	US 12,187,698 B2
	Crystalline forms of C₂₁H₂₂Cl₂N₄O₂
Gary DeCrescenzo, Parkville, MO (US); Dean Welsch, Parkville, MO (US); Petinka I. Vlahova, West Lafayette, IN (US); Stephan X. M. Boerrigter, West Lafayette, IN (US); Alexander Aronov, Newton, MA (US); Ali Keshavarz-Shokri, San Diego, CA (US); Alexander N. Scangas, Wilmington, MA (US); Kathy Stavropoulos, Quincy, MA (US); Benjamin Littler, Carlsbad, CA (US); Irina Nikolaevna Kadiyala, Newton, MA (US); and Rossitza Gueorguieva Alargova, Brighton, MA (US)
Assigned to BIOMED VALLEY DISCOVERIES, INC., Kansas City, MO (US); and VERTEX PHARMACEUTICALS INCORPORATED, Boston, MA (US)
Filed by BIOMED VALLEY DISCOVERIES, INC., Kansas City, MO (US); and VERTEX PHARMACEUTICALS INCORPORATED, Boston, MA (US)
Filed on Jun. 16, 2022, as Appl. No. 17/842,632.
Application 17/842,632 is a continuation of application No. 16/922,365, filed on Jul. 7, 2020, granted, now 11,390,600.
Application 16/922,365 is a continuation of application No. 16/227,820, filed on Dec. 20, 2018, granted, now 10,738,027, issued on Aug. 11, 2020.
Application 16/227,820 is a continuation of application No. 15/598,181, filed on May 17, 2017, granted, now 10,183,927, issued on Jan. 22, 2019.
Application 15/598,181 is a continuation of application No. 15/011,377, filed on Jan. 29, 2016, granted, now 9,676,746, issued on Jun. 13, 2017.
Claims priority of provisional application 62/110,449, filed on Jan. 30, 2015.
Prior Publication US 2022/0324832 A1, Oct. 13, 2022
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 401/04 (2006.01); A61K 31/4439 (2006.01); A61K 45/06 (2006.01); A61P 35/00 (2006.01)

CPC C07D 401/04 (2013.01) [A61K 31/4439 (2013.01); A61K 45/06 (2013.01); A61P 35/00 (2018.01)]

10 Claims

1. A method for treating a cancer in a subject in need thereof, comprising administering to the subject a combination of:

1) An effective amount of a first agent selected from:

i) a crystalline free base 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2-hydroxyethyl]amide mono HCl having (i) an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at about 9.1, 15.4, 19.5, and 21.4° 2θ; and (ii) a Fourier transform infrared spectroscopy (FT-IR) spectrum comprising one or more peaks at about 1603, 1533, 1487, 1080, 857, and 681 cm⁻¹; or

ii) a form C crystalline 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2-hydroxyethyl]amide mono HCl having (i) an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at about 6.7, 11.0, 17.6, and 19.9° 2θ; and (ii) a Fourier transform infrared spectroscopy (FT-IR) spectrum comprising one or more peaks at about 1610, 1523, 1219, 1141, 1076, and 845 cm⁻¹; or

iii) a form A crystalline 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2-hydroxyethyl]amide HCl hydrate having (i) an XRPD pattern comprising one or more peaks at about 6.2, 10.5, 22.4, and 28.5° 20; and (ii) a FT-IR spectrum comprising one or more peaks at about 1573, 1237, 1163, 946, and 790 cm⁻¹; or

iv) a form D crystalline 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2-hydroxyethyl]amide HCl having (i) an XRPD pattern comprising one or more peaks at about 6.0, 12.7, and 18.1° 20; and (ii) a FT-IR spectrum comprising one or more peaks at about 1537, 1471, 1239, 1163, 1067, and 946 cm⁻¹; or

v) a pharmaceutical composition comprising at least one of i to iv, and

2) an effective amount of a second agent selected from the group consisting of a hormone, a hormone-interfering compound, a histone deacetylase inhibitor (HDACi), a cyclin-dependent kinase inhibitor (CDKi), a poly ADP ribose polymerase (PARP) inhibitor, and combinations thereof.