solution of the free base in EtOAc (. about.100 mg/mL) at a 1:1 molar ratio and stirred at room temperature. About 3mg of fumarate salt form 1 seed was added and the solution became cloudy. The suspension was stirred overnight and sampled by XRPD (fig. 27), confirming that the pattern was consistent with fumarate salt form 1. The suspension was stirred at 50 ℃ for 3 more days to increase the crystallinity, and then centrifuged. The filter cake was dried at 50 ℃ for 4 hours. Yield: 186.6mg, yield 76.2%.

Table 36: representative XRPD peaks of compound C form 1

Table 37: representative XRPD peaks of compound C form 2

And (6) summarizing. Compound a free base was determined to be in amorphous solid form with a weight loss < 0.5% prior to decomposition and a melting point of about 87 ℃. Its hygroscopicity at 95% RH < 1% and epimer content < 1%. Its solubility at 37 ℃ was about 6.6 mg/mL. The XRPD pattern of this amorphous form is provided in figure 32. Compound C form 1 is a crystalline solid with a weight loss < 0.5% prior to decomposition and a melting point of about 165-174 ℃. Compound C was obtained in various forms depending on the solvent. Its hygroscopicity at 95% RH < 1.5% and epimer content < 1%. Its solubility at 37 ℃ was about 6.6 mg/mL. Compound B form B is a crystalline solid with a weight loss < 0.5% prior to decomposition and a melting point of about 168 ℃. Anhydrous form B exists as a single form. Its hygroscopicity at 95% RH < 1% and epimer content < 2.5%. Its solubility at 37 ℃ was about 5.9 mg/mL. The anhydrous form of compound B form B was found to be a stable pure crystalline form with more favorable properties than forms D, E and F described herein.

Example 33:

safety, pharmacokinetics and activity evaluation of compound B. Breast cancer is the most frequently diagnosed cancer in women, with an estimated 167 million new cases reported in 2012 worldwide (Ferlay et al, 2013). Breast cancer accounts for approximately 15% of all cancer deaths (approximately 522,000 cases).

Approximately 80% of all breast cancers express Estrogen Receptor (ER) factor, and the vast majority of them rely on the ER to promote tumor growth and progression. Modulation of estrogen activity and/or synthesis is an important basis for therapeutic approaches in women with ER-positive breast cancer. However, despite the effectiveness of available endocrine therapies such as ER antagonists (e.g., tamoxifen), aromatase inhibitors (e.g., anastrozole, letrozole, and exemestane), and full ER antagonists/degradants (e.g., fulvestrant), many patients eventually relapse or develop resistance to these drugs, and further treatment is needed to optimally control the disease.

Despite being refractory to aromatase inhibitors or tamoxifen, the growth and survival of drug resistant tumor cells is still dependent on ER signaling; thus, ER-positive breast cancer patients may still respond to second-or third-line endocrine therapy after receiving prior treatment (Di Leo et al, 2010; Baselga et al, 2012). There is increasing evidence that in the endocrine resistant state, ERs can signal in a ligand-independent manner via inputs from other signaling pathways (Miller et al, 2010; Van Tine et al, 2011). Without being bound by any particular theory, agents with dual mechanisms of action (ER antagonism plus degradation) have the potential to target both ligand-dependent and ligand-independent ER signaling and thus improve the therapeutic outcome of advanced ER-positive breast cancer. In addition, recent studies have identified mutations in ESR1 (i.e., the gene encoding ER α) that affect the Ligand Binding Domain (LBD) of ER (Segal and Dowsett 2014). In a non-clinical model, mutant ERs can drive transcription and proliferation in the absence of estrogen, suggesting that LBD-mutant forms of ERs may be involved in the mediation of clinical resistance to some endocrine therapies (Li et al, 2013; Robinson et al, 2013; Toy et al, 2013). ER antagonists that are effective against these ligand-independent constitutively active ER-mutated receptors may have great therapeutic benefit.

Therefore, new ER-targeted therapies with improved anti-tumor activity are needed to further delay disease progression and/or overcome resistance to currently available endocrine therapies and ultimately extend survival in women with ER-positive breast cancer.

