(12) Patent Application Publication (10) Pub. No.: US 2016/0221987 A1 Decrescenzo Et Al

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US 2016.0221987A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0221987 A1 DeCrescenzo et al. (43) Pub. Date: Aug. 4, 2016

(54) CRYSTALLINE FORMS OF C21H22CL2N4O2 Publication Classification (71) Applicants: BIOMED VALLEY DISCOVERIES, (51) Int. Cl. INC., Kansas City, MO (US); VERTEX C07D40 L/04 (2006.01) PHARMACEUTICALS A6II 45/06 (2006.01) INCORPORATED, Boston, MA (US) A613 L/4439 (2006.01) (52) U.S. Cl. (72) Inventors: Gary DeCrescenzo, Parkville, MO CPC ...... C07D401/04 (2013.01); A61 K3I/4439 (US); Dean Welsch, Parkville, MO (US); (2013.01); A61K 45/06 (2013.01) Petinka I. Vlahova, West Lafayette, IN (US); Stephan X.M. Boerrigter, West (57) ABSTRACT Lafayette, IN (US); Alexander Aronov, The present invention provides crystalline forms of a com Newton, MA (US); Ali pound of formula (I): 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); Rossitza Gueorguieva Alargova, Brighton, MA (US) C. (21) Appl. No.: 15/011,377

(22) Filed: Jan. 29, 2016 Also provided are pharmaceutical compositions that include Related U.S. Application Data the provided crystalline forms and methods of using the pro (60) Provisional application No. 62/110,449, filed on Jan. vided crystalline forms and pharmaceutical compositions for 30, 2015. the treatment of cancer. Patent Application Publication Aug. 4, 2016 Sheet 1 of 14 US 2016/0221987 A1

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CRYSTALLINE FORMS OF C21H22CL2N4O2 be prepared which exhibit improved properties, e.g. Surpris ingly improved stability and improved solubility characteris CROSS-REFERENCE TO RELATED tics. APPLICATIONS 0007 Thus, the present invention provides crystalline 0001. This patent application claims the benefit of U.S. 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2- Provisional Patent Application No. 62/110,449, filed Jan. 30. carboxylic acid 1-(3-chlorophenyl)-2-hydroxyethylamide. 2015, which is incorporated by reference herein in its entirety. 0008. The present invention also provides crystalline free base 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyr FIELD OF THE INVENTION role-2-carboxylic acid 1-(3-chlorophenyl)-2-hydroxyethyl amide. 0002 The present invention relates to crystalline forms of 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2- 0009. The present invention also provides a crystalline carboxylic acid 1-(3-chlorophenyl)-2-hydroxyethylamide, free base of a compound of formula: which is useful as an inhibitor of ERK protein kinase.

BACKGROUND OF THE INVENTION 0003 Mitogen-activated protein kinase (MAPK) path ways mediate signals which control diverse cellular processes including growth, differentiation, migration, proliferation and apoptosis. One MAPK pathway, the extracellular signal regulated kinase (ERK) signaling pathway, is often found to C be up-regulated in tumors. Pathway members, therefore, rep resent attractive blockade targets in the development of can cer therapies (Kohno and Pouyssegur, 2006). For example, U.S. Pat. No. 7.354,939 B2 discloses, interalia, compounds effective as inhibitors of ERK protein kinase. One of these compounds, 4-(5-Chloro-2-isopropylaminopyridin-4-yl)- having an X-ray powder diffraction (XRPD) pattern compris 1H-pyrrole-2-carboxylic acid 1-(3-chlorophenyl)-2-hy ing a characteristic peak at about 19.5° 20. droxyethylamide, is a compound according to formula (I): 0010. The present invention also provides a crystalline free base of a compound of formula:

0004 Pharmaceutical compositions are often formulated having an XRPD pattern comprising characteristic peaks at with a crystalline solid of the active pharmaceutical ingredi about 9.1 and 19.5° 20. ent (API). The specific crystalline form of the API can have 0011. The present invention also provides a crystalline significant effects on properties Such as stability and solubil free base of a compound of formula: ity/bioavailability. Instability and solubility characteristics

can limit the ability to formulate a composition with an adequate shelf life or to effectively deliver a desired amount of a drug over a given time frame (Peterson et al., 2006). 0005 There exists an unmet need for crystalline forms of 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2- carboxylic acid 1-(3-chlorophenyl)-2-hydroxyethylamide which exhibit improved properties for formulation of phar maceutical compositions. The present application is directed C to meeting this and other needs. SUMMARY OF THE INVENTION 0006. It has been discovered that crystalline forms of 4-(5- Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-car having an XRPD pattern comprising characteristic peaks at boxylic acid 1-(3-chlorophenyl)-2-hydroxyethylamide can about 9.1, 15.4, 19.5 and 21.4° 20. US 2016/022 1987 A1 Aug. 4, 2016

0012. The present invention also provides a crystalline having an X-ray powder diffraction (XRPD) pattern compris free base of a compound of formula: ing a characteristic peak at about 6.7° 20. 0019. The present invention also provides a crystalline hydrochloride salt of a compound of formula:

C having one or more XRPD 20-reflections () selected from the group consisting of about 9. 1, 12.5, 15.2, 15.4, 19.2, 19.5, 20.3, 20.5, 21.4, 21.7, 21.9, 23.1, 23.3, 23.6, and 24.3. 0013 The present invention also provides a crystalline free base of a compound of formula: having an XRPD pattern comprising characteristic peaks at about 6.7 and 11.0° 20.

0020. The present invention also provides a crystalline hydrochloride salt of a compound of formula:

C having an XRPD pattern substantially as shown in FIG. 1. 0014. The present invention also provides pharmaceutical compositions comprising any of the crystalline compounds of the present invention. 0015 The present invention also provides a method of treating a cancer in a subject in need thereof comprising administering to the Subject an effective amount of any of the crystalline compounds of the present invention. 0016. The present invention also provides a method of having an XRPD pattern comprising characteristic peaks at treating a cancer in a subject in need thereof comprising about 6.7, 11.0, 17.6 and 19.9° 20. administering to the Subject an effective amount of any of the pharmaceutical compositions of the present invention. 0021. The present invention also provides a crystalline 0017. The present invention also provides crystalline 4-(5- hydrochloride salt of a compound of formula: Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-car boxylic acid 1-(3-chlorophenyl)-2-hydroxyethylamide mono HC1. 0018. The present invention also provides a crystalline hydrochloride salt of a compound of formula:

having one or more XRPD 20-reflections () selected from the group consisting of about 6.1, 6.7, 11.0, 12.1, 13.7, 15.2. 16.5, 17.6, 17.9, 18.4, 18.7, 19.6, 19.9, and 20.4. US 2016/022 1987 A1 Aug. 4, 2016

0022. The present invention also provides a crystalline 0026. The present invention also provides a crystalline hydrochloride salt of a compound of formula: hydrochloride salt of a compound of formula:

having an XRPD pattern comprising characteristic peaks at about 6.2, 10.5, 22.4 and 28.5° 20. 0027. The present invention also provides a crystalline hydrochloride salt of a compound of formula: having an XRPD pattern substantially as shown in FIG. 4. 0023 The present invention also provides crystalline 4-(5- Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-car boxylic acid 1-(3-chlorophenyl)-2-hydroxyethylamide HCl hydrate. 0024. The present invention also provides a crystalline hydrochloride salt of a compound of formula: C

having one or more XRPD 20-reflections () selected from the group consisting of about 5.8, 5.9, 6.2, 10.5, 11.8, 12.4. 15.9, 17.6, 17.8, 20.0, 20.4, 21.1, 21.4, 21.9, 22.4, 23.1, 24.0, 24.2, 24.9, and 25.3. 0028. The present invention also provides a crystalline C hydrochloride salt of a compound of formula:

having an X-ray powder diffraction (XRPD) pattern compris ing a characteristic peak at about 10.5° 20. C 0025. The present invention also provides a crystalline hydrochloride salt of a compound of formula: having an XRPD pattern substantially as shown in FIG. 7.

0029. The present invention also provides a crystalline hydrochloride salt of a compound of formula:

C having an XRPD pattern comprising characteristic peaks at about 6.2 and 10.5° 20. US 2016/022 1987 A1 Aug. 4, 2016 having an X-ray powder diffraction (XRPD) pattern compris 0033. The present invention also provides a crystalline ing a characteristic peak at about 10.7° 20. hydrochloride salt of a compound of formula: 0030 The present invention also provides a crystalline hydrochloride salt of a compound of formula:

having an XRPD pattern substantially as shown in FIG. 10.

BRIEF DESCRIPTION OF THE DRAWINGS having an XRPD pattern comprising characteristic peaks at 0034. The following drawings form part of the present about 10.7 and 18.1° 20. specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in 0031. The present invention also provides a crystalline combination with the detailed description of specific embodi hydrochloride salt of a compound of formula: ments presented herein. 0035 FIG. 1 shows the XRPD of 4-(5-Chloro-2-isopro

pylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3- chlorophenyl)-2-hydroxyethylamide free base acquired in transmission mode. 0036 FIG. 2 shows the FT-IR spectrum of 4-(5-Chloro-2- isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlorophenyl)-2-hydroxyethylamide free base. C 0037 FIG.3 shows the DSC thermogram of 4-(5-Chloro 2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlorophenyl)-2-hydroxyethylamide free base. 0038 FIG. 4 shows the XRPD of 4-(5-Chloro-2-isopro pylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3- chlorophenyl)-2-hydroxyethylamide Form C acquired in having an XRPD pattern comprising characteristic peaks at transmission mode. about 6.0, 10.7, 12.7, and 18.1° 20. 0039 FIG. 5 shows the FT-IR spectrum of 4-(5-Chloro-2- isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid 0032. The present invention also provides a crystalline 1-(3-chlorophenyl)-2-hydroxyethylamide Form C. hydrochloride salt of a compound of formula: 0040 FIG. 6 shows the DSC thermogram of 4-(5-Chloro 2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlorophenyl)-2-hydroxyethylamide Form C. 004.1 FIG. 7 shows the XRPD of 4-(5-Chloro-2-isopro pylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3- chlorophenyl)-2-hydroxyethylamide Form A acquired in transmission mode. 0042 FIG. 8 shows the FT-IR spectrum of 4-(5-Chloro-2- C isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlorophenyl)-2-hydroxyethylamide Form A. 0043 FIG.9 shows the DSC thermogram of 4-(5-Chloro 2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlorophenyl)-2-hydroxyethylamide Form A. 0044 FIG. 10 shows the XRPD of 4-(5-Chloro-2-isopro having one or more XRPD 20-reflections () selected from pylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3- the group consisting of about 6.0, 6.3, 10.7, 12.0, 12.7, 15.6, chlorophenyl)-2-hydroxyethylamide Form D acquired in 16.2, 16.3, 16.7, 17.9, 18.1, and 21.4. reflection mode. US 2016/022 1987 A1 Aug. 4, 2016

004.5 FIG. 11 shows the FT-IR spectrum of 4-(5-Chloro 0053. The present invention also provides a crystalline 2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic free base of a compound of formula: acid 1-(3-chlorophenyl)-2-hydroxyethylamide Form D.

0046 FIG. 12 shows the DSC thermogram of 4-(5- Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-car boxylic acid 1-(3-chlorophenyl)-2-hydroxyethylamide Form D. 0047 FIG. 13 shows a comparison of the Raman spectra from 1000-1600 cm for 4-(5-Chloro-2-isopropylaminopy ridin-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlorophe C nyl)-2-hydroxyethylamide Forms A and C. 0048 FIG. 14 shows a comparison of the Raman spectra from 950-1030 cm for 4-(5-Chloro-2-isopropylaminopyri din-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlorophenyl)- having an XRPD pattern comprising characteristic peaks at 2-hydroxyethylamide Forms A and C. about 9.1, 15.4, 19.5 and 21.4° 20. 0054 The present invention also provides a crystalline DETAILED DESCRIPTION OF THE INVENTION free base of a compound of formula: 0049. The present invention provides crystalline 4-(5- Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-car boxylic acid 1-(3-chlorophenyl)-2-hydroxyethylamide. 0050. The present invention also provides crystalline free base 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyr role-2-carboxylic acid 1-(3-chlorophenyl)-2-hydroxyethyl amide. C 0051. The present invention also provides a crystalline free base of a compound of formula:

having one or more XRPD 20-reflections () selected from the group consisting of about 9.1, 12.5, 15.2, 15.4, 19.2, 19.5, 20.3, 20.5, 21.4, 21.7, 21.9, 23.1, 23.3, 23.6, and 24.3. 0055. The present invention also provides a crystalline free base of a compound of formula: C

having an X-ray powder diffraction (XRPD) pattern compris ing a characteristic peak at about 19.5° 20. 0052. The present invention also provides a crystalline C free base of a compound of formula:

having an XRPD pattern substantially as shown in FIG. 1. 0056. The present invention also provides crystalline free base 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyr role-2-carboxylic acid 1-(3-chlorophenyl)-2-hydroxyethyl amide mono HCl having a Fourier transform infrared spec C troscopy (FT-IR) spectrum comprising one or more peaks at about 1603, 1533, 1487, 1080, 857, and 681 cm. 0057 The present invention also provides crystalline free base 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyr role-2-carboxylic acid 1-(3-chlorophenyl)-2-hydroxyethyl having an XRPD pattern comprising characteristic peaks at amide mono HCl having an FT-IR spectrum substantially as about 9.1 and 19.5° 20. shown in FIG. 2. US 2016/022 1987 A1 Aug. 4, 2016

0058. The present invention also provides crystalline free having an X-ray powder diffraction (XRPD) pattern compris base 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyr ing a characteristic peak at about 6.7° 20. role-2-carboxylic acid 1-(3-chlorophenyl)-2-hydroxyethyl amide mono HCl having (i) an XRPD pattern comprising one 0074 The present invention also provides a crystalline or more peaks at about 9. 1, 15.4, 19.5 and 21.4° 20; and (ii) a hydrochloride salt of a compound of formula: FT-IR spectrum comprising one or more peaks at about 1603,

1533, 1487, 1080, 857, and 681 cm. 0059. The present invention also provides crystalline free base 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyr role-2-carboxylic acid 1-(3-chlorophenyl)-2-hydroxyethyl amide mono HCl having a DSC thermogram with an endot herm having an onset temperature of approximately 184°C. 0060. The present invention also provides crystalline free base 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyr C role-2-carboxylic acid 1-(3-chlorophenyl)-2-hydroxyethyl amide mono HCl having a DSC thermogram substantially as shown in FIG. 3. 0061 The present invention also provides a pharmaceuti cal composition comprising a crystalline compound of the present invention. 0062 The present invention also provides a method of having an XRPD pattern comprising characteristic peaks at treating a cancer in a subject in need thereof comprising about 6.7 and 11.0° 20. administering to the Subject an effective amount of a crystal line compound of the present invention. 0075. The present invention also provides a crystalline 0063. In some embodiments, the subject is a mammal. hydrochloride salt of a compound of formula: 0064. In some embodiments, the mammal is selected from the group consisting of humans, primates, farm animals, and domestic animals. 0065. In some embodiments, the mammal is a human. 0.066. In some embodiments, the method further com prises administering to the Subject at least one additional anti-cancer agent. 0067 The present invention also provides a method of treating a cancer in a subject in need thereof comprising C administering to the Subject an effective amount of a pharma ceutical composition of the present invention. 0068. In some embodiments, the subject is a mammal. 0069. In some embodiments, the mammal is selected from the group consisting of humans, primates, farm animals, and domestic animals. 0070. In some embodiments, the mammal is a human. having an XRPD pattern comprising characteristic peaks at 0071. In some embodiments, the method further com about 6.7, 11.0, 17.6 and 19.9° 20. prises administering to the Subject at least one additional 0076. The present invention also provides a crystalline anti-cancer agent. hydrochloride salt of a compound of formula: 0072 The present invention also provides crystalline 4-(5- Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-car boxylic acid 1-(3-chlorophenyl)-2-hydroxyethylamide mono HC1. 0073. The present invention also provides a crystalline hydrochloride salt of a compound of formula:

