Solid forms of an fgfr inhibitor and processes for preparing the same
AssigneeIncyte Corporation
InventorsWilliam Frietze, Zhongjiang Jia, Ming Tao, Dengjin Wang, Jiacheng Zhou, Qun Li, Timothy C. Burn, Phillip C. Liu
Life of this patent
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Abstract
The present disclosure relates to 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4, 7-tetrahydro-2H-pyrrolo[3′,2′: 5,6]pyrido[4,3-d]pyrimidin-2-one, solid forms and polymorphs thereof, methods of preparation thereof, and intermediates in the preparation thereof, which are useful in the treatment of the FGFR-associated or mediated diseases such as cancer.
Claims65
A solid form of Compound 1 having the formula:
- wherein the solid form has crystalline Form I.
A solid form of Compound 1 having the formula:
- wherein the solid form has crystalline Form II, Form III, Form IV, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVI, Form XVII, Form XVIII, Form XIX, Form XX, Form XXI, Form XXII, Form XXIII, Form XXIV, Form XXV or Form XXVI.
A solid form of Compound 1 having the formula:
- wherein the solid form is amorphous.
A process for preparing Form I of Compound 1, having the formula
- comprising crystallizing Compound 1 from a solvent.
14-18. (canceled)
A process for preparing Compound 1 having the formula
- comprising:
- a) deprotecting compound F8 having the formula:
- with a base to afford Compound 1, wherein P1 is an amino protecting group.
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26-30. (canceled)
32-33. (canceled)
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37-41. (canceled)
A process for preparing Compound 1 comprising:
- a) contacting Compound 2 having the formula:
- with N-formylmorphline in the presence of a base to form Compound 2a having the formula:
- b) reacting Compound 2a with morpholine in the presence of an acid and a reducing agent to form Compound 3 having the formula:
- c) converting Compound 3 to Compound 4 having the formula:
- d) reacting Compound 4 with Compound 5 having the formula:
- in the presence of a Lewis acid and a reducing agent to form Compound 6 having the formula:
- e) reacting Compound 6 with ethyl isocyanate to form Compound 7 having the formula:
- f) contacting Compound 7 with a base to form Compound 8 having the formula:
- and,
- g) contacting Compound 8 with a base.
43-50. (canceled)
52-56. (canceled)
A process for preparing Compound 4 having the formula:
- comprising:
- a) contacting 2-amino-4-chloropyridine with a bromination agent to form 5-bromo-4-chloropyridin-2-amine;
- b) contacting 5-bromo-4-chloropyridin-2-amine with an iodination agent to form 5-bromo-4-chloro-3-iodopyridin-2-amine;
- c) reacting 5-bromo-4-chloro-3-iodopyridin-2-amine with 4-(prop-2-ynyl)morpholine in the presence of a catalyst to form Compound 9 having the formula:
- d) reacting Compound 9 with a base to form Compound 10 having the formula:
- e) reacting compound 10 with benzenesulfonyl chloride in the presence of a base to form compound 11 having the formula:
- f) contacting compound 11 with an alkyl-magnesium halide agent to form a mixture and adding N,N-dimethylformamide to the mixture to produce Compound 4.
58-64. (canceled)
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A compound of Formula F1:
- or a salt thereof, wherein:
- P1 is an amino protecting group;
- R1 is Cl, Br or I;
- R2 and R3 are each independently C1-6 alkoxy;
- or
- R2 and R3 taken together with the carbon atom to which they are attached form 1,3-dioxolan-2-yl or 1,3-dioxan-2-yl;
- or
- R2 and R3 taken together form oxo.
68-79. (canceled)
A method of treating cholangiocarcinoma in a patient in need thereof comprising administering to the patient a therapeutically effective amount of Compound 1 having the formula:
92-95. (canceled)
99-104. (canceled)
A method of treating myeloid/lymphoid neoplasms in a patient in need thereof comprising administering to the patient a therapeutically effective amount of Compound 1 having the formula:
113-118. (canceled)
A method of increasing survival or progression-free survival in a patient that has cholangiocarcinoma, wherein the cholangiocarcinoma is characterized by an FGFR2 fusion, comprising administering Compound 1 to the patient.
Dependencies are inferred from the claim text.