Compound B is an effective, orally bioavailable small molecule therapeutic that is being developed for the treatment of ER positive breast cancer patients. As provided herein, compound B, including its solid forms (e.g., form B), is a stable compound with advantageous properties for sustained drug development. Without being bound by any particular theory, compound B appears to antagonize the effects of estrogen at nanomolar potency via competitive binding to the LBD of both wild type and mutant ER. After binding, and without being bound by any particular theory, compound B will induce an inactive conformation of ER LBD as measured by displacement of the coactivating peptide. In addition to its direct antagonist properties, without being bound by any particular theory, the mechanism of action of compound B also includes a reduction in the level of ER α protein through proteasome-mediated degradation. Degradation of ER is suspected to completely inhibit ER signaling, which was not achieved with first generation ER therapeutics exhibiting partial agonism, such as tamoxifen. Compound B will effectively inhibit the proliferation of a variety of ER positive breast cancer cell lines in vitro, including cells engineered to express clinically relevant mutations in the ER.

In vivo, compound B showed dose-dependent anti-tumor activity in a xenograft model of ER-positive breast cancer, including in a patient-derived xenograft model having the ESR1 mutation (er.y537s). An effective dose range was found to be 0.1-10 mg/kg/day, and all doses were well tolerated. Fulvestrant is less effective in the xenograft model evaluated than compound B when administered according to a clinically relevant dosing regimen. Thus, compound B showed robust non-clinical activity in ER positive breast cancer models of ESR1 wild-type and disease carrying the ESR1 mutation.

Example 34:

in vitro and in vivo efficacy analysis of compound B. Compound B exhibited superior ER degradation and ER pathway inhibition compared to both GDC-0927 and GDC-0810. In addition, compound B has better DMPK properties than both GDC-0927 and GDC-0810-resulting in the same in vivo efficacy as GDC-0927, but at 100-fold lower doses (e.g., 1mg or 10mg doses). (see fig. 34 and 35).

Pharmacokinetics and metabolism. Compound B was found to have low to moderate clearance, large volume of distribution, and a final elimination half-life of 7-24 hours after a single IV administration to rats, dogs, and monkeys. Oral bioavailability was moderate (41% -55%) in rats and dogs, and low (17%) in monkeys. In vitro data show that plasma protein binding of compound B is high in all species, with binding rates ranging from 98% to 99%.

In vitro metabolite identification experiments showed that UGT1a4 mediated glucuronidation is the major in vitro metabolic pathway for compound B. Contributions from CYP450 isoforms are minor and include CYP3a4 and CYP2C 9. In vitro CYP inhibition studies in human liver microsomes and induction studies in human hepatocytes indicate low to moderate potential for drug-drug interactions. Compound B directly inhibits CYP3A4, 50% Inhibitory Concentration (IC)₅₀) Values of 6.5 μ M (midazolam 1' -hydroxylation) and 26 μ M (testosterone 6 β -hydroxylation); IC for CYP2B6 and CYP2C8 inhibition₅₀13 μ M and 21 μ M, respectively. Compound B showed a weak CYP2C9 metabolism dependent inhibition.

Toxicology. Good Laboratory Practice (GLP) repeated dose oral toxicity studies for four weeks in female rats and monkeys were performed and a comprehensive assessment of neurological (rats, monkeys), respiratory (monkeys) and cardiovascular (monkeys) function was performed to characterize the non-clinical safety profile of compound B.

In the rat study, compound B was tolerated at exemplary dose levels (10, 30 and 100mg/kg), with side effects mainly in the kidney and liver at 100 mg/kg. In monkey studies (20, 60 and 200mg/kg), the Maximum Tolerated Dose (MTD) was considered to be 60mg/kg, since a high dose of 200mg/kg was not tolerated. Side effects are mainly observed at high dose levels of 200mg/kg and the lack of tolerance is due to kidney and liver damage and nutritional deficiencies.

Dose-dependent PLD was observed in rats and monkeys in many organs when exposed to higher than expected at the initial dose in phase I humans (at least 44-fold and 6-fold based on area under the concentration-time curve [ AUC ], respectively), with adverse organ effects largely localized to the kidney and liver. In rats, PLD was not observed at 10mg/kg (18-fold exposure factor), but from 30 to 100mg/kg, incidence and severity increased. In monkeys, dose-responsive PLD was present at all doses, but was limited to minimal changes in the lungs at 20mg/kg (6-fold exposure factor). These fold exposures provide evidence of a lower risk of PLD-related toxicity to humans at the phase I starting dose.

The translational ability of PLDs from non-clinical species to patients is uncertain but can be inferred (Reasor et al 2006). Although drugs such as tamoxifen and palbociclib found PLD in non-clinical studies, they did not show any clinical problems. Although compound B was associated with PLD in multiple tissues in both rats and monkeys, there was no light microscopic evidence in these studies showing involvement of key organs such as the heart, eyes or neurons (Chatman et al, 2009).