0077. The present invention also provides a crystalline 0090. In some embodiments, the subject is a mammal. hydrochloride salt of a compound of formula: 0091. In some embodiments, the mammal is selected from the group consisting of humans, primates, farm animals, and domestic animals. 0092. In some embodiments, the mammal is a human. 0093. In some embodiments, the method further com prises administering to the Subject at least one additional anti-cancer agent. 0094. The present invention also provides crystalline 4-(5- Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-car C boxylic acid 1-(3-chlorophenyl)-2-hydroxyethylamide HCl hydrate. 0.095 The present invention also provides a crystalline hydrochloride salt of a compound of formula:

having an XRPD pattern substantially as shown in FIG. 4. 0078. The present invention also provides form C crystal line 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyr role-2-carboxylic acid 1-(3-chlorophenyl)-2-hydroxyethyl amide mono HCl having a Fourier transform infrared spectroscopy (FT-IR) spectrum comprising one or more peaks at about 1610, 1523, 1219, 1141, 1076, and 845 cm. 007.9 The present invention also provides form C crystal C line 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyr role-2-carboxylic acid 1-(3-chlorophenyl)-2-hydroxyethyl amide mono HCl having an FT-IR spectrum substantially as shown in FIG. 5. 0080. The present invention also provides form C crystal having an X-ray powder diffraction (XRPD) pattern compris line 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyr ing a characteristic peak at about 10.5° 20. role-2-carboxylic acid 1-(3-chlorophenyl)-2-hydroxyethyl 0096. The present invention also provides a crystalline amide mono HCl having (i) an XRPD pattern comprising one hydrochloride salt of a compound of formula: or more peaks at about 6.7, 11.0, 17.6, and 19.9° 20; and (ii) a FT-IR spectrum comprising one or more peaks at about 1610, 1523, 1219, 1141, 1076, and 845 cm. 0081. The present invention also provides form C crystal line 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyr role-2-carboxylic acid 1-(3-chlorophenyl)-2-hydroxyethyl amide mono HCl having a DSC thermogram with an endotherm having an onset temperature of approximately 2399 C. 0082. The present invention also provides form C crystal C line 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyr role-2-carboxylic acid 1-(3-chlorophenyl)-2-hydroxyethyl amide mono HCl having a DSC thermogram substantially as shown in FIG. 6. 0083. The present invention also provides a pharmaceuti having an XRPD pattern comprising characteristic peaks at cal composition comprising a crystalline compound of the about 6.2 and 10.5° 20. present invention. 0097. The present invention also provides a crystalline 0084 The present invention also provides a method of hydrochloride salt of a compound of formula: treating a cancer in a subject in need thereof comprising administering to the Subject an effective amount of a crystal line compound of the present invention. 0085. In some embodiments, the subject is a mammal. 0.086. In some embodiments, the mammal is selected from the group consisting of humans, primates, farm animals, and domestic animals. 0087. In some embodiments, the mammal is a human. 0088. In some embodiments, the method further com C prises administering to the Subject at least one additional anti-cancer agent. 0089 The present invention also provides a method of treating a cancer in a subject in need thereof comprising administering to the Subject an effective amount of a pharma having an XRPD pattern comprising characteristic peaks at ceutical composition of the present invention. about 6.2, 10.5, 22.4 and 28.5° 20. US 2016/022 1987 A1 Aug. 4, 2016

0098. The present invention also provides a crystalline administering to the Subject an effective amount of a crystal hydrochloride salt of a compound of formula: line compound of the present invention. 01.06 In some embodiments, the Subject is a mammal. 0107. In some embodiments, the mammal is selected from the group consisting of humans, primates, farm animals, and domestic animals. 0108 In some embodiments, the mammal is a human. 0109. In some embodiments, the method further com C prises administering to the Subject at least one additional anti-cancer agent. 0110. The present invention also provides a method of treating a cancer in a subject in need thereof comprising having one or more XRPD 20-reflections () selected from administering to the Subject an effective amount of a pharma the group consisting of about 5.8, 5.9, 6.2, 10.5, 11.8, 12.4. ceutical composition of the present invention. 15.9, 17.6, 17.8, 20.0, 20.4, 21.1, 21.4, 21.9, 22.4, 23.1, 24.0, 0111 In some embodiments, the Subject is a mammal. 24.2, 24.9, and 25.3. 0099. The present invention also provides a crystalline 0.112. In some embodiments, the mammal is selected from hydrochloride salt of a compound of formula: the group consisting of humans, primates, farm animals, and domestic animals.

0113 In some embodiments, the mammal is a human. 0114. In some embodiments, the method further com prises administering to the Subject at least one additional anti-cancer agent. 0115 The present invention also provides a crystalline C hydrochloride salt of a compound of formula:

having an XRPD pattern substantially as shown in FIG. 7. 0100. The present invention also provides form A crystal line 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyr role-2-carboxylic acid 1-(3-chlorophenyl)-2-hydroxyethyl C amide HCl hydrate having a Fourier transform infrared spectroscopy (FT-IR) spectrum comprising one or more peaks at about 1573, 1237, 1163,946, and 790 cm. 0101 The present invention also provides form A crystal line 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyr role-2-carboxylic acid 1-(3-chlorophenyl)-2-hydroxyethyl having an X-ray powder diffraction (XRPD) pattern compris amide HCl hydrate having an FT-IR spectrum substantially as ing a characteristic peak at about 10.7° 20. shown in FIG. 8. 0102 The present invention also provides form A crystal 0116. The present invention also provides a crystalline line 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyr hydrochloride salt of a compound of formula: role-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 28.520; and (ii) a FT-IR spectrum comprising one or more peaks at about 1573, 1237, 1163,946, and 790 cm. 0103) The present invention also provides form A crystal line 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyr role-2-carboxylic acid 1-(3-chlorophenyl)-2-hydroxyethyl amide HCl hydrate having a DSC thermogram substantially C as shown in FIG. 9. 0104. The present invention also provides a pharmaceuti cal composition comprising a crystalline compound of the present invention. 0105. The present invention also provides a method of having an XRPD pattern comprising characteristic peaks at treating a cancer in a subject in need thereof comprising about 10.7 and 18.1° 20. US 2016/022 1987 A1 Aug. 4, 2016

0117 The present invention also provides a crystalline 0.122 The present invention also provides form D crystal hydrochloride salt of a compound of formula: line 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyr role-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 18.120; and (ii) a FT-IR spectrum comprising one or more peaks at about 1537, 1471, 1239, 1163, 1067, and 946 cm. I0123. The present invention also provides form D crystal line 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyr role-2-carboxylic acid 1-(3-chlorophenyl)-2-hydroxyethyl C amide HCl having a DSC thermogram substantially as shown in FIG. 12. 0.124. The present invention also provides a pharmaceuti cal composition comprising a crystalline compound of the present invention. 0.125. The present invention also provides a method of having an XRPD pattern comprising characteristic peaks at treating a cancer in a subject in need thereof comprising about 6.0, 10.7, 12.7, and 18.1° 20. administering to the Subject an effective amount of a crystal 0118. The present invention also provides a crystalline line compound of the present invention. hydrochloride salt of a compound of formula: I0126. In some embodiments, the subject is a mammal. 0127. In some embodiments, the mammal is selected from the group consisting of humans, primates, farm animals, and domestic animals. 0128. In some embodiments, the mammal is a human. 0129. In some embodiments, the method further com prises administering to the Subject at least one additional anti-cancer agent. 0.130. The present invention also provides a method of C treating a cancer in a subject in need thereof comprising administering to the Subject an effective amount of a pharma ceutical composition of the present invention. I0131. In some embodiments, the subject is a mammal. (0132. In some embodiments, the mammal is selected from having one or more XRPD 20-reflections () selected from the group consisting of humans, primates, farm animals, and the group consisting of about 6.0, 6.3, 10.7, 12.0, 12.7, 15.6, domestic animals. 16.2, 16.3, 16.7, 17.9, 18.1, and 21.4. 0133. In some embodiments, the mammal is a human. 0119 The present invention also provides a crystalline 0.134. In some embodiments, the method further com hydrochloride salt of a compound of formula: prises administering to the Subject at least one additional anti-cancer agent.

0.135 The term “solid form is often used to refer to a class or type of solid-state material. One kind of solid form is a "polymorph” which refers to two or more compounds having the same chemical formula but differing in solid-state struc ture. Salts may be polymorphic. When polymorphs are ele ments, they are termed allotropes. Carbon possesses the well known allotropes of graphite, diamond, and C buckminsterfullerene. Polymorphs of molecular compounds, such as active pharmaceutical ingredients (APIs), are often prepared and studied in order to identify compounds meeting Scientific or commercial needs including, but not limited to, improved solubility, dissolution rate, hygroscopicity, and sta bility. having an XRPD pattern substantially as shown in FIG. 10. 0.136. Other solid forms include solvates and hydrates of 0120. The present invention also provides form D crystal compounds including salts. A Solvate is a compound wherein line 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyr a solvent molecule is present in the crystal structure together role-2-carboxylic acid 1-(3-chlorophenyl)-2-hydroxyethyl with another compound, such as an API. When the solvent is amide HCl having a Fourier transform infrared spectroscopy water, the solvent is termed a hydrate. Solvates and hydrates (FT-IR) spectrum comprising one or more peaks at about may be stoichiometric or non-stoichiometric. A monohydrate 1537, 1471, 1239, 1163, 1067, and 946 cm. is the term used when there is one water molecule, stoichio 0121 The present invention also provides form D crystal metrically, with respect to, for example, an API, in the unit line 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyr cell. role-2-carboxylic acid 1-(3-chlorophenyl)-2-hydroxyethyl 0.137 In order to identify the presence of a particular solid amide HCl having an FT-IR spectrum substantially as shown form, one of ordinary skill typically uses a suitable analytical in FIG. 11. technique to collect data on the form for analysis. For US 2016/022 1987 A1 Aug. 4, 2016

example, chemical identity of solid forms can often be deter ing water in the unit cell and the other not. Thus, this feature mined with solution-state techniques such as 'C-NMR or alone may be used to distinguish the forms of the compound 'H-NMR spectroscopy and such techniques may also be valu and it may not be necessary to identify peaks in the anhydrate, able in determining the Stoichiometry and presence of for example, which are not present in the hydrate or vice 'guests' Such as water or solvent in a hydrate or Solvate, WSa. respectively. These spectroscopic techniques may also be used to distinguish, for example, Solid forms without water or 0.142 X-ray powder diffraction patterns are some of the solvent in the unit cell (often referred to as “anhydrates”), most commonly used solid-state analytical techniques used to from hydrates or solvates. characterize solid forms. An X-ray powder diffraction pattern 0138 Solution-state analytical techniques do not provide is an X-ygraph with the diffraction angle, 20 (), on the X-axis information about the Solid state as a Substance and thus, for and intensity on the y-axis. The peaks within this plot may be example, Solid-state techniques may be used to distinguish used to characterize a crystalline solid form. The data is often among Solid forms such as anhydrates. Examples of Solid represented by the position of the peaks on the x-axis rather state techniques which may be used to analyze and charac than the intensity of peaks on the y-axis because peak inten terize solid forms, including anhydrates and hydrates, include sity can be particularly sensitive to sample orientation (see single crystal X-ray diffraction, X-ray powder diffraction Pharmaceutical Analysis, Lee & Web, pp. 255-257 (2003)). (XRPD), solid-state 'C-NMR, Infrared (“IR”) spectros Thus, intensity is not typically used by those skilled in the art copy, including Fourier Transform Infrared (FT-IR) spectros to characterize solid forms. copy, Raman spectroscopy, and thermal techniques such as 0143. As with any data measurement, there is variability in Differential Scanning calorimetry (DSC), melting point, and X-ray powder diffraction data. In addition to the variability in hot stage microscopy. peak intensity, there is also variability in the position of peaks 0139 Polymorphs are a subset of crystalline forms that on the x-axis. This variability can, however, typically be share the same chemical structure but differ in how the mol accounted for when reporting the positions of peaks for pur ecules are packed in a solid. When attempting to distinguish poses of characterization. Such variability in the position of polymorphs based on analytical data, one looks for data peaks along the X-axis derives from several Sources. One which characterize the form. For example, when there are two comes from sample preparation. Samples of the same crys polymorphs of a compound (e.g., Form I and Form II), one talline material, prepared under different conditions may can use X-ray powder diffraction peaks to characterize the yield slightly different diffractograms. Factors such as par forms when one finds a peak in a Form I pattern at angles ticle size, moisture content, solvent content, and orientation where no such peak is present in the Form II pattern. In Such may all affect how a sample diffracts X-rays. Another source a case, that single peak for Form I distinguishes it from Form of variability comes from instrument parameters. Different II and may further act to characterize Form I. When more X-ray instruments operate using different parameters and forms are present, then the same analysis is also done for the these may lead to slightly different diffraction patterns from other polymorphs. Thus, to characterize Form I against the the same crystalline solid form. Likewise, different software other polymorphs, one would look for peaks in Form I at packages process X-ray data differently and this also leads to angles where Such peaks are not present in the X-ray powder variability. These and other sources of variability are known diffraction patterns of the other polymorphs. The collection to those of ordinary skill in the pharmaceutical arts. of peaks, or indeed a single peak, which distinguishes Form I from the other known polymorphs is a collection of peaks 0144. Due to such sources of variability, it is common to which may be used to characterize Form I. If, for example, recite X-ray diffraction peaks using the word “about prior to two peaks characterize a polymorph then those two peaks can the peak value in degrees (20) (sometimes expressed hereinas be used to identify the presence of that polymorph and hence “20-reflections)()'), which presents the data to within 0.1 or characterize the polymorph. Those of ordinary skill in the art 0.2 (20) of the stated peak value depending on the circum will recognize that there are often multiple ways, including stances. The X-ray powder diffraction data corresponding to multiple ways using the same analytical technique, to char the solid forms of the present invention were collected on acterize polymorphic polymorphs. For example, one may instruments which were routinely calibrated and operated by find that three X-ray powder diffraction peaks characterize a skilled scientists. In the present invention, XRPD values are polymorph. Additional peaks could also be used, but are not preferably obtained using Cu KO. X-ray radiation according necessary, to characterize the polymorph up to and including to the method described in Example 1. Accordingly, the vari an entire diffraction pattern. Although all the peaks within an ability associated with these data would be expected to be entire diffractogram may be used to characterize a crystalline closer to +0.1 ° 20 than to +0.220 and indeed likely less than form, one may instead, and typically does as disclosed herein, 0.1 with the instruments used herein. However, to take into use a Subset of that data to characterize Sucha crystalline form account that instruments used elsewhere by those of ordinary depending on the circumstances. skill in the art may not be so maintained, for example, all 0140 For example, as used herein, “characteristic peaks' X-ray powder diffraction peaks cited herein have been are a subset of observed peaks and are used to differentiate reported with a variability on the order of +0.2 ° 20 and are one crystalline polymorph from another crystalline poly intended to be reported with such a variability whenever morph. Characteristic peaks are determined by evaluating disclosed herein and are reported in the specification to one which observed peaks, if any, are present in one crystalline significant figure after the decimal even though analytical polymorph of a compound againstall other known crystalline output may suggest higher precision on its face. polymorphs of that compound to within +0.2° 20. 0145 Single-crystal X-ray diffraction provides three-di 0141 When analyzing data to distinguish an anhydrate mensional structural information about the positions of atoms from a hydrate, for example, one can rely on the fact that the and bonds in a crystal. It is not always possible or feasible, two solid forms have different chemical structures—one hav however, to obtain Such a structure from a crystal, due to, for US 2016/022 1987 A1 Aug. 4, 2016

example, insufficient crystal size or difficulty in preparing within the scope of the present invention include, for crystals of Sufficient quality for single-crystal X-ray diffrac example, farm animals, domestic animals, laboratory ani tion. mals, etc. Some examples of farm animals include cows, pigs, 0146 X-ray powder diffraction data may also be used, in horses, goats, etc. Some examples of domestic animals Some circumstances, to determine the crystallographic unit include dogs, cats, etc. Some examples of laboratory animals cell of the crystalline structure. The method by which this is include primates, rats, mice, rabbits, guinea pigs, etc. done is called “indexing.” Indexing is the process of deter 0153 Cancers include both solid and hemotologic can mining the size and shape of the crystallographic unit cell cers. Non-limiting examples of solid cancers include adreno consistent with the peak positions in a Suitable X-ray powder cortical carcinoma, anal cancer, bladder cancer, bone cancer diffraction pattern. Indexing provides solutions for the three (such as osteosarcoma), brain cancer, breast cancer, carcinoid unit cell lengths (a, b, c), three unit cell angles (C, B, Y), and cancer, carcinoma, cervical cancer, colon cancer, endometrial three Miller index labels (h, k, 1) for each peak. The lengths cancer, esophageal cancer, extrahepatic bile duct cancer, are typically reported in Angstrom units and the angles in Ewing family of cancers, extracranial germ cell cancer, eye degree units. The Miller index labels are unitless integers. cancer, gallbladder cancer, gastric cancer, germ cell tumor, Successful indexing indicates that the sample is composed of gestational trophoblastic tumor, head and neck cancer, one crystalline phase and is therefore not a mixture of crys hypopharyngeal cancer, islet cell carcinoma, kidney cancer, talline phases. large intestine cancer, laryngeal cancer, leukemia, lip and oral 0147 IR spectroscopy, particularly FT-IR, is another tech cavity cancer, liver cancer, lung cancer, lymphoma, malig nique that may be used to characterize Solid forms together nant mesothelioma, Merkel cell carcinoma, mycosis fun with or separately from X-ray powder diffraction. In an IR goides, myelodysplastic syndrome, myeloproliferative disor spectrum, absorbed light is plotted on the X-axis of a graph in ders, nasopharyngeal cancer, neuroblastoma, oral cancer, the units of “wavenumber” (cm), with intensity on the oropharyngeal cancer, osteosarcoma, ovarian epithelial can y-axis. Variation in the position of IR peaks also exists and cer, ovarian germ cell cancer, pancreatic cancer, paranasal may be due to sample conditions as well as data collection and sinus and nasal cavity cancer, parathyroid cancer, penile can processing. The typical variability in IR spectra reported cer, pituitary cancer, plasma cell neoplasm, prostate cancer, herein is on the order of plus or minus 2.0 cm. Thus, the use rhabdomyosarcoma, rectal cancer, renal cell cancer, transi of the word “about when referencing IR peaks is meant to tional cell cancer of the renal pelvis and ureter, salivary gland include this variability and all IR peaks disclosed herein are cancer, Sezary syndrome, skin cancers (such as cutaneous intended to be reported with such variability. t-cell lymphoma, Kaposi’s sarcoma, mast cell tumor, and 0148. Thermal methods are another typical technique to melanoma), Small intestine cancer, Soft tissue sarcoma, stom characterize solid forms. Different polymorphs of the same ach cancer, testicular cancer, thymoma, thyroid cancer, ure compound often melt at different temperatures. Thus, the thral cancer, uterine cancer, vaginal cancer, Vulvar cancer, and melting point of a polymorph, as measured by methods such Wilms tumor. as capillary melting point, DSC, and hot stage microscopy, 0154 Examples of hematologic cancers include, but are alone or in combination with techniques such as X-ray pow not limited to, leukemias, such as adult/childhood acute lym der diffraction, IR spectroscopy, including FT-IR, or both, phoblastic leukemia, adult/childhood acute myeloid leuke may be used to characterize polymorphs or other Solid forms. mia, chronic lymphocytic leukemia, chronic myelogenous 0149. As with any analytical technique, melting point leukemia, and hairy cell leukemia, lymphomas, such as determinations are also subject to variability. Common AIDS-related lymphoma, cutaneous T-cell lymphoma, adult/ sources of variability, in addition to instrumental variability, childhood Hodgkin lymphoma, mycosis fungoides, adult/ are due to colligative properties such as the presence of other childhood non-Hodgkin lymphoma, primary central nervous solid forms or other impurities within a sample whose melt system lymphoma, Sezary syndrome, cutaneous T-cell lym ing point is being measured. phoma, and Waldenstrom macroglobulinemia, as well as 0150. As used herein, the terms “treat,” “treating,” “treat other proliferative disorders such as chronic myeloprolifera ment' and grammatical variations thereof mean Subjecting an tive disorders, Langerhans cell histiocytosis, multiple individual Subject to a protocol, regimen, process or remedy, myeloma/plasma cell neoplasm, myelodysplastic Syn in which it is desired to obtain a physiologic response or dromes, and myelodysplastic/myeloproliferative neoplasms. outcome in that Subject, e.g., a patient. In particular, the A preferred set of cancers that may be treated according to the methods and compositions of the present invention may be present invention include neuroblastoma, leukemia, lym used to slow the development of disease symptoms or delay phoma, liver cancer, lung cancer, skin cancer, testicular can the onset of the disease or condition, or halt the progression of cer, and thyroid cancer. Preferably, the cancer is melanoma. disease development. However, because every treated subject 0155 The methods of the present invention may option may not respond to a particular treatment protocol, regimen, ally further include administering to the Subject at least one process or remedy, treating does not require that the desired additional therapeutic agent effective for treating or amelio physiologic response or outcome be achieved in each and rating the effects of the cancer. The additional therapeutic every Subject or Subject population, e.g., patient population. agent may be selected from the group consisting of an anti Accordingly, a given Subject or subject population, e.g., body or fragment thereof, a chemotherapeutic agent, an patient population may fail to respond or respond inad immunotherapeutic agent, a radionuclide, a photoactive equately to treatment. therapeutic agent, a radiosensitizing agent, and combinations 0151. As used herein, the terms “ameliorate”, “ameliorat thereof. ing” and grammatical variations thereof mean to decrease the 0156 The crystalline, free base, and salt forms of 4-(5- severity of the symptoms of a disease in a Subject. Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-car 0152. As used herein, a “subject' is a mammal, preferably, boxylic acid 1-(3-chlorophenyl)-2-hydroxyethylamide a human. In addition to humans, categories of mammals (hereinafter “solid forms of the present invention') and the US 2016/022 1987 A1 Aug. 4, 2016

anti-cancer agent(s) used in the co-treatment therapy may be (GlaxoSmithKline), pralatrexate (Spectrum Pharmaceuti administered to the subject, either simultaneously or at dif cals), 6-thioguanine (Gate Pharmaceuticals), forodesine ferent times, as deemed most appropriate. If the solid forms of (BioCryst Pharmaceuticals), pentostatin (Bedford Laborato the present invention and the other anti-cancer agent(s) are ries), Sapacitabine (Cyclacel Pharmaceuticals, Inc.), aminop administered at different times, for example, by serial admin terin (Sigma Aldrich), azathioprine (GlaxoSmithKline), istration, then the solid forms of the present invention may be pharmaceutically acceptable salts thereof, and combinations administered to the Subject before the other anti-cancer agent. thereof. Alternatively, the other anti-cancer agent(s) may be adminis 0163 As used herein, a “pyrimidine' is a compound that tered to the subject before the 4-(5-Chloro-2-isopropylami contains a six-membered nitrogen-containing ring. Non-lim nopyridin-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlo iting examples of pyrimidines that are important for cellular rophenyl)-2-hydroxyethylamide. metabolism include uracil, thymine, cytosine, and orotic acid. 0157. As used herein, an “antibody' encompasses natu A“pyrimidine inhibitor is a substance that alters, reduces, or rally occurring immunoglobulins as well as non-naturally Suppresses the production of a pyrimidine or the use of a occurring immunoglobulins, including, for example, single pyrimidine by the a cell. Non-limiting examples of pyrimi chain antibodies, chimeric antibodies (e.g., humanized dine inhibitors include 5-fluorouracil (Tocris Bioscience), murine antibodies), and heteroconjugate antibodies (e.g., tegafur (LGM Pharma), capecitabine (Xeloda) (Roche), bispecific antibodies). Fragments of antibodies include those cladribine (LGM Pharma), gemcitabine (Eli Lilly), cytara that bind antigen, (e.g., Fab'. F(ab')2, Fab, Fv, and rIgG). See bine (Bedford Laboratories), decitabine (Eisai Inc.), floxuri also, e.g., Pierce Catalog and Handbook, 1994-1995 (Pierce dine (Bedford Laboratories), 5-azacytidine (Pharm ion Phar Chemical Co., Rockford, Ill.); Kuby, J., Immunology, 3rd maceuticals), doxifluridine (Cayman Chemicals), thiarabine Ed., W.H. Freeman & Co., New York (1998). The term anti (Access Pharmaceuticals), troxacitabine (SGX Pharmaceuti body also includes bivalent or bispecific molecules, diabod cals), raltitrexed (AstraZeneca), carmofur (Santa Cruz Bio ies, triabodies, and tetrabodies. The term “antibody' further technology, Inc.), 6-azauracil (MP Biomedicals, LLC), phar includes both polyclonal and monoclonal antibodies. maceutically acceptable salts thereof, and combinations 0158 Examples of therapeutic antibodies that may be thereof. used in the present invention include rituximab (Rituxan), 0164. In a preferred aspect of the present invention, the Cetuximab (Erbitux), bevacizumab (Avastin), and Ibritumo anti-metabolite agent is selected from the group consisting of mab (Zevalin). 5-fluorouracil (Tocris Bioscience), tegafur (LGM Pharma), 0159. As used herein, "chemotherapeutic agent’ means capecitabine (Xeloda) (Roche), cladribine (LGM Pharma), any therapeutic agent that is compatible with the Solid forms methotrexate (DuraMed Pharmaceuticals, Inc.), pemetrexed of the present invention treatment of the present invention and (Eli Lilly), hydroxyurea (Bristol-Myers Squibb), 2-mercap that uses cytotoxic and/or cytostatic agents against cancer topurine (Sigma-Aldrich), 6-mercaptopurine (Sigma-Ald cells or cells that are associated with or Support cancer cells. rich), fludarabine (Ben Venue Laboratories), gemcitabine (Eli In a preferred embodiment, the chemotherapeutic agent is an Lilly), clofarabine (Genzyme Corp.), cytarabine (Bedford agent selected from the group consisting of an anti-metabo Laboratories), decitabine (Eisai Inc.), floxuridine (Bedford lite, a microtubule inhibitor, a DNA damaging agent, an anti Laboratories), nelarabine (GlaxoSmithKline), pralatrexate biotic, an anti-angiogenesis agent, a vascular disrupting (Spectrum Pharmaceuticals), 6-thioguanine (Gate Pharma agent, a molecularly targeted agent, and combinations ceuticals), 5-azacytidine (Pharm ion Pharmaceuticals), doxi thereof. fluridine (Cayman Chemicals), forodesine (BioCryst Phar 0160. As used herein, an “anti-metabolite' is a substance maceuticals), pentostatin (Bedford Laboratories), that reduces or inhibits a cells use of a chemical that is part of Sapacitabine (Cyclacel Pharmaceuticals, Inc.), thiarabine normal metabolism. Non-limiting examples of anti-metabo (Access Pharmaceuticals), troxacitabine (SGX Pharmaceuti lite agents or analogs thereof according to the present inven cals), raltitrexed (AstraZeneca), aminopterin (Sigma Ald tion include antifolates, purine inhibitors, pyrimidine inhibi rich), carmofur (Santa Cruz, Biotechnology, Inc.), azathio tors, and combinations thereof. prine (GlaxoSmithKline), 6-azauracil (MP Biomedicals, 0161. As used herein, an “antifolate' is a substance that LLC), pharmaceutically acceptable salts thereof, and combi alters, reduces, or inhibits the use offolic acid (vitamin B9) by nations thereof. cells. Non-limiting examples of antifolates include methotr 0.165. As used herein, a “microtubule inhibitor is a sub exate (DuraMed Pharmaceuticals, Inc.), pemetrexed (Eli stance that disrupts the functioning of a microtubule. Such as Lilly), pralatrexate (Spectrum Pharmaceuticals), am inop the polymerization or the depolymerization of individual terin (Sigma Aldrich), pharmaceutically acceptable salts microtubule units. In one aspect of the present invention, the thereof, and combinations thereof. microtubule inhibitor may be selected from the group con 0162. As used herein, a “purine' is a compound that con sisting of a microtubule-destabilizing agent, a microtubule tains a fused six-membered and a five-membered nitrogen stabilizing agent, and combinations thereof. A microtubule containing ring. Non-limiting examples of purines that are inhibitor of the present invention may also be selected from important for cellular metabolism include adenine, guanine, the group consisting of a taxane, a Vinca alkaloid, an hypoxanthine, and xanthine. A “purine inhibitor is a sub epothilone, and combinations thereof. Non-limiting stance that alters, reduces or Suppresses the production of a examples of microtubule inhibitors according to the present purine or the use of a purine by a cell. Non-limiting examples invention include BT-062 (Biotest), HMN-214 (D. Western of purine inhibitors include methotrexate (DuraMed Pharma Therapeutics), eribulin mesylate (Eisai), vindesine (Eli ceuticals, Inc.), pemetrexed (Eli Lilly), hydroxyurea (Bristol Lilly), EC-1069 (Endocyte), EC-1456 (Endocyte), EC-531 Myers Squibb), 2-mercaptopurine (Sigma-Aldrich), 6-mer (Endocyte), vintafolide (Endocyte), 2-methoxyestradiol (En captopurine (Sigma-Aldrich), fludarabine (Ben Venue treMed), GTX-230 (GTX), trastuzumab emtansine (Hoff Laboratories), clofarabine (Genzyme Corp.), nelarabine mann-La Roche), crolibulin (Immune Pharmaceuticals), US 2016/022 1987 A1 Aug. 4, 2016

D1302A-maytansinoid conjugates (ImmunoGen), IMGN tion state. Platinum-based agents of the present invention 529 (ImmunoGen), lorvotuzumab mertansine (ImmunoGen), include, but are not limited to, 1,2-diaminocyclohexane SAR-3419 (ImmunoGen), SAR-566658 (ImmunoGen), (DACH) derivatives, phenanthroimidazole Pt(II) complexes, IMP-03138 (Impact Therapeutics), topotecan/vincristine platinum IV compounds, bi- and tri-nuclear platinum com combinations (LipoCure), BPH-8 (Molecular Discovery Sys pounds, demethylcantharidin-integrated platinum com tems), fosbretabulin tromethamine (OXiGENE), estramus plexes, platinum-conjugated compounds, cisplatin nanopar tine phosphate sodium (Pfizer), Vincristine (Pierre Fabre), ticles and polymer micelles, sterically hindered platinum vinflunine (Pierre Fabre), vinorelbine (Pierre Fabre), complexes, oxaliplatin (Debiopharm), satraplatin (Johnson RX-21101 (Rexahn), cabazitaxel (Sanofi), STA-9584 (Synta Matthey), BBR3464 (Novuspharma S.p.A.), ZD0473 (Astra Pharmaceuticals), vinblastine, epothilone A, patupilone (No Zeneca), cisplatin (Nippon Kayaku), JM-11 (Johnson Mat vartis), ixabepilone (Bristol-Myers Squibb), Epothilone D they), PAD (cis-dichlorobiscyclopentylamine platinum (II)), (Kosan Biosciences), paclitaxel (Bristol-Myers Squibb), doc MBA ((trans-1,2-diaminocyclohexane) bisbromoacetato etaxel (Sanofi-Aventis), HAI abraxane, DJ-927 (Daiichi San platinum (II)). PHM ((1,2-Cyclohexanediamine) malonato kyo), discodermolide (CAS No: 127943-53-7), eleutherobin platinum (II)), SHP (1,2-Cyclohexanediamine) sulphato (CAS No.: 174545-76-7), pharmaceutically acceptable salts platinum (II)), neo-PHM (trans-R.R-1,2-Cyclohexanedi thereof, and combinations thereof. amine) malonato platinum (II)), neo-SHP ((trans-R.R-1,2- 0166 DNA damaging agents of the present invention Cyclohexanediamine)sulphato platinum (II)), JM-82 include, but are not limited to, alkylating agents, platinum (Johnson Matthey), PYP (1,2-Cyclohexanediamine) based agents, intercalating agents, and inhibitors of DNA bispyruvato platinum (II)), PHIC ((1,2-Cyclohexanedi replication. amine) isocitrato platinum (II)), TRK-710 (trans-R.R-1,2- 0167 As used herein, an “alkylating agent' is a substance cyclohexanediamine) 3-Acetyl-5-methyl-2,4(3H,5H)- that adds one or more alkyl groups (CnHm, where n and mare furandionato platinum (II)), BOP ((1.2- integers) to a nucleic acid. In the present invention, an alky Cyclooctanediamine) bisbromoacetato platinum (II)), JM-40 lating agent is selected from the group consisting of nitrogen (Johnson Matthey), enloplatin (UnionPharma), Zeniplatin mustards, nitrosoureas, alkyl Sulfonates, triazines, ethylen (LGM Pharma), CI-973 (Parke-Davis), lobaplatin (Zentaris imines, and combinations thereof. Non-limiting examples of AG/Hainan Tianwang International Pharmaceutical), cyclo nitrogen mustards include mechlorethamine (Lundbeck), platam (LGM Pharma), WA2114R (miboplatin/lobaplatin) chlorambucil (GlaxoSmithKline), cyclophosphamide (Mead (Chembest Research Laboratories, Ltd.), heptaplatin Johnson Co.), bendamustine (Astellas), ifosfamide (Baxter (SKI2053R) (SK Chemicals), TNO-6 (spiroplatin) (Haihang International), melphalan (Ligand), melphalan flufenamide Industry Co., Ltd.), ormaplatin (tetraplatin) (LGM Pharma), (Oncopeptides), and pharmaceutically acceptable salts JM-9 (iproplatin) (Johnson Matthey), BBR3610 (Novusp thereof. Non-limiting examples of nitrosoureas include Strep harma S.p.A.), BBR3005 (Novuspharma S.p.A.), BBR3571 toZocin (Teva), carmustine (Eisai), lomustine (Sanofi), and (Novuspharma S.p.A.), BBR3537 (Novuspharma S.p.A.), pharmaceutically acceptable salts thereof. Non-limiting aroplatin (L-NDDP) (BOC Sciences), Pt-ACRAMTU ({Pt examples of alkyl sulfonates include busulfan (Jazz Pharma (en) CI(ACRAMTU-S) (NO3)2 (en-ethane-1,2-diamine, ceuticals) and pharmaceutically acceptable salts thereof. ACRAMTU=1-2-(acridin-9-ylamino)ethyl-1,3-dimeth Non-limiting examples of triazines include dacarbazine ylthiourea)}), cisplatin-loaded liposomes (LiPlasomes), SPI (Bayer), temozolomide (Cancer Research Technology), and 077 (Alza), lipoplatin (Regulon), lipoxal (Regulon), carbopl pharmaceutically acceptable salts thereof. Non-limiting atin (Johnson Matthey), nedaplatin (Shionogi Seiyaku), examples of ethylenimines include thiotepa (Bedford Labo miriplatin hydrate (Dainippon Sumitomo Pharma), ormapl ratories), altretamine (MGI Pharma), and pharmaceutically atin (LGM Pharma), enloplatin (Lederle Laboratories), acceptable salts thereof. Other alkylating agents include Pro CI973 (Parke-Davis), PEGylated cisplatin, PEGylated carbo Lindac (Access), Ac-225 BC-8 (Actinium Pharmaceuticals), platin, PEGylated oxaliplatin, transplatin (trans-diam ALF-2111 (Alfact Innovation), trofosfamide (Baxter Interna minedichloroplatinum (II); mixedZ:trans-PtCl2(Z— tional), MDX-1203 (Bristol-Myers Squibb), thioureidobuty HN=C(OMe)Me}(NH3)), CD-37 (estradiol-platinum(II) ronitrile (CellCeutix), mitobronitol (Chinoin), mitolactol hybrid molecule), picoplatin (Poniard Pharmaceuticals), (Chinoin), nimustine (Daiichi Sankyo), glufosfamide (Elei son Pharmaceuticals), HuMax-TAC and PBD ADC combi nations (Genmab), BP-C1 (Meabco), treosulfan (Medac), YP NP Y C nifurtimox (Metronomx), improsulfan tosilate (Mitsubishi C111. YNH, Cl - Pt na N , tanabe Pharma), ranimustine (Mitsubishi tanabe Pharma), ND-01 (NanoCarrier), HH-1 (Nordic Nanovector), 22P1G cells and ifosfamide combinations (Nuvilex), estramustine Q phosphate (Pfizer), prednimustine (Pfizer), lurbinectedin (PharmaMar), trabectedin (PharmaMar), altreatamine H HN C =N-Clt CH *N11 - (Sanofi), SGN-CD33A (Seattle Genetics), fotemustine 1NN= C HN (Servier), nedaplatin (Shionogi), heptaplatin (Sk Holdings), H apaziquone (Spectrum Pharmaceuticals), SG-2000 (Spiro gen), TLK-58747 (Telik), laromustine (Vion Pharmaceuti cals), procarbazine (Alkem Laboratories Ltd.), and pharma ceutically acceptable salts thereof. AH44 (Komeda et al., 2006: Harris et al., 2005; Qu et al., 0168 As used herein, a “platinum-based agent' is an anti 2004), triplatinNC (Harris et al., 2005; Quet al., 2004), Pro cancer Substance that contains the metal platinum and ana Lindac (Access), pharmaceutically acceptable salts thereof, logs of Such Substances. The platinum may be in any oxida and combinations thereof. US 2016/022 1987 A1 Aug. 4, 2016