The increase in systemic exposure of compound B after oral administration to rats and monkeys for 28 days was proportional to the dose. Based on the nature and reversibility of clinical signs, clinical pathology and histopathological findings, for rats, the dose that would be severely toxic to 10% of animals (STD)₁₀) Determined as 100mg/kg, corresponding to the maximum plasma concentration (C)_max) And 0 to 24 hour AUC (AUC)_0-24) Values were 6560ng/mL and 143,000 ng-hr/mL, respectively. In monkeys, the highest non-severely toxic dose was determined to be 60 mg/kg/day, corresponding to C, due to clinical signs and death at 200 mg/kg/day_maxAnd AUC_0-24The values were 841ng/mL and 16,200 ng-hr/mL, respectively.

In summary, the results of the non-clinical toxicity and safe pharmacological studies completed to date provide a robust characterization of the toxicity profile of compound B and support administration to cancer patients in phase I trials.

Administration of compound B as a monotherapy. Compound B showed robust non-clinical activity in ER positive breast cancer models of ESR1 wild-type and disease carrying the ESR1 mutation. The safety, Pharmacokinetic (PK), Pharmacodynamic (PD) activity and primary antitumor activity of compound B as a single agent were analyzed in a phase Ia/Ib, multicenter, open label study in patients with locally advanced or metastatic ER positive breast cancer. Patients were recruited for an escalating phase of cohort dose followed by an extended phase of cohort recruitment. During single dose escalation, cohorts were evaluated at escalated dose levels to determine MTD or Maximum Administered Dose (MAD).

Once a single-drug MTD or MAD is established, an ascending dose cohort for treatment with compound B (at or below the MTD or MAD) or compound B in combination with palbociclib may be recruited. In addition, patients were enrolled in the cohort extension phase and treated with compound B alone or in combination with palbociclib and/or LHRH agonists at or below single-drug MTD or MAD. Single dose escalation two different dose levels of compound B with and without LHRH agonist can be assessed.

Patients were monitored for adverse events during the dose-limiting toxicity (DLT) evaluation window, defined as days 7 to 28 of cycle 1 (single-dose cohort). For DLT evaluation, toxicity was graded according to the national cancer institute adverse event general term standard version 4.0 (NCI CTCAE v 4.0).

Patients were enrolled into a single drug compound B dose escalation phase that included a screening phase, a PK introduction phase, a treatment phase, and a safe follow-up phase. Continuous once daily dosing was initiated during the treatment period beginning on day 1 of cycle 1. The starting dose of the single drug compound B was 10mg administered orally to the first cohort of patients continuously over a 28 day period. For each successive cohort, the dose will be increased by 200% of the previous dose level until a critical safety issue is observed (e.g., DLT, any patient with clinically significant toxicity ≧ 2 or overall adverse event characteristics unsuitable for 200% increments). Once critical safety issues are observed, dose escalation will not exceed 100% increments.

The half-life of compound B was about 40 hours. As described above, compound B exposure was scaled up from 10mg to 30mg with normal variability.

Treatment of six patients was initiated with an initial dose of 10mg QD over a 28 day cycle as described herein. As shown in table 38 below, with FES-PET, all patients receiving treatment had qualitative Near Complete (NC) or Complete Remission (CR). No DLT, SAE, AESI or clinically significant laboratory abnormalities were observed in the treated patients. All related AEs were grade 1 or grade 2 events.

Table 38: response of patients to treatment with compound B:

one treated patient was diagnosed with ER + PR + breast cancer. The patient has undergone prior surgery and prior treatment with an anti-cancer agent, including SERM therapy and AI therapy, prior to enrollment and treatment. The patient was treated with compound B at a dose of 10mg and showed a response to treatment after 3 cycles, as indicated in figure 36a and figure 36B.

Another patient was diagnosed with early HR + breast cancer and had previously undergone surgery and treatment with anti-cancer drugs including cytotoxins, CDK4/6 inhibitors and AIs. The patient was treated with compound B at a dose of 10mg and showed a response to treatment after 3 cycles, as indicated in figure 37a and figure 37B. The patient was enrolled in our trial at a dose of 10mg for 3 months in 2018.

Patients receiving treatment to date demonstrated good tolerability of compound B administration at 10mg and 30mg with only grade 1 and 2 AEs. Typically, after a single administration, the plasma exposure of compound B increases proportionally with the dose from 10 to 30 mg. From 10mg to 30mg, the steady state exposure appears to increase in a manner higher than the dose ratio. An estimated half-life of about 40 hours supports once daily dosing.

This written description uses examples to disclose the invention, including the best mode, and also to enable any person skilled in the art to practice the invention, including making and using any devices or systems and performing any incorporated methods. The patentable scope of the invention is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal languages of the claims.