0169. As used herein, an “intercalating agent' includes, 0173 VEGFR antagonists of the present invention but is not limited to, doxorubicin (Adriamycin), daunorubi include, but are not limited to, paZopanib, regorafenib, len cin, idarubicin, mitoxantrone, pharmaceutically acceptable Vatinib, Sorafenib, Sunitinib, axitinib, Vandetanib, cabozan salts thereof, prodrugs, and combinations thereof. tinib, vatalanib, semaxanib, ZD6474, SU6668, AG-013736, 0170 Non-limiting examples of inhibitors of DNA repli AZD2171, AEE788, MF1/MC-18F1, DC101/IMC-1C11, cation include, but are not limited to topoisomerase inhibi ramucirumab, and motesanib. VEGFR antagonists may also tors. As used herein, a “topoisomerase inhibitor is a sub include, VEGF inhibitors such as bevacizumab, aflibercept, stance that decreases the expression or the activity of a 2C3, r84, VEGF-Trap, and ranibizumab. topoisomerase. The topoisomerase inhibitors according to 0.174 Angiostatic steroids of the present invention include the present invention may inhibit topoisomerase I, topoi any Steroid that inhibits, attenuates, prevents angiogenesis or Somerase II, or both topoisomerase I and topoisomerase II. neovascularization, or causes regression of pathological vas Non-limiting examples oftopoisomerase I inhibitors accord cularization. Angiostatic steroids of the present invention ing to the present invention include irinotecan (Alchemic), include those disclosed in European Patent Application Serial APH-0804 (Aphios), camptothecin (Aphios), cositecan No. EP1236471 A2, as well as those 20-substituted steroids (BioNumerik), topotecan (GlaxoSmithKline), belotecan disclosed in U.S. Pat. No. 4,599.331, those 21-hydroxy ste hydrochloride (Chon Kun Dang), firtecan pegol (Enzon), roids disclosed in U.S. Pat. No. 4,771,042, those C11-func HN-30181A (Hanmi), hRS7-SN-38 (Immunomedics), tionalized Steroids disclosed in International Application labetuzumab-SN-38 (Immunomedics), etirinotecan pegol Serial No. WO 1987/02672, 6C-fluoro17C,21-dihydroxy (Nektar Therapeutics), NK-012 (Nippon Kayaku). SER-203 16C.-methylpregna-4.9(11)-diene-320-dione 21-acetate, (Serina Therapeutics), simmitecan hydrochloride prodrug 6.C.-fluoro-17C,21-dihydroxy-16? 3-methylpregna-4.9(11)-di (Shanghai HaiHe Pharmaceuticals), gimatecan (Sigma-Tau), ene-320-dione, 6C.-fluoro-17C,21-dihydroxy-16? 3-methyl namitecan (Sigma-Tau), SN-38 (Supratek Pharma), TLC-388 pregna-4.9(11)-diene-3,20-dione 21-phosphonooxy and hydrochloride (Taiwan Liposome Company), Iamellarin D pharmaceutically acceptable salts thereof, hydrocortisone, (PharmaMar), pharmaceutically acceptable salts thereof, and tetrahydrocortisol, 17O-hydroxy-progesterone, 11 C-epihy combinations thereof. Non-limiting examples of inhibitors of drocortisone, cortexolone, corticosterone, desoxycorticoster topoisomerase type II according to the present invention one, dexamethasone, cortisone 21-acetate, hydrocortisone include Adva-27a (Advanomics), Zoptarelin doxorubicin 21-phosphate, 17O-hydroxy-6C.-methylpregn-4-ene-3,20-di (Aeterna Zentaris), valrubicin (Anthra Pharmaceuticals), one 17-acetate, 6C.-fluoro-17C,21-dihydroxy-16C.-methyl razoxane (AstraZeneca), doxorubicin (Avena Therapeutics), pregna-4.9(11)-diene-320-dione, and A9(11)-etianic esters, amsacrine (Bristol-Myers Squibb), etoposide phosphate all disclosed in International Application Serial No. WO (Bristol-Myers Squibb), etoposide (Novartis), dexrazoxane 1990/O1581.6 A1. (Cancer Research Technology), cytarabine? daunorubicin 0.175 Cartilage-derived angiogenesis inhibitor factors combination (Celator Pharmaceuticals), CAP7.1 (CellAct include, but are not limited to, peptide troponin and chondro Pharma), aldoxorubicin (CytRX), amrubicin hydrochloride modulin I. (Dainippon Sumitomo Pharma), VosaroXin (Dainippon 0176 Matrix metalloproteinase inhibitors of the present Sumitomo Pharma), daunorubicin (Gilead Sciences), milatu invention include, but are not limited to. Succinyl hydroxam Zumab? doxorubicin combination (Immunomedics), aclarubi ates such as marimastat and SC903, sulphonamide hydrox cin (Kyowa Hakko Kirin), mitoxantrone (Meda), pirarubicin amates such as CGS27023A, phosphinamide hydroxamates, (Meiji), epirubicin (Pfizer), teniposide (Novartis), F-14512 carboxylate inhibitors such as BAY12-9566, thiol inhibitors (Pierre Fabre), elliptinium acetate (Sanofi), Zorubicin Such as Compound B, aminomethyl benzimidazole ana (Sanofi), dexraZOxane (TopoTarget), Sobuzoxane (Zenyaku logues, peptides Such as regaSepin, and tetracyclines such as Kogyo), idarubicin (Pfizer), HU-331 (Cayman Chemical), minocycline. aurintricarboxylic acid (Sigma Aldrich), pharmaceutically 0177 C.VfB3 inhibitors include, but are not limited to, acceptable salts thereof, and combinations thereof. IS201, P11 peptide, EMD 85189, and 66203, RGD peptide, 0171 Chemotherapeutic antibiotics according to the RGD mimetics such as S 36578-2, echistatin, antibodies or present invention include, but are not limited to, actinomycin, antibody fragments against CVB3 integrin Such as Vitaxin, anthracyclines, valrubicin, epirubicin, bleomycin, plicamy which targets the extracellular domain of the dimer, cilen cin, mitomycin, pharmaceutically acceptable salts thereof, gitide, and peptidomimetics such as S247. prodrugs, and combinations thereof. 0.178 Anti-angiogenic siRNAs include, but are not limited 0172. As used herein, the term “anti-angiogenesis agent' to, siRNAS targeting mRNAS that are upregulated during means any compound that prevents or delays nascent blood angiogenesis, optionally PEGylated siRNAs targeting VEGF vessel formation from existing vessels. In the present inven or VEGFR mRNAs, and siRNAs targeting UPR (unfolded tion, examples of anti-angiogenesis agents include, but are protein response)-IRE1C, XBP-1, and ATF6 mRNAs. Addi not limited to, pegaptainib, ranibizumab, bevacizumab (avas tionally, it has been shown that siRNAs that are, at minimum, tin), carboxyamidotriazole, TNP-470, CM101, IFN-O, IL-12, 21 nucleotides in length, regardless of targeting sequence, platelet factor 4, Suramin, SU5416, thrombospondin, VEGFR Suppress neovascularization (Kleinman, et al., 2008) and may antagonists, angiostatic steroids and heparin, cartilage-de be included in the anti-angiogenic siRNAs of the present rived angiogenesis inhibitory factor, matrix metalloprotein invention. ase inhibitors, angiostatin, endostatin, 2-methoxyestradiol. 0179 Inhibitors of the complement system include, but tecogalan, prolactin, CVB3 inhibitors, linomide, VEGF-Trap, are not limited to, modified native complement components am inosterols, cortisone, tyrosine kinase inhibitors, anti-an Such as soluble complement receptor type 1, Soluble comple giogenic siRNA, inhibitors of the complement system, Vas ment receptor type 1 lacking long homologous repeat-A, cular disrupting agents, and combinations thereof. Prefer soluble Complement Receptor Type 1-Sialyl LewisX, ably, the anti-angiogenesis agent is bevacizumab. complement receptor type 2, Soluble decay accelerating fac US 2016/022 1987 A1 Aug. 4, 2016

tor, soluble membrane cofactor protein, soluble CD59, decay 0.184 As used herein, a “B-Raf inhibitor of the present accelerating factor-CD59 hybrid, membrane cofactor pro invention is a substance that (i) directly interacts with B-Raf, tein-decay accelerating factor hybrid, C1 inhibitor, and C1q. e.g., by binding to B-Raf and (ii) decreases the expression or receptor, complement-inhibitory antibodies such as anti-C5 the activity of B-Raf. B-Raf inhibitors may be classified into monoclonal antibody and anti-05 single chain Fv, Synthetic two types by their respective binding modes. As used herein, inhibitors of complement activation Such as antagonistic pep “Type 1 B-Raf inhibitors are those inhibitors that target the tides and analogs targeting C5a receptor, and naturally occur ATP binding sites of the kinase in its active conformation. ring compounds that block complement activation Such as “Type 2 B-Raf inhibitors are those inhibitors that preferen heparin and related glycosaminoglycan compounds. Addi tially bind to an inactive conformation of the kinase. Non tional inhibitors of the complement system are disclosed by limiting examples of Type 1 B-Raf inhibitors of the present Makrides (Makrides, 1998). invention include: 0180. As used herein, the term “vascular disrupting agent' means any compound that targets existing vasculature, e.g. tumor vasculature, damages ordestroys said vasculature, and/ Compound 7 or causes central tumor necrosis. In the present invention, examples of vascular disrupting agents include, but are not limited to, ABT-751 (Abbott), AVE8062 (Aventis), BCN105 2 (Bionomics), BMXAA (Antisoma), CA-4-P (OxiGene), CA-1-P (OxiGene), CYT997 (Cytopia), MPC-6827 (Myriad O O N s Pharmaceuticals), MN-029 (MediciNova), NPI-2358 (Nereus), Oxia.503 (Oxigene), TZT-1027 (Daichi Pharma N ceuticals), ZD6126 (AstraZeneca and Angiogene), pharma O HN C ceutically acceptable salts thereof, and combinations thereof. N1s-- N lsN N H H 0181. As used herein, a “molecularly targeted agent” is a substance that interferes with the function of a single mol 21 ecule or group of molecules, preferably those that are (Liet al., 2010) involved in tumor growth and progression, when adminis tered to a subject. Non-limiting examples of molecularly targeted agents of the present invention include signal trans Compound 9 duction inhibitors, modulators of gene expression and other cellular functions, immune system modulators, antibody drug conjugates (ADCs), and combinations thereof. Cl, O 0182. As used herein, a “signal transduction inhibitor” is a Substance that disrupts communication between cells, such as N when an extracellular signaling molecule activates a cell Sur HN face receptor. Non-limiting examples of signal transduction Or NX-SH inhibitors of the present invention include anaplastic lym phoma kinase (ALK) inhibitors, B-Raf inhibitors, epidermal growth factor inhibitors (EGFRi), ERK inhibitors, Janus (Id.) kinase inhibitors, MEK inhibitors, mammalian target of rapa mycin (mTor) inhibitors, phosphoinositide 3-kinase inhibi tors (PI3Ki), and Ras inhibitors. 0183. As used herein, an “anaplastic lymphoma kinase Compound 10 (ALK) inhibitor is a substance that (i) directly interacts with ALK, e.g., by binding to ALK and (ii) decreases the expres sion or the activity of ALK. Non-limiting examples of ana plastic lymphoma kinase (ALK) inhibitors of the present invention include crizotinib (Pfizer, New York, N.Y.), O CH5424802 (Chugai Pharmaceutical Co., Tokyo, Japan), GSK1838705 (GlaxoSmithKline, United Kingdom), Chugai N N 13d (Chugai Pharmaceutical Co., Tokyo, Japan), CEP28122 (Teva Pharmaceutical Industries, Ltd., Israel), AP26113 1. M S (Ariad Pharmaceuticals, Cambridge, Mass.), Cephalon 30 O N N u (Teva Pharmaceutical Industries, Ltd., Israel), X-396 (Xcov OH, ery, Inc., West Palm Beach, Fla.), Amgen 36 (Amgen Phar maceuticals, Thousand Oaks, Calif.), ASP3026 (Astellas Pharma US, Inc., Northbrook, Ill.), and Amgen 49 (Amgen Pharmaceuticals, Thousand Oaks, Calif.), pharmaceutically acceptable salts thereof, and combinations thereof. US 2016/022 1987 A1 Aug. 4, 2016 16

-continued -continued Compound 13 Compound 18 CF N

H H Clu N N CC2

(Id.) Compound 19 HO 2 CF 21 Compound 14 H H rolN N N-N. (Id.) Compound 20 h

O 21 dabrafenib (GlaxoSmithKline), GDC-0879 (Genentech), 1s-N- L-779450 B-Raf (Merck), PLX3202 (Plexxikon), PLX4720 H (Plexxikon), SB-590885 (GlaxoSmithKline), SB-6993.93 O (GlaxoSmithKline), Vemurafenib (Plexxikon), pharmaceuti cally acceptable salts thereof, and combinations thereof. Pref (Id.) erably, the type 1 RAF inhibitor is dabrafenib or a pharma Compound 21 ceutically acceptable salt thereof. 0185. Non-limiting examples of Type 2 B-Raf inhibitors O of the present invention include: H HCO N Nn N ls s H Compound 15 2 HCO N CF C O OCH (Id.) N O N N W NHMe, Compound 22

(Liet al., 2010) Compound 16 Br O Ol y O n NHMe, -{ l (Id.) / (Id.) US 2016/022 1987 A1 Aug. 4, 2016 17

-continued -continued Compound 23 Compound 28 C O O H N. N.n N ls s C O H 2 N N Y-1 (Id.) N O Compound 24 N O ... H \ / H3CO N N O ls n N s H (Id.) 2 Compound 30 H3CO N C OCH (Id.) C Compound 25

N f \ NH N O O N O

N 2 N ls s H (Id.) Compound 26

Compound 31 HCO NH N O O O

HCO N 2 N ls s H OCH (Id.) Compound 27

Compound 32

O N

(Id.)

(Id.) US 2016/022 1987 A1 Aug. 4, 2016

-continued -continued Compound 33 Compound 38 CF3

H N

(Id.) Compound 39 (Id.) CF

Compound 34

H N CF in-( N C O O N H, O (Id.) ls 2N Compound 40

N N CF (Id.) C Compound 35 O N l N H H

C (Id.) Sorafenib (Onyx Pharmaceuticals), ZM-336372 (AstraZen eca), pharmaceutically acceptable salts thereof, and combi N 1, nations thereof (Id.) 0186. Other B-Raf inhibitors include, without limitation, AAL881 (Novartis); AB-024 (Ambit Biosciences), ARQ-736 Compound 36 (ArCule), ARQ-761 (ArQule), AZ628 (AxonMedchem BV), BeiGene-283 (BeiGene), BUB-024 (MLN 2480) (Sunesis & Takeda), b raf inhibitor (Sareum), BRAF kinase inhibitor (Selexagen Therapeutics), BRAF siRNA 313 (tacaccag CF in-( caagctagatgca) and 253 (cctategttagagtct tcctg) (Liu et al., C NH, 2007), CTT239065 (Institute of Cancer Research), DP-4978 (Deciphera Pharmaceuticals), HM-95573 (Hanmi), GW 5074 (Sigma Aldrich), ISIS 5132 (Novartis), LErafAON 2NN (NeoPharm, Inc.), LBT613 (Novartis), LGX818 (Novartis), N 1, pazopanib (GlaxoSmithKline), PLX5568 (Plexxikon), RAF (Id.) 265 (Novartis), RAF-365 (Novartis), regorafenib (Bayer Healthcare Pharmaceuticals, Inc.), RO 5126766 (Hoffmann Compound 37 La Roche), TAK 632 (Takeda), TL-241 (Telligene), XL-281 (Exelixis), pharmaceutically acceptable salts thereof, and combinations thereof. 0187. As used herein, an “EGFR inhibitor is a substance NH, that (i) directly interacts with EGFR, e.g. by binding to EGFR C and (ii) decreases the expression or the activity of EGFR. Non-limiting examples of EGFR inhibitors according to the present invention include (+)-Aeroplysinin-1 (CAS #28656 91-9), 3-(4-lsopropylbenzylidenyl)-indolin-2-one, ABT-806 N 1. (Life Science Pharmaceuticals), AC-480 (Bristol-Myers (Id.) Squibb), afatinib (Boehringer Ingelheim), AG 1478 (CAS #153436-53-4), AG 494 (CAS #133550-35-3), AG 555 (CAS #133550-34-2), AG 556 (CAS #133550-41-1), AG825 (CAS #149092-50-2), AG-490 (CAS #134036-52-5), antro quinonol (Golden Biotechnology), AP-26113 (Ariad), ARRY334543 (CAS #845272-21-1), AST 1306 (CAS US 2016/022 1987 A1 Aug. 4, 2016

#897383-62-9), AVL-301 (Celgene), AZD8931 (CAS the activity of a Janus kinase. Janus kinases of the present #848942-61-0), BIBU 1361 (CAS #793726-84-8), BIBX invention include Tyk2, Jak1, Jak2, and Jak3. Non-limiting 1382 (CAS #196612-93-8), BMS-690514 (Bristol-Myers examples of Janus kinase inhibitors of the present invention Squibb), BPIQ-I (CAS #174709-30-9), Canertinib (Pfizer), include ruxolitinib (Incyte Corporation, Wilmington, Del.), cetuximab (Actavis), cipatinib (Jiangsu Hengrui Medicine), baricitinib (Incyte Corporation, Wilmington, Del.), tofaci CL-387,785 (Santa Cruz Biotech), compound 56 (CAS tinib (Pfizer, New York, N.Y.), VX-509 (Vertex Pharmaceu #171745-13-4), CTX-023 (CytomX Therapeutics), CUDC ticals, Inc., Boston, Mass.), GLPG0634 (Galapagos NV, Bel 101 (Curis), dacomitinib (Pfizer), DAPH (CAS #145915-58 gium), CEP-33779 (Teva Pharmaceuticals, Israel), 8), daphnetin (Santa Cruz Biotech), dovitinib lactate (Novar pharmaceutically acceptable salts thereof, and combinations tis), EGFR Inhibitor (CAS #879127-07-8), epitinib thereof (Hutchison China MediTech), erbstatin Analog (CAS 0190. As used herein, a “MEK inhibitor is a substance #631 77-57-1), erlotinib (Astellas), gefitinib (AstraZeneca), that (i) directly interacts with MEK, e.g., by binding to MEK GT-MAB 5.2-GEX (Glycotope), GW 583340 (CAS and (ii) decreases the expression or the activity of MEK. #388082-81-3), GW2974 (CAS #202272-68-2), HDS 029 Therefore, inhibitors that act upstream of MEK, such as RAS (CAS #881001-19-0), Hypericin (Santa Cruz, Biotech), ico inhibitors and RAF inhibitors, are not MEK inhibitors tinib hydrochloride (Betapharma), JNJ-26483327 (Johnson according to the present invention. MEK inhibitors may be & Johnson), JNJ-28871063 (Johnson & Johnson), KD-020 classified into two types depending on whether the inhibitor (Kadmon Pharmaceuticals), lapatinib ditosylate (Glaxo competes with ATP. As used herein, a “Type 1 MEK inhibi SmithKline), Lavendustin A (Sigma), Lavendustin C tor is an inhibitor that competes with ATP for binding to (Sigma), LY-3016859 (Eli Lilly), MEHD-7945A (Hoffmann MEK. A “Type 2 MEK inhibitor is an inhibitor that does not La Roche), MM-151 (Merrimack), MT-062 (Medisyn Tech compete with ATP for binding to MEK. Non-limiting nologies), necitumumab (Eli Lilly), neratinib (Pfizer), nimo examples of type 1 MEK inhibitors according to the present tuzumab (Center of Molecular Immunology), NT-004 invention include bentamapimod (Merck KGaA), L783.277 (NewGen Therapeutics), pantiumumab (Amgen), PD 153035 (Merck), RO092210 (Roche), pharmaceutically acceptable (CAS #153436-54-5), PD 161570 (CAS #192705-80-9), PD salts thereof, and combinations thereof. Preferably, the type 1 168393, PD 174265 (CAS #216163-53-0), pirotinib (Sihuan MEK inhibitor is RO092210 (Roche) or a pharmaceutically Pharmaceutical), poziotinib (Hanmi), PP3 (CAS #5334-30 acceptable salt thereof. Non-limiting examples of type 2 5), PR-610 (Proacta), pyrotinib (Jiangsu Hengrui Medicine), MEK inhibitors according to the present invention include RG-13022 (CAS #136831-48-6), rindopepimut (Celldex anthrax toxin, lethal factor portion of anthrax toxin, ARRY Therapeutics), RPI-1 (CAS #269730-03-2), S-222611 142886 (6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3- (Shionogi), TAK 285 (CAS #871026-44-7), TAS-2913 methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy (Taiho), theliatinib (Hutchison China MediTech), Tyrphostin ethoxy)-amide) (Array BioPharma), ARRY-438162 (Array 47 (RG-50864, AG-213) (CAS #118409-60-2), Tyrphostin BioPharma), AS-1940477 (Astellas), MEK162 (Array BioP 51 (CAS #122520-90-5), Tyrphostin AG 1478 (CAS harma), PD 098059 (2-(2-amino-3'-methoxyphenyl)-ox #175178-82-2), Tyrphostin AG 183 (CAS #126433-07-6), anaphthalen-4-one), PD 184352 (CI-1040), PD-0325901 Tyrphostin AG 528 (CAS #133550-49-9). Tyrphostin AG 99 (Pfizer), pimasertib (Santhera Pharmaceuticals), refametinib (CAS #118409-59-9). Tyrphostin B42 (Santa Cruz, Biotech), (AstraZeneca), selumetinib (AZD6244) (AstraZeneca), Tyrphostin B44 (Santa Cruz, Biotech), Tyrphostin RG 14620 TAK-733 (Takeda), trametinib (Japan Tobacco), UO126 (1,4- (CAS #136831-49-7), Vandetanib (AstraZeneca), Varlitinib diamino-2, 3-dicyano-1,4-bis(2-aminophenylthio)butadi (Array BioPharma), Vatalanib (Novartis), WZ 3146 (CAS ene) (Sigma), RDEA119 (Ardea Biosciences/Bayer), phar #1214265-56-1), WZ 4002 (CAS #1213269-23-8), WZ8040 maceutically acceptable salts thereof, and combinations (CAS #1214265-57-2), XL-647 (Exelixis), Z-650 (HEC thereof. Preferably, the type 2 MEK inhibitor is trametinib or Pharm), ZM323881 (CAS #324077-30-7), pharmaceutically a pharmaceutically acceptable salt thereof. Other MEK acceptable salts thereof, and combinations thereof. Prefer inhibitors include, without limitation, antroduinonol (Golden ably, the EGFR inhibitor is selected from the group consisting Biotechnology), AS-1940477 (Astellas), AS-703988 (Merck of panitumumab, erlotinib, pharmaceutically acceptable salts KGaA), BI-847325 (Boehringer Ingelheim), E-6201 (Eisai), thereof, and combinations thereof. GDC-0623 (Hoffmann-La Roche), GDC-0973, RG422, 0188 As noted above, the solid forms of the present inven RO4987655, RO5126766, SL327, WX-554 (Wilex), Yop) tion are ERK inhibitors. As used herein, an “ERK inhibitor polypeptide, pharmaceutically acceptable salts thereof, and is a substance that (i) directly interacts with ERK, including combinations thereof. ERK1 and ERK2, e.g., by binding to ERK and (ii) decreases (0191 As used herein, an “mTOR inhibitor” is a substance the expression or the activity of an ERK protein kinase. that (i) directly interacts with mTOR, e.g. by binding to Therefore, inhibitors that act upstream of ERK, such as MEK mTOR and (ii) decreases the expression or the activity of inhibitors and RAF inhibitors, are not ERK inhibitors accord mTOR. Non-limiting examples of mTOR inhibitors accord ing to the present invention. The solid forms of the present ing to the present invention include Zotarolimus (AbbVie), invention may be administered as a combination therapy umirolimus (Biosensors), temsirolimus (Pfizer), sirolimus together with other ERK inhibitors, which include, for (Pfizer), sirolimus NanoCrystal (Elan Pharmaceutical Tech example, AEZS-131 (Aeterna Zentaris), AEZS-136 (Aeterna nologies), Sirolimus TransDerm (TransDerm), Sirolimus Zentaris), SCH-722984 (Merck & Co.), SCH-772984 (Merck PNP (Samyang), everolimus (Novartis), biolimus A9 (Bio & Co.), SCH-900353 (MK-8353) (Merck & Co.), pharma sensors), ridaforolimus (Ariad), rapamycin, TCD-10023 ceutically acceptable salts thereof, and combinations thereof. (Terumo), DE-109 (MacuSight), MS-R001 (MacuSight), 0189 As used herein, a “Janus kinase inhibitor is a sub MS-R002 (MacuSight), MS-R003 (MacuSight), Perceiva stance that (i) directly interacts with a Janus kinase, e.g., by (MacuSight), XL-765 (Exelixis), quinacrine (Cleveland binding to a Janus kinase and (ii) decreases the expression or BioLabs), PKI-587 (Pfizer), PF-04691502 (Pfizer), GDC US 2016/022 1987 A1 Aug. 4, 2016 20

0980 (Genentech and Piramed), dactolisib (Novartis), inhibitors, Intellikine (Intellikine Inc., La Jolla, Calif.), PI3 CC-223 (Celgene), PWT-33597 (Pathway Therapeutics), delta inhibitors, Pathway Therapeutics-1 (Pathway Thera P-7170 (Piramal Life Sciences), LY-3023414 (Eli Lilly), peutics Ltd.), PI3-delta inhibitors, Pathway Therapeutics-2 INK-128 (Takeda), GDC-0084 (Genentech), DS-7423 (Dai (Pathway Therapeutics Ltd.), PI3-delta/gamma inhibitors, chi Sankyo), DS-3078 (Daiichi Sankyo), CC-115 (Celgene), Cellzome (Cellzome AG), PI3-delta/gamma inhibitors, Cell CBLC-137 (Cleveland BioLabs), AZD-2014 (AstraZeneca), Zome (Cellzome AG), PI3-delta/gamma inhibitors, Intellik X-480 (Xcovery), X-414 (Xcovery), EC-0371 (Endocyte), ine (Intellikine Inc.), PI3-delta/gamma inhibitors, Intellikine VS-5584 (Verastem), PQR-401 (Piqur), PQR-316 (Piqur), (Intellikine Inc.), PI3-delta/gamma inhibitors, Pathway PQR-311 (Piqur), PQR-309 (Piqur), PF-06465603 (Pfizer), Therapeutics (Pathway Therapeutics Ltd.), PI3-delta/gamma NV-128 (Novogen), nPT-MTOR (Biotica Technology), inhibitors, Pathway Therapeutics (Pathway Therapeutics BC-210 (Biotica Technology), WAY-600 (Biotica Technol Ltd.), PI3-gamma inhibitor Evotec (Evotec), PI3-gamma ogy), WYE-354 (Biotica Technology), WYE-687 (Biotica inhibitor, Cellzome (Cellzome AG), PI3-gamma inhibitors, Technology), LOR-220 (Lorus Therapeutics), HMPL-518 Pathway Therapeutics (Pathway Therapeutics Ltd.), PI3K (Hutchison China MediTech), GNE-317 (Genentech), delta/gamma inhibitors, Intellikine-1 (Intellikine Inc.), PI3K EC-0565 (Endocyte), CC-214 (Celgene), and ABTL-0812 delta/gamma inhibitors, Intellikine-1 (Intellikine Inc.), pictil (Ability Pharmaceuticals). isib (GDC-0941) (Roche Holdings Inc.), PIK-90 (CAS (0192. As used herein, a “PI3K inhibitor is a substance #677338-12-4), SC-103980 (Pfizer, New York, N.Y.), that decreases the expression or the activity of phosphatidyli SF-1126 (Semafore Pharmaceuticals, Indianapolis, Ind.), nositol-3 kinases (PI3Ks) or downstream proteins, such as SH-5, SH-6, Tetrahydro Curcumin, TG100-115 (Targegen Akt. PI3Ks, when activated, phosphorylate the inositol ring Inc., San Diego, Calif.), Triciribine, X-339 (Xcovery, West 3'-OH group in inositol phospholipids to generate the second Palm Beach, Fla.), XL-499 (Evotech, Hamburg, Germany), messenger phosphatidylinositol-3,4,5-trisphosphate (PI-3,4, pharmaceutically acceptable salts thereof, and combinations 5-P(3)). Akt interacts with a phospholipid, causing it to trans thereof. Preferably, the inhibitor of the PI3K/Akt pathway is locate to the inner membrane, where it is phosphorylated and pictilisib (GDC-0941) or a pharmaceutically acceptable salt activated. Activated Akt modulates the function of numerous thereof. substrates involved in the regulation of cell survival, cell cycle 0194 As used herein, a “RAS inhibitor” is a substance that progression and cellular growth. (i) directly interacts with RAS, e.g., by binding to RAS and 0193 Non-limiting examples of PI3K inhibitors accord (ii) decreases the expression or the activity of RAS. Non ing to the present invention include A-674563 (CAS limiting examples of RAS inhibitors according to the present #552325-73-2), AGL 2263, AMG-319 (Amgen, Thousand invention include farnesyl transferase inhibitors (such as, Oaks, Calif.), AS-041164 (5-benzo. 1.3dioxol-5-ylmethyl e.g., tipifarnib and lonafarnib), farnesyl group-containing ene-thiazolidine-2,4-dione), AS-604850 (5-(2,2-Difluoro Small molecules (such as, e.g., Salirasib and TLN-4601), benzo. 1.3dioxol-5-ylmethylene)-thiazolidine-2,4-dione), DCAI, as described by Maurer (Maurer, et al., 2012), AS-605240 (5-quinoxilin-6-methylene-1,3-thiazolidine-2,4- Kobe0065 and Kobe2602, as described by Shima (Shima, et dione), AT7867 (CAS #857531-00-1), benzimidazole series, al., 2013), and HBS 3 (Patgiri, et al., 2011), and AIK-4 (Al Genentech (Roche Holdings Inc., South San Francisco, linky), pharmaceutically acceptable salts thereof, and combi Calif.), BML-257 (CAS #32387-96-5), CAL-120 (Gilead nations thereof. Sciences, Foster City, Calif.), CAL-129 (Gilead Sciences), 0.195 As used herein, “gene expression' is a process by CAL-130 (Gilead Sciences), CAL-253 (Gilead Sciences), which the information from DNA is used in the formation of CAL-263 (Gilead Sciences), CAS #612847-09-3, CAS a polypeptide. A "modulator of gene expression and other #68.1281-88-9, CAS #75747-14-7, CAS #925681-41-0, CAS cellular functions' is a Substance that affects gene expression #98510-80-6, CCT128930 (CAS #885.499-61-6), and other works of a cell. Non-limiting examples of Such CH5132799 (CAS #1007207-67-1), CHR-4432 (Chroma modulators include hormones, histone deacetylase inhibitors Therapeutics, Ltd., Abingdon, UK), FPA 124 (CAS #902779 (HDACi), and cyclin-dependent kinase inhibitors (CDKi), 59-3), GS-1 101 (CAL-101) (Gilead Sciences), GSK 690693 and poly ADP ribose polymerase (PARP) inhibitors. (CAS #937174-76-0), H-89 (CAS #127243-85-0), Honokiol, 0196. In the present invention, a “hormone' is a substance IC87114 (Gilead Science), IPI-145 (Intellikine Inc.), KAR released by cells in one part of a body that affects cells in 4139 (Karus Therapeutics, Chilworth, UK), KAR-4141 another part of the body. Non-limiting examples of hormones (Karus Therapeutics), KIN-1 (Karus Therapeutics), KT 5720 according to the present invention include prostaglandins, (CAS #108068-98-0), Miltefosine, MK-2206 dihydrochlo leukotrienes, prostacyclin, thromboxane, amylin, antimulle ride (CAS #1032350-13-2), ML-9 (CAS #105637-50-1), rian hormone, adiponectin, adrenocorticotropic hormone, Naltrindole Hydrochloride, OXY-111A (NormOxys Inc., angiotensinogen, angiotensin, Vasopressin, atriopeptin, brain Brighton, Mass.), perifosine, PHT-427 (CAS #1191951-57 natriuretic peptide, calcitonin, cholecystokinin, corticotro 1), PI3 kinase delta inhibitor, Merck KGaA (Merck & Co., pin-releasing hormone, encephalin, endothelin, erythropoi Whitehouse Station, N.J.), PI3 kinase delta inhibitors, etin, follicle-stimulating hormone, galanin, gastrin, ghrelin, Genentech (Roche Holdings Inc.), PI3 kinase delta inhibitors, glucagon, gonadotropin-releasing hormone, growth hor Incozen (Incozen Therapeutics, Pvt. Ltd., Hydrabad, India), mone-releasing hormone, human chorionic gonadotropin, PI3 kinase delta inhibitors-2, Incozen (Incozen Therapeu human placental lactogen, growth hormone, inhibin, insulin, tics), PI3 kinase inhibitor, Roche-4 (Roche Holdings Inc.), Somatomedin, leptin, liptropin, luteinizing hormone, melano PI3 kinase inhibitors, Roche (Roche Holdings Inc.), PI3 cyte stimulating hormone, motilin, orexin, oxytocin, pancre kinase inhibitors, Roche-5 (Roche Holdings Inc.), PI3-alpha/ atic polypeptide, parathyroid hormone, prolactin, prolactin delta inhibitors, Pathway Therapeutics (Pathway Therapeu releasing hormone, relaxin, renin, secretin, Somatostain, tics Ltd., South San Francisco, Calif.), PI3-delta inhibitors, thrombopoietin, thyroid-stimulating hormone, testosterone, Cellzome (Cellzome AG, Heidelberg, Germany), PI3-delta dehydroepiandrosterone, androstenedione, dihydrotestoster US 2016/022 1987 A1 Aug. 4, 2016

one, aldosterone, estradiol, estrone, estriol, cortisol, proges and cdk11. A “CDK inhibitor is a substance that (i) directly terone, calcitriol, and calcidiol. interacts with CDK, e.g. by binding to CDK and (ii) decreases 0197) Some compounds interfere with the activity of cer the expression or the activity of CDK. Non-limiting examples tain hormones or stop the production of certain hormones. of CDK inhibitors according to the present invention include Non-limiting examples of hormone-interfering compounds 2-Hydroxybohemine, 3-ATA, 5-Iodo-Indirubin-3'-mon according to the present invention include tamoxifen (Nolva Oxime, 9-Cyanopaullone, Aloisine A, Alsterpaullone 2-Cya dex(R), anastrozole (Arimidex(R), letrozole (Femara.R.), and noethyl, alvocidib (Sanofi), AM-5992 (Amgen), Aminopur fulvestrant (Faslodex(R). Such compounds are also within the valanol A, Arcyriaflavin A, AT-7519 (Astex meaning of hormone in the present invention. Pharmaceuticals), AZD 5438 (CAS #602306-29-6), BMS 0198 As used herein, an “HDAC inhibitor is a substance 265246 (CAS #5823 15-72-8), BS-181 (CAS #1092443-52 that (i) directly interacts with HDAC, e.g., by binding to 1), Butyrolactone I (CAS #87414-49-1), Cdk/Crk Inhibitor HDAC and (ii) decreases the expression or the activity of (CAS #784211-09-2), Cdk1/5 Inhibitor (CAS #40254-90-8), HDAC. Non-limiting examples of HDAC inhibitors accord Cdk2 Inhibitor II (CAS #222035-13-4), Cdk2 Inhibitor IV. ing to the present invention include 4SC-201 (4SCAG), 4SC NU6140 (CAS #444723-13-1), Cdk4 Inhibitor (CAS 202 (Takeda), abexinostat (Celera), AN-1 (Titan Pharmaceu #546102-60-7), Cdk4 Inhibitor III (CAS #265312-55-8), ticals, Inc.), Apicidine (Merck & Co., Inc.), AR-42 (Arno Cdk4/6 Inhibitor IV (CAS #359886-84-3), Cdk9 Inhibitor II Therapeutics), ARQ-700RP (ArOule), AVugane (TopoTarget (CAS #140651-18-9), CGP74514A, CR8, CYC-065 (Cycla AS), azelaic-1-hydroxamate-9-anilide (AAHA), belinostat cel), dinaciclib (Ligand), (R)-DRF053 dihydrochloride (CAS (TopoTarget), butyrate (Enzo Life Sciences, Inc.), CG-1255 #105.6016-06-8), Fascaplysin, Flavopiridol, Hygrolidin, (Errant Gene Therapeutics, LLC), CG-1521 (Errant Gene Indirubin, LEE-011 (Astex Pharmaceuticals), LY-2835219 Therapeutics, LLC), CG-200745 (CrystalGenomics, Inc.), (Eli Lilly), milciclib maleate (Nerviano Medical Sciences), chidamide (Shenzhen Chipscreen Biosciences), CHR-3996 MM-D37K (Maxwell Biotech), N9-Isopropyl-olomoucine, (Chroma Therapeutics), CRA-024781 (Pharmacyclics), NSC 625987 (CAS #141992-47-4), NU2058 (CAS #161058 CS-3158 (Shenzhen Chipscreen Biosciences), CU-903 83-9), NU6102 (CAS #444722-95-6), Olomoucine, (Curis), DAC-60 (Genextra), entinostat (Bayer), hyaluronic ON-108600 (Onconova), ON-123300 (Onconova), Oxindole acid butyric acid ester (HA-But), IKH-02 (IkerChem), IKH I, P-1446-05 (Piramal), P-276-00 (Piramal), palbociclib 35 (IkerChem), ITF-2357 (Ital farmaco), ITF-A (Ital far (Pfizer), PHA-767491 (CAS #845714-00-3), PHA-793887 maco), JNJ-1624 1199 (Johnson & Johnson), KA-001 (Karus (CAS #718630-59-2), PHA-848.125 (CAS #802539-81-7), Therapeutics), KAR-3000 (Karus Therapeutics), KD-5150 Purvalanol A, Purvalanol B, R547 (CAS #741713-40-6), (Kalypsys), KD-5170 (Kalypsys), KLYP-278 (Kalypsys), RO-3306 (CAS #872573-93-8), Roscovitine, SB-1317 KLYP-298 (Kalypsys), KLYP-319 (Kalypsys), KLYP-722 (SBIO), SCH 900776 (CAS #891494-63-6), SEL-120 (Kalypsys), m-carboxycinnamic acid bis-hydroxamide (Selvita), seliciclib (Cyclacel), SNS-032 (CAS #345627-80 (CBHA), MG-2856 (MethylGene), MG-3290 (MethylGene), 7), SU9516 (CAS #377090-84-1), WHI-P180 (CAS MG-4230 (MethylGene), MG-4915 (MethylGene), #211555-08-7), pharmaceutically acceptable salts thereof, MG-5026 (MethylGene), MGCD-0103 (MethylGene Inc.), and combinations thereof. Preferably, the CDK inhibitor is mocetinostat (MethylGene), MS-27-275 (Schering AG), selected from the group consisting of dinaciclib, palbociclib, NBM-HD-1 (NatureWise), NVP-LAQ824 (Novartis), pharmaceutically acceptable salts thereof, and combinations OCID-4681-S-01 (Orchid Pharmaceuticals), oxamflatin thereof. ((2E)-5-[3-(phenylsulfonyl) aminol phenyl-pent-2-en-4- 0200. As used herein, a “poly ADP ribose polymerase ynohydroxamic acid), panobinostat (Novartis), PCI-34051 (PARP) inhibitor” is a substance that decreases the expression (Pharmacyclics), phenylbutyrate (Enzo Life Sciences, Inc.), or activity of poly ADPribose polymerases (PARPs) or down pivaloyloxymethylbutyrate (AN-9. Titan Pharmaceuticals, stream proteins. Non-limiting examples of poly ADP ribose Inc.), pivanex (Titan Pharmaceuticals, Inc.), pracinostat polymerase (PARP) inhibitors of the present invention (SBIO), PX-117794 (TopoTarget AS), PXD-118490 (LEO include PF01367338 (Pfizer, New York, N.Y.), olaparib (As 80140) (TopoTarget AS), pyroxamide (suberoyl-3-aminopy traZeneca, United Kingdom), iniparib (Sanofi-Aventis, Paris, ridineamide hydroxamic acid), resminostat (Takeda), France), veliparib (Abbott Laboratories, Abbott Park, Ill.), RG-2833 (Repligen), ricolinostat (Acetylon), romidepsin MK 4827 (Merck, White House Station, N.J.), CEP 9722 (Astellas), SB-1304 (S*BIO), SB-1354 (S*BIO), SB-623 (Teva Pharmaceuticals, Israel), LT-673 (Biomarin, San (Merrion Research I Limited), SB-624 (Merrion Research I Rafael, Calif.), and BSI 401 (Sanofi-Aventis, Paris, France), Limited), SB-639 (Merrion Research I Limited), SB-939 pharmaceutically acceptable salts thereof, and combinations (SBIO), Scriptaid (N-Hydroxy-1,3-dioxo-1H-benzdeiso thereof. quinoline-2(3H)-hexan amide), SK-7041 (In2Gen/SK 0201 As used herein, “immunotherapeutic agent’ means Chemical Co.), SK-7068 (In2Gen/SK Chemical Co.), sub any anti-cancer agent that is compatible with the solid forms eroylanilide hydroxamic acid (SAHA), sulfonamide hydrox of the present invention and that uses a Substance that alters amic acid, tributyrin (Sigma Aldrich), trichostatin A (TSA) the immune response by augmenting or reducing the ability (Sigma Aldrich), Valporic acid (VPA) (Sigma Aldrich), Vori of the immune system to produce antibodies or sensitized nostat (Zollinza), WF-27082B (Fujisawa Pharmaceutical cells that recognize and react with the antigen that initiated Company, Ltd.), pharmaceutically acceptable salts thereof, their production. Immunotherapeutic agents may be recom and combinations thereof. Preferably, the HDAC inhibitor is binant, synthetic, or natural preparations and include cytok romidepsin, pharmaceutically acceptable salts thereof, and ines, corticosteroids, cytotoxic agents, thymosin, and immu combinations thereof. noglobulins. Some immunotherapeutic agents are naturally (0199. As used herein, “CDK' is a family of protein present in the body, and certain of these are available in kinases that regulate the cell cycle. Known CDKs include pharmacologic preparations. Examples of immunotherapeu cdk1, cdk2, ckd3, ckd4, ccdk5, ccdk6, cdk7, cdk8, cdk9, ccdk10, tic agents include, but are not limited to, granulocyte colony US 2016/022 1987 A1 Aug. 4, 2016 22 stimulating factor (G-CSF), interferons, imiquimod and cel mg/kg per day, Such as from about 1 mg/kg to about 1200 lular membrane fractions from bacteria, IL-2, IL-7, IL-12, mg/kg per day, 75 mg/kg per day to about 300 mg/kg per day, CCL3, CCL26, CXCL7, and synthetic cytosine phosphate including from about 1 mg/kg to about 100 mg/kg per day. guanosine (CpG). Other representative dosages of Such agents include about 1 0202 In one preferred embodiment, the immunotherapeu mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 tic agent is an immune checkpoint inhibitor. As used herein, mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 60 mg/kg, an “immune checkpoint inhibitor” means a Substance that 70 mg/kg, 75 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, 125 blocks the activity of molecules involved in attenuating the mg/kg, 150 mg/kg, 175 mg/kg, 200 mg/kg, 250 mg/kg, 300 immune response. Such molecules include, for example, mg/kg, 400 mg/kg, 500 mg/kg, 600 mg/kg, 700 mg/kg, 800 cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and mg/kg, 900 mg/kg, 1000 mg/kg, 1100 mg/kg, 1200 mg/kg, programmed cell death protein 1 (PD-1). Immune checkpoint 1300 mg/kg, 1400 mg/kg, 1500 mg/kg, 1600 mg/kg, 1700 inhibitors of the present invention include, but are not limited mg/kg, 1800 mg/kg, 1900 mg/kg, 2000 mg/kg, 2100 mg/kg, to, ipilimumab (Bristol-Myers Squibb), tremelimumab 2200 mg/kg, and 2300 mg/kg per day. The effective dose of a (Pfizer), MDX-1106 (Medarex, Inc.), MK3475 (Merck), Solid form of the present invention or otheranti-cancer agents CT-011 (CureTech, Ltd.), AMP-224 (Amplmmune), MDX disclosed herein may be administered as two, three, four, five, 1105 (Medarex, Inc.), IMP321 (Immutep S.A.), and six or more Sub-doses, administered separately at appropriate MGA271 (Macrogenics). intervals throughout the day. 0203. In the present invention, the term “radionuclide' 0208. The solid form of the present invention or other means a radioactive Substance administered to the patient, anti-cancer agents or pharmaceutical compositions contain e.g., intravenously or orally, after which it penetrates via the ing same of the present invention may be administered in any patient’s normal metabolism into the target organ or tissue, desired and effective manner: for oral ingestion, or as an where it delivers local radiation for a short time. Examples of ointment or drop for local administration to the eyes, or for radionuclides include, but are not limited to, I-125, At-211, parenteral or other administration in any appropriate manner Lu-177, Cu-67, I-131, Sm-153, Re-186, P-32, Re-188, Such as intraperitoneal, Subcutaneous, topical, intradermal, In-114m, and Y-90. inhalation, intrapulmonary, rectal, vaginal, Sublingual, intra 0204. In the present invention, the term “photoactive muscular, intravenous, intraarterial, intrathecal, or intralym therapeutic agent’ means compounds and compositions that phatic. Further, the solid form of the present invention or become active upon exposure to light. Certain examples of otheranti-cancer agents orpharmaceutical compositions con photoactive therapeutic agents are disclosed, e.g., in U.S. taining same of the present invention may be administered in Patent Application Serial No. 2011/0152230 A1, “Photoac conjunction with other treatments. The solid form of the tive Metal Nitrosyls For Blood Pressure Regulation And Can present invention or other anti-cancer agents or the pharma cer Therapy.” ceutical compositions of the present invention may be encap 0205. In the present invention, the term “radiosensitizing Sulated or otherwise protected against gastric or other secre agent’ means a compound that makes tumor cells more sen tions, if desired. sitive to radiation therapy. Examples of radiosensitizing 0209. The pharmaceutical compositions of the invention agents include misonidazole, metronidazole, tirapazamine, may comprise one or more active ingredients, e.g., one or and trans Sodium crocetinate. more solid forms of the present invention optionally in com 0206. In the present invention, an “effective amount’ or a bination with other anti-cancer agents anti-cancer agents, in “therapeutically effective amount of one or more of the solid admixture with one or more pharmaceutically-acceptable forms of the present invention or anotheranti-cancer agent of diluents or carriers and, optionally, one or more other com the invention, including the pharmaceutical compositions pounds, drugs, ingredients and/or materials. Regardless of the containing same, is an amount of such solid form or compo route of administration selected, the agents/compounds of the sition that is sufficient to effect beneficial or desired results as present invention are formulated into pharmaceutically-ac described herein when administered to a subject. Effective ceptable dosage forms by conventional methods known to dosage forms, modes of administration, and dosage amounts those of skill in the art. See, e.g., Remington, The Science and may be determined empirically, and making Such determina Practice of Pharmacy (21st Edition, Lippincott Williams and tions is within the skill of the art. It is understood by those Wilkins, Philadelphia, Pa.). skilled in the art that the dosage amount will vary with the 0210 Pharmaceutically acceptable diluents or carriers are route of administration, the rate of excretion, the duration of well known in the art (see, e.g., Remington, The Science and the treatment, the identity of any other drugs being adminis Practice of Pharmacy (21st Edition, Lippincott Williams and tered, the age, size, and species of Subject, e.g., human Wilkins, Philadelphia, Pa.) and The National Formulary patient, and like factors well known in the arts of medicine (American Pharmaceutical Association, Washington, D.C.)) and Veterinary medicine. In general, a Suitable dose of one or and include Sugars (e.g., lactose, Sucrose, mannitol, and Sor more of the solid forms of the present invention or a pharma bitol), starches, cellulose preparations, calcium phosphates ceutical composition according to the invention will be that (e.g., dicalcium phosphate, tricalcium phosphate and calcium amount of the solid form or pharmaceutical composition, hydrogen phosphate), sodium citrate, water, aqueous solu which is the lowest dose effective to produce the desired tions (e.g., Saline, sodium chloride injection, Ringer's injec effect. The effective dose of a solid form or pharmaceutical tion, dextrose injection, dextrose and sodium chloride injec composition of the present invention may be administered as tion, lactated Ringers injection), alcohols (e.g., ethyl two, three, four, five, six or more sub-doses, administered alcohol, propyl alcohol, and benzyl alcohol), polyols (e.g., separately at appropriate intervals throughout the day. glycerol, propylene glycol, and polyethylene glycol), organic 0207. A suitable, non-limiting example of a dosage of a esters (e.g., ethyl oleate and triglycerides), biodegradable Solid form of the present invention or another anti-cancer polymers (e.g., polylactide-polyglycolide, poly(orthoesters), agent disclosed herein is from about 1 mg/kg to about 2400 and poly(anhydrides)), elastomeric matrices, liposomes, US 2016/022 1987 A1 Aug. 4, 2016 microspheres, oils (e.g., corn, germ, olive, castor, Sesame, known in the art, and acceptable ingredients and materials for cottonseed, and groundnut), cocoa butter, waxes (e.g., Sup a chosen dosage form and method of administration may be pository waxes), paraffins, silicones, talc, silicylate, etc. Each determined using ordinary skill in the art. pharmaceutically acceptable diluent or carrier used in a phar 0212. The pharmaceutical compositions of the present maceutical composition of the invention must be “accept invention suitable for oral administration may be in the form able' in the sense of being compatible with the other ingre of capsules, cachets, pills, tablets, powders, granules, a solu dients of the formulation and not injurious to the subject. tion or a Suspension in an aqueous or non-aqueous liquid, an Diluents or carriers suitable for a selected dosage form and oil-in-water or water-in-oil liquid emulsion, an elixir or intended route of administration are well known in theart, and syrup, a pastille, a bolus, an electuary or a paste. These for acceptable diluents or carriers for a chosen dosage form and mulations may be prepared by methods known in the art, e.g., method of administration can be determined using ordinary by means of conventional pan-coating, mixing, granulation or skill in the art. lyophilization processes. 0211. The pharmaceutical compositions of the invention 0213 Solid dosage forms for oral administration (cap may, optionally, contain additional ingredients and/or mate Sules, tablets, pills, dragees, powders, granules and the like) rials commonly used in pharmaceutical compositions. These may be prepared, e.g., by mixing the active ingredient(s) with ingredients and materials are well known in the art and one or more pharmaceutically-acceptable diluents or carriers include (1) fillers or extenders, such as starches, lactose, and, optionally, one or more fillers, extenders, binders, Sucrose, glucose, mannitol, and silicic acid; (2) binders. Such humectants, disintegrating agents, Solution retarding agents, as carboxymethylcellulose, alginates, gelatin, polyvinyl pyr absorption accelerators, wetting agents, absorbents, lubri rolidone, hydroxypropylmethyl cellulose. Sucrose and aca cants, and/or coloring agents. Solid compositions of a similar cia; (3) humectants, such as glycerol; (4) disintegrating type may be employed as fillers in soft and hard-filled gelatin agents, such as agar-agar, calcium carbonate, potato or tapi capsules using a Suitable excipient. A tablet may be made by oca Starch, alginic acid, certain silicates, Sodium starch gly compression or molding, optionally with one or more acces colate, cross-linked sodium carboxymethyl cellulose and sory ingredients. Compressed tablets may be prepared using Sodium carbonate; (5) Solution retarding agents, such as par a suitable binder, lubricant, inert diluent, preservative, disin affin; (6) absorption accelerators, such as quaternary ammo tegrant, Surface-active or dispersing agent. Molded tablets nium compounds; (7) wetting agents, such as cetyl alcohol may be made by molding in a suitable machine. The tablets, and glycerol monostearate; (8) absorbents, such as kaolin and and other Solid dosage forms, such as dragees, capsules, pills bentonite clay; (9) lubricants, such as talc, calcium stearate, and granules, may optionally be scored or prepared with magnesium Stearate, Solid polyethylene glycols, and sodium coatings and shells, such as enteric coatings and other coat lauryl Sulfate; (10) Suspending agents, such as ethoxylated ings well known in the pharmaceutical-formulating art. They isostearyl alcohols, polyoxyethylene Sorbitol and Sorbitan may also be formulated so as to provide slow or controlled esters, microcrystalline cellulose, aluminum metahydroxide, release of the active ingredient therein. They may be sterilized bentonite, agar-agar and tragacanth; (11) buffering agents; by, for example, filtration through a bacteria-retaining filter. (12) excipients, such as lactose, milk Sugars, polyethylene These compositions may also optionally contain opacifying glycols, animal and vegetable fats, oils, waxes, paraffins, agents and may be of a composition Such that they release the cocoa butter, starches, tragacanth, cellulose derivatives, poly active ingredient only, or preferentially, in a certain portion of ethylene glycol, silicones, bentonites, silicic acid, talc, Sali the gastrointestinal tract, optionally, in a delayed manner. The cylate, Zinc oxide, aluminum hydroxide, calcium silicates, active ingredient can also be in microencapsulated form. and polyamide powder, (13) inert diluents, such as water or 0214 Liquid dosage forms for oral administration include other solvents; (14) preservatives; (15) Surface-active agents; pharmaceutically-acceptable emulsions, microemulsions, (16) dispersing agents; (17) control-release or absorption Solutions, Suspensions, syrups and elixirs. The liquid dosage delaying agents. Such as hydroxypropylmethyl cellulose, forms may contain Suitable inert diluents commonly used in other polymer matrices, biodegradable polymers, liposomes, the art. Besides inert diluents, the oral compositions may also microspheres, aluminum monostearate, gelatin, and waxes; include adjuvants, such as wetting agents, emulsifying and (18) opacifying agents; (19) adjuvants; (20) wetting agents; Suspending agents, Sweetening, flavoring, coloring, perfum (21) emulsifying and Suspending agents; (22), Solubilizing ing and preservative agents. Suspensions may contain Sus agents and emulsifiers, such as ethyl alcohol, isopropyl alco pending agents. hol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl 0215. The pharmaceutical compositions of the present benzoate, propylene glycol, 1,3-butylene glycol, oils (in par invention for rectal or vaginal administration may be pre ticular, cottonseed, groundnut, corn, germ, olive, castor and sented as a Suppository, which may be prepared by mixing sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene one or more active ingredient(s) with one or more Suitable glycols and fatty acid esters of sorbitan; (23) propellants. Such nonirritating diluents or carriers which are solid at room as chlorofluorohydrocarbons and volatile unsubstituted temperature, but liquid at body temperature and, therefore, hydrocarbons. Such as butane and propane; (24) antioxidants; will melt in the rectum or vaginal cavity and release the active (25) agents which render the formulation isotonic with the compound. The pharmaceutical compositions of the present blood of the intended recipient, such as Sugars and sodium invention which are suitable for vaginal administration also chloride; (26) thickening agents; (27) coating materials. Such include pessaries, tampons, creams, gels, pastes, foams or as lecithin; and (28) Sweetening, flavoring, coloring, perfum spray formulations containing Such pharmaceutically-ac ing and preservative agents. Each Such ingredient or material ceptable diluents or carriers as are known in the art to be must be “acceptable' in the sense of being compatible with appropriate. the other ingredients of the formulation and not injurious to 0216 Dosage forms for the topical or transdermal admin the Subject. Ingredients and materials suitable for a selected istration include powders, sprays, ointments, pastes, creams, dosage form and intended route of administration are well lotions, gels, Solutions, patches, drops and inhalants. The US 2016/022 1987 A1 Aug. 4, 2016 24 active agent(s)/compound(s), including the solid forms of the fine-focus source. An elliptically graded multilayer mirror present invention, may be mixed understerile conditions with was used to focus Cu KO. X-ray radiation through the speci a suitable pharmaceutically-acceptable diluent or carrier. The men and onto the detector. Prior to the analysis, a silicon ointments, pastes, creams and gels may contain excipients. specimen (NIST SRM 640d) was analyzed to verify that the Powders and sprays may contain excipients and propellants. observed position of the Si 111 peak was consistent with the 0217. The pharmaceutical compositions of the present NIST-certified position. A specimen of the sample was sand invention suitable for parenteral administrations may com prise one or more agent(s)/compound(s) in combination with wiched between 3-um-thick films and analyzed in transmis one or more pharmaceutically-acceptable sterile isotonic sion geometry. A beam-stop, short antiscatter extension, and aqueous or non-aqueous solutions, dispersions, suspensions antiscatter knife edge were used to minimize the background or emulsions, or sterile powders which may be reconstituted generated by air. Soller slits for the incident and diffracted into sterile injectable solutions or dispersions just prior to use. beams were used to minimize broadening from axial diver which may contain suitable antioxidants, buffers, solutes gence. Diffraction patterns were collected using a scanning which render the formulation isotonic with the blood of the position-sensitive detector located 240 mm from the speci intended recipient, or suspending or thickening agents. men. Preferred orientation and particle static effects were not Proper fluidity can be maintained, for example, by the use of assessed. coating materials, by the maintenance of the required particle 0223 Reflection mode XRPD patterns were collected size in the case of dispersions, and by the use of surfactants. using an incident beam of Cu KO. radiation produced using a These pharmaceutical compositions may also contain Suit fine-focus source and a nickel filter. The diffractometer was able adjuvants, such as wetting agents, emulsifying agents configured using the symmetric Bragg-Brentano geometry. and dispersing agents. It may also be desirable to include isotonic agents. In addition, prolonged absorption of the Prior to the analysis, a silicon specimen (NIST SRM 640d) injectable pharmaceutical form may be brought about by the was analyzed to verify that the observed position of the Si 111 inclusion of agents which delay absorption. peak was consistent with the NIST-certified position. A speci 0218. In some cases, in order to prolong the effect of a drug men of the sample was prepared as a thin, circular layer (e.g., pharmaceutical formulation), it is desirable to slow its centered on a silicon Zero-background substrate. Antiscatter absorption from subcutaneous or intramuscular injection. slits (SS) were used to minimize the background generated by This may be accomplished by the use of a liquid suspension of air. Soller slits for the incident and diffracted beams were used crystalline or amorphous material having poor water solubil to minimize broadening from axial divergence. Diffraction 1ty. patterns were collected using a scanning position-sensitive 0219. The rate of absorption of the active agent/drug, detector located 240 mm from the sample. Preferred orienta including the solid forms of the present invention, then tion and particle static effects were not assessed. depends upon its rate of dissolution which, in turn, may 0224 Under most circumstances, peaks within the range depend upon crystal size and crystalline form. Alternatively, of up to about 30°20 were selected. The location of the peaks delayed absorption of a parenterally-administered agent/drug along the x-axis (20) were rounded to one significant figure may be accomplished by dissolving or suspending the active after the decimal point. Peak position variabilities are given to agent/drug in an oil vehicle. Injectable depot forms may be within +0.220 based upon recommendations outlined in the made by forming microencapsule matrices of the active USP discussion of variability in X-ray powder diffraction. ingredient in biodegradable polymers. Depending on the ratio The accuracy and precision associated with any particular of the active ingredient to polymer, and the nature of the measurement was not determined. Moreover, third party particular polymer employed, the rate of active ingredient measurements on independently prepared samples on differ release can be controlled. Depot injectable formulations are ent instruments may lead to variability which is greater than also prepared by entrapping the drug in liposomes or micro +0.2°20. Per USP guidelines, variable hydrates and solvates emulsions which are compatible with body tissue. The inject may display peak variances greater than 0.220 and therefore able materials can be sterilized for example, by filtration peak variances of 0.2°20 are not applicable to these materials. through a bacterial-retaining filter. For d-space listings, the wavelength used to calculate d-spac 0220. The formulations may be present in unit-dose or ings was 1.5405929 A, the Cu-Ko.1 wavelength. Variability multi-dose sealed containers, for example, ampules and Vials, associated with d-spacing estimates was calculated from the and may be stored in a lyophilized condition requiring only USP recommendation, at each d-spacing, and provided in the the addition of the sterile liquid diluent or carrier, for example respective data tables. water for injection, immediately prior to use. Extemporane ous injection solutions and suspensions may be prepared Fourier Transform Infrared (FT-IR) Spectroscopy from sterile powders, granules and tablets of the type described above. 0225 FT-IR spectra were acquired using a Fourier trans 0221) The following examples are provided to further form infrared spectrophotometer equipped with a mid/far IR illustrate the compounds, compositions and methods of the source, an extended range potassium bromide (KBr) beam present invention. These examples are illustrative only and splitter, and a deuterated triglycine sulfate (DTGS) detector. are not intended to limit the scope of the invention in any way. Wavelength verification was performed using NIST SRM 1921b (polystyrene). An attenuated total reflectance (ATR) EXAMPLES accessory with a germanium (Ge) crystal was used for data Example 1 acquisition. 256 co-added scans were collected at a spectral Experimental Methods resolution of 2 cm'. A background data set was acquired with a clean Ge crystal. A Log 1/R (R-reflectance) spectrum X-Ray Powder Diffraction (XRPD) was obtained by taking a ratio of these two data sets against 0222 Transmission mode XRPD patterns were collected each other. Peak picking was performed using an absolute using an incident beam of Cu radiation produced using a threshold near the baseline and a sensitivity of 75. US 2016/022 1987 A1 Aug. 4, 2016

Differential Scanning Calorimetry (DSC) mately 103 mW of laser power at the tip of the probe. The spectra were collected using an exposure time of 5 up to 15 0226. DSC analysis was performed using a differential seconds and with 5 spectrum accumulations. Wavelength and scanning calorimeter. Temperature calibration was per laser wavelength calibration were performed using an inter formed using NIST-traceable indium metal. The sample was nal neon standard, and diamond Raman shift standard, placed into an aluminum DSC pan, covered with a lid, and the respectively. The intensity calibration was performed using a weight was accurately recorded. A weighed aluminum TOHSMP pan configured as the sample pan was placed on the Kaiser Raman calibration accessory (Kaiser Optical Systems reference side of the cell. Reported temperatures are rounded Inc., Ann Arbor, Mich.). to 1 degree unless specified otherwise. Example 2 Raman Spectroscopy Preparation of Crystalline Free Base 4-(5-Chloro-2- 0227 Raman spectroscopy was performed using a disper isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxy sive RamanRXN3 (Kaiser Optical Systems Inc., Ann Arbor, lic acid 1-(3-chlorophenyl)-2-hydroxyethylamide Mich.) for in-situ reaction monitoring. The Raman RXN3 0228 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H system uses an excitation wavelength of 785 nm, with an pyrrole-2-carboxylic acid 1-(3-chlorophenyl)-2-hydroxy external cavity-stabilized, diode laser. All spectra were ethylamide free base was prepared according to the follow acquired using a /4" immersion optics probe with approxi ing synthesis scheme.

Step 1 I I

C 1. Isopropylamine -e- 65-750 C. 2 71.77% yield N 2 N 1. r)N F H CHCIFIN C8H10CIIN2 257.43 296.54 ASYM-111606 ASYM-112060 Step 2

(HO)2B 1. I 1. Anhydrous sodium carbonate 2. Palladium acetate N O)-cos. 3. Tricyclohexylphosphonium N C N tetrafluoroborate -- SO 2 75-850 C. 2 N N N 74.94% yield COOCH H C C8H10CIIN N 296.54 HC Ts ASYM-112060 C2H22CIN3O4S C3H4BNO6S 447.94 323.13 ASYM-112393 ASYM-111938 1. 1. Step 3 1. Lithium hydroxide monohydrate N1 N 2. Diethylamine N1 N --- 60-70° C. 2 74.00%o yieldWe 2 N N COOCH COOH C C N NH \, C3H4CIN3O2 279.72 C2H22CIN3O4S ASYM-112394 447.94 ASYM-112393 US 2016/022 1987 A1 Aug. 4, 2016 26

-continued Step 4 1. NH NH2 1. s OH 1. HOBTH2O 1N 2. EDCI 2 N 3. DIEA N NH -- Her 15-250 C. C s 2 N 78.81% yield NH s OH COOH C C NH C8H10CINO 171.62 C3H4CIN3O2 279.72 ASYM-111888 Cl ASYM-112394 C2H2Cl2N4O2 433.33 ASYM-111935

0229. In Step 1, a clean and dry 200 L. glass-lined reactor filled with nitrogen to normal pressure. This was repeated for was evacuated to s–0.08 MPa, and then filled with nitrogen to ten times until residual oxygen was 300 ppm. The mixture normal pressure three times. Anhydrous ethanol (49.90 kg) was heated to 75-85°C. for refluxing. The mixture reacted at was charged into the 200 L. glass-lined reactor. ASYM 75-85°C. After 4h, the mixture was sampled and analyzed by 111606 (Asymchem) (12.70 kg) and isopropylamine (29.00 HPLC every 2-3 h for content of ASYM-112060. The content kg) were added into the mixture in turn. The mixture was of ASYM-112060 was 6.18%, so additional ASYM-11 1938 heated to 65-75° C. for refluxing. The mixture reacted at (0.72 kg) was added and continued reaction until the content 65-75° C. After 20h, the reaction was sampled and analyzed of ASYM-112060 was s3%. The mixture was cooled to by HPLC every 4-6 huntil the content of ASYM-111606 was 25-35°C. and filtered with a 30 L stainless steel vacuum filter. 1%. The mixture was cooled to 40-45° C. and was concen The filter cake was soaked and washed twice with THF (14.10 trated at s45° C. under reduced pressure (s-0.08 MPa) until kg). The filtrate and washing liquor were combined and con 13-26 L remained. The organic phase was washed with a centrated at s50° C. under reduced pressure (s-0.08 MPa) sodium chloride solution and was stirred for 20-30 min and until 10-15 L remained. The mixture was cooled to 15-25°C. settled for 20-30 min before separation. The organic phase Methanol (11.05 kg) was added into the concentrated mix was concentrated at s30°C. under reduced pressure (s-0.06 ture. Then the mixture was stirred for crystallization. After 2 MPa) until 13-20 L remained. Petroleum ether (8.55 kg) was h, the mixture was sampled and analyzed by HPLC every 2-4 added into the concentrated mixture. The mixture was trans huntil the wt % of the mother liquor was s2%. The mixture ferred into a 20 L rotary evaporator and continued concen was filtered with a 3.0 L stainless steel vacuum filter. The filter trating at s30°C. under reduced pressure (s-0.06 MPa) until cake was soaked and washed twice with methanol (8.30 kg). 13-20 L remained. Then petroleum ether (8.55 kg) was added The filter cake was transferred into a 50 L plastic drum. Then into the concentrated mixture. The mixture was cooled to 0-5° ethyl acetate (7.10 kg) and petroleum ether (46.30 kg) were C. and stirred for crystallization. After 1 h, the mixture was added into the drum. The mixture was stirred for 1.5-2 hand sampled and analyzed by wt % every 1-2 huntil the wt % of then filtered with a nutsche filter. The filter cake was soaked the mother liquor was s 11% or the change of the wt % and washed with petroleum ether (20.50 kg). The filter cake between consecutive samples was s1%. The mixture was was dried in the nutsche filter under nitrogen at 30-40°C. filtered with a 10 L filter flask. The filter cake was sampled After 8 h, the solid was sampled and Karl Fischer (KF) and analyzed for purity by HPLC. 10.50 kg of product was analysis was performed in intervals of 4-8 h to monitor the recovered as a brownish yellow solid at 99.39% purity. drying process. Drying was completed when the KF result 0230. In Step 2, a clean and dry 300 L. glass-lined reactor was s1.0% water. During drying, the solid was turned over was evacuated to s–0.08 MPa, and then filled with nitrogen to and mixed every 4-6 h. 12.15 kg of product was recovered as normal pressure three times. Glycol dimethyl ether (73.10kg) a brownish yellow solid at 98.32% purity. was charged into the 300 L. glass-lined reactor at 20-30°C. 0231. In Step 3, a clean and dry 300 L. glass-lined reactor ASYM-112060 (Asymchem) (10.46 kg) and ASYM-1 11938 was evacuated to s–0.08 MPa, and then filled with nitrogen to (Asymchem) (12.34 kg, 11.64 kg after corrected) were added normal pressure three times. THF (62.58 kg) was charged into into the mixture in turn under the protection of nitrogen. the 300 L. glass-lined reactor at 15-30°C. Then the stirrer was Maintaining the temperature at 20-30°C., purified water (10. started. ASYM-112393 (12.00 kg, 11.70 kg after corrected) 50 kg) and anhydrous sodium carbonate (5.67 kg) were added was added into the mixture. The mixture was stirred until the into the mixture. Palladium acetate (0.239 kg) and tricyclo Solid dissolved completely. Maintaining the temperature at hexylphosphonium tetrafluoroborate (0.522 kg) were added 15-30°C., a lithium hydroxide solution which was prepared into the mixture under the protection of nitrogen. After addi with lithium hydroxide monohydrate (5.50 kg) in purified tion, the mixture was evacuated to s-0.06 MPa, and then water (70.28 kg) was added into the mixture. Then diethy US 2016/022 1987 A1 Aug. 4, 2016 27 lamine (3.86 kg) was added. The mixture was heated to cooled to -10 to -20°C. and 1-hydroxybenzotriazole hydrate 60-70° C. for refluxing. The mixture reacted at 60-70° C. (2.10 kg) was added into the mixture at -10 to -20°C. Then After 30 h., the reaction was sampled and analyzed by HPLC EDCI (2.41 kg) was added into the mixture in five portions at every 4-6 huntil the content of intermediate at relative reten an interval of about 5-10 min. The mixture was cooled to -20 tion time (RRT)=1.39-1.44 was <1% and the content of to -30° C. and ASYM-111888 (Asymchem) (1.96 kg) was ASYM-112393 was <1%. HPLC conditions for this analysis added into the mixture at -20 to -30°C. Then DIEA (1.77 kg) are set forth in Table 1. was added into the mixture at the rate of 3-4 kg/h. The mixture was heated to 15-25° C. at the rate of 5-10°C./h. The mixture TABLE 1. was reacted at 15-25°C. After 6-8 h, the mixture was sampled and analyzed by HPLC every 2-4 h until the content of HPLC Parameters ASYM-112394 was s2%. The mixture was cooled to 0-10° Column: ACE 3 C18, 4.6 x 150 mm, (ACE-111-1546) C. and the reaction mixture was quenched with a solution Column 30° C. which was prepared from ethyl acetate (28.80 kg) in purified Temperature: Flow rate 1.1 mL/min water (12.80 kg) at 0-10°C. The mixture was extracted three Injection 10 IL times with ethyl acetate (28.80 kg). For each extraction the Volume: mixture was stirred for 20-30 min and settled for 20-30 min Mobile Phase A: 0.05% TFA in water (v/v) before separation. The organic phases were combined and Mobile Phase B: 0.05% TFA in Acetonitrile (v/v) washed twice with purified water (12.80 kg). The mixture was stirred for 20-30 min and settled for 20-30 min before sepa Gradient Table: T(min): B. 90 ration for each time. Then the obtained organic phase was O.O 5 filtered through an in-line fluid filter. The filtrate was trans 4.0 2O 14.O 85 ferred into a 300 L. glass-lined reactor. The mixture was 14.1 5 washed twice with a 5% acetic acid solution, which was 18.5 5 prepared from acetic acid (2.24 kg) in purified water (42.50 kg). The solution was added at the rate of 10-20 kg/h. The Detection: UV at 215 mm organic phase was washed twice with a sodium carbonate Run time 18.5 min solution, which was prepared from sodium carbonate (9.41 kg) in purified water (48.00 kg). The organic phase was 0232. The mixture was cooled to 25-35° C. and MTBE washed twice with a sodium chloride solution, which was (25.97 kg) was added into the mixture. The mixture was prepared from sodium chloride (16.00 kg) in purified water stirred for 20-30 minand filtered via an in-line fluid filter. The (44.80 kg). The organic phase was transferred into a 300 L filtrate was transferred into a 300 L. glass-lined reactor and glass-lined reactor. Anhydrous sodium sulfate (9.70 kg) was settled for 20-30 min before separation. The pH of the added into the mixture and the mixture was stirred for 2-4 hat obtained aqueous phase was adjusted with a 6 Nhydrochloric 15-30°C. The mixture was filtered with a nutsche filter, which acid solution which was prepared from concentrated hydro was pre-loaded with about 1 cm thick silica gel (7.50 kg). The chloric acid (14.86 kg) in purified water (10.88 kg) at the rate filter cake was soaked and washed with ethyl acetate (14.40 of 5-8 kg/h at 15-25° C. until the pH was 1-2. The pH of the kg) before filtration. The filtrates were combined and the mixture was adjusted again with a Saturated sodium carbon combined filtrate was added into a 72 L flask through an ate solution which was prepared from sodium carbonate (5.03 in-line fluid filter. The mixture was concentrated at TsA.0°C. kg) in purified water (23.56 kg) at the rate of 3-5 kg/h at under reduced pressure (Ps-0.08 MPa) until 3-4L remained. 15-25°C. until the pH was 6.4-6.7. Then the pH of the mixture Then MTBE (4.78 kg) was added into the mixture. The mix was adjusted with a hydrochloric acid solution which was ture was cooled to 0-10°C. for crystallization with stirring. prepared from concentrated hydrochloric acid (1.09 kg) in After 1 h, the mixture was sampled and analyzed by wt % purified water (0.80 kg) until the pH was 6.2-6.4. The mixture every 1-2 huntil the wt % of the mother liquor was s5% or the was filtered with a nutsche filter. The filter cake was trans change of wt % between consecutive samples was %. The ferred into a 300 L. glass-lined reactor and purified water mixture was filtered with a vacuum filter flask and the filter (117.00 kg) was added. The mixture was stirred and sampled cake was dried in the tray drier under nitrogen at 30-40°C. and analyzed by HPLC until the p-toluenesulfonic acid resi until KFs0.5%. 3.55 kg of product was recovered as an off due of the filter cake was s().5%. Then the mixture was white solid at 100% purity. filtered. The filter cake was dried in the tray drier under 0234. The resulting 4-(5-Chloro-2-isopropylaminopyri nitrogen at 55-65° C. until KFs 10%. The solid and MTBE din-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlorophenyl)- (8.81 kg) were charged into a 50 L stainless steel drum. The 2-hydroxyethylamide free base was analyzed by XRPD mixture was stirred for 1-2 h. The mixture was filtered with a (FIG. 1). Peaks shown in FIG. 1 are listed in Table 2, promi 30 L stainless steel vacuum filter. The filter cake was dried in nent peaks are listed in Table 3. the nutsche filter at 50-60°C. After 8 h, the solid was sampled and analyzed by KF every 4-8 huntil KFs5%. During drying, TABLE 2 the solid was turned over and mixed every 4-6 h. 6.3 kg of XRPD peaks observed for 4-(5-Chloro-2-isopropylaminopyridin product was recovered as an off-white solid at 98.07% purity. 4-yl)-1H-pyrrole-2-carboxylic acid (1-(3-chlorophenyl)- 0233. In Step 4, a dry and clean 50 L flask was purged with 2-hydroxyethylamide free base. nitrogen for 20 min. DMF (30.20 kg) was charged into the 50 L flask reactor. Then the stirrer was started. Maintaining the 20 () d space (A) Intensity (%) temperature at 15-25° C., ASYM-112394 (3.22 kg, 2.76 kg 9.1 O2 9.690 - 0.212 12 after corrected) was added into the mixture. The mixture was 1.O.O. O.2 8.869 O.178 2 stirred until the solid dissolved completely. The mixture was

US 2016/022 1987 A1 Aug. 4, 2016 29

Example 3A Example 3B Preparation of 4-(5-Chloro-2-isopropylaminopyri Alternative Preparation of 4-(5-Chloro-2-isopropy din-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlo laminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid rophenyl)-2-hydroxyethylamide Form C 1-(3-chlorophenyl)-2-hydroxyethylamide Form C 0240 0237)

1. NH 1. Anhydrous es ethanol 2. Methanol N1 N HCI N N O 3. Isopropanol OH -e- 4. HCl gas / EtOH, -- 2 HN-. MeOH, 21 N NH 70-75° C. 88.65% N % PrOH C yield C NH O ( )—c 90:5:5 NH s OH

Cl C2H22Cl2N4O2 433.33 ASYM-111935

oHC

0238 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H s OH pyrrole-2-carboxylic acid 1-(3-chlorophenyl)-2-hydroxy ethylamide Form C was prepared from 4-(5-Chloro-2-iso propylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid 1 (3-chlorophenyl)-2-hydroxyethylamide free base as Cl follows. ASYM-11 1935 (10.4 kg) was added to a stirred C2H23Cl3N4O2 mixture of anhydrous ethanol (73.9 kg), methanol (4.1 kg) 469.79 and isopropanol (4.1 kg). The mixture was heated to 70-75° BVD-523 C. and stirred until all the solids dissolved. Anhydrous HCl ASYM-115985 (37 wt %, 1.1 eq) in a mixture of ethanol/methanol/isopro panol (90:5:5) was added and the mixture maintained at 70-75° C. for 2 hours after the addition was completed. The 0241 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H mixture was then cooled to 15-25° C. at a rate of 5-15°C. per pyrrole-2-carboxylic acid 1-(3-chlorophenyl)-2-hydroxy hour and stirred at this temperature until the desired polymor ethylamide Form C was also prepared from 4-(5-Chloro-2- phic purity was reached. The end point of the crystallization/ isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid polymorph conversion was determined by the absence of an 1-(3-chlorophenyl)-2-hydroxyethylamide free base as fol XRPD peak at about 10.5° 20 in three successive samples. lows. A dry and clean 72 L flask was purged with nitrogen for 20 min. Anhydrous ethanol (21.35 kg) methanol (1.17 kg)and 0239. The mixture was then filtered and washed succes isopropanol (1.19 kg) were charged into the 72 L flask at sively with a pre-prepared solution of anhydrous ethanol 15-25° C. and the mixture was stirred for 20-30 min. ASYM (14.8 kg), methanol (0.8 kg) and isopropanol (0.8 kg), fol 111935 (3.01 kg) was added into the mixture and heated to lowed by MTBE (2x21 kg). Avoidance of delay in the wash 70-75° C. at the rate of 15-25° C./h and stirred until the Solid ing of the filter cake is preferable because the polymorph may dissolved completely. be unstable in the wet filter cake in the presence of reagent 0242 An alcohol/HCl solution was prepared as follows. alcohol and improved stability was observed after the MTBE Anhydrous ethanol (1.500 kg) methanol (0.088 kg) and iso wash has been performed. The wet filter cake was then dried propanol (0.087 kg) were charged into a 5 L flask at 15-25°C. in a heated filter funnel or a tray drier at 40-50° C. until dry. and the mixture was stirred for 20-30 min. The mixture was Typical yields were about 85-90%. bubbled with hydrogen chloride through a dip tube under US 2016/022 1987 A1 Aug. 4, 2016 30 stirring at 10-25° C. After 2 h, the mixture was sampled and TABLE 5-continued analyzed every 2-4 huntil the wt % of hydrogen chloride was s35%. XRPD peaks observed for 4-(5-Chloro-2-isopropylaminopyridin 4-yl)-1H-pyrrole-2-carboxylic acid (1-(3-chlorophenyl)- 0243 The alcohol/HCl solution (0.519 kg) prepared above 2-hydroxyethylamide Form C. was added dropwise into the mixture at the rate of 0.5-1.0 kg/h at 70-75° C. Seed crystal (0.009 kg) was added into the 20 () d space (A) Intensity (%) mixture and the alcohol/HCl solution (0.173 kg) prepared 26.40.2 3.375 O.O2S 8 above was added into the mixture at the rate of 0.5-1.0 kg/hat 27.7 O.2 3.224 0.023 22 70-75° C. After addition, the mixture was stirred for 1-2 hat 28.0 O2 3.182 0.022 11 70-75° C. The mixture was cooled to 15-25° C. at the rate of 28.3 - 0.2 3.147 O.O22 8 29.2 0.2 3.056 O.O2O 4 5-15° C./h and stirred for 4-6 h. The mixture was heated to 29.6 0.2 3.02O, O.O2O 7 70-75° C. at the rate of 15-25° C./h and stirred for 8-10 h at 29.90.2 2.983 O.O19 28 70-75° C. The mixture was cooled to 15-25° C. at the rate of 30.2 - 0.2 2.957 0.019 10 5-15°C./h and stirred for 4-6 h. The mixture was filtered with a vacuum filter flask. The filter cake was soaked and rinsed with a solution which was prepared from anhydrous ethanol (4.25 kg) and methanol (0.24 kg) and isopropanol (0.24 kg) TABLE 6 before filtration. The filter cake was dried in a drying room Prominent XRPD peaks for 4-(5-Chloro-2-isopropylaminopyridin under nitrogen at 40-50° C. until the ethanol residue was 4-yl)-1H-pyrrole-2-carboxylic acid (1-(3-chlorophenyl)- <0.5% and methanol residue was <0.3% and isopropanol 2-hydroxyethylamide Form C. residue was <0.3%. 2.89 kg of product was recovered as a 20 () d space (A) Intensity (%) white solid at 99.97% purity. 0244. The resulting 4-(5-Chloro-2-isopropylaminopyri 6.1 O.2 14.436 0.472 17 6.7 O.2 13.099 0.388 61 din-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlorophenyl)- 11.O. O.2 8.039 O.146 15 2-hydroxyethylamide Form C was analyzed by XRPD (FIG. 12.10.2 7.335 0.121 15 4). Peaks shown in FIG. 4 are listed in Table 5, prominent 13.7 O2 6.467, O.O94 10 15.2 0.2 S.828 O.O76 38 peaks are listed in Table 6. 16.5 - 0.2 5.363 - 0.064 18 17.6 O.2 S.O23 O.OS6 59 TABLE 5 17.9 O.2 4.949, O.OSS 37 18.4 O.2 4.818 - O.052 32 XRPD peaks observed for 4-(5-Chloro-2-isopropylaminopyridin 18.7 O2 4.743 O.OSO 13 4-yl)-1H-pyrrole-2-carboxylic acid (1-(3-chlorophenyl)- 19.6 O.2 4.529 O.046 14 2-hydroxyethylamide Form C. 1990.2 4.450 0.044 1OO 20.4 0.2 4.354 - 0.042 18 20 () d space (A) Intensity (%) 20.6 - 0.2 4.318 O.042 28 20.8 - 0.2 4.272, O.O41 52 6.1 O.2 14.436 O.472 17 21.5 + 0.2 4.122 O.O38 28 6.7 O.2 13.0990.388 61 22.6 0.2 3.935, O.O34 28 8.6 O.2 10.287 0.239 5 22.7 - 0.2 3.923 O.O34 27 O.8 O2 8.196 O. 152 5 23.50.2 3.785, O.O32 43 1.O. O.2 8.039 O.146 15 24.O. O.2 3704 O.O3O 29 2.1 - 0.2 7.335 0.121 15 24.30.2 3.664 O.O3O 12 2.4 + 0.2 7.108 - 0.114 6 24.90.2 3.573 0.028 56 3.5 + 0.2 6.533 O.096 8 25.40.2 3.498 0.027 60 3.7 O.2 6.467 O.O94 10 25.7 O2 3.467 O.O27 37 5.2 0.2 S.828 O.O76 38 27.7 O.2 3.224 0.023 22 6.5 O.2 5.363 - 0.064 18 28.0 O2 3.182 0.022 11 6.9 O.2 5.258 (0.062 7 29.90.2 2.983 O.O19 28 7.2 0.2 S.139 O.O59 5 30.2 - 0.2 2.957 0.019 10 7.6 0.2 S.O23 O.OS6 59 7.9 O.2 4.949, O.OSS 37 8.4 O.2 4.818 - O.052 32 8.7 O.2 4.743 O.OSO 13 0245 FT-IR was performed on a sample of Form C as 9.O. O.2 4.671 O.049 4 described in Example 1 (FIG. 5). Observed peaks from FIG. 9.2 0.2 4.628 O.048 4 9.6 0.2 4.529 O.046 14 5 are listed in Table 7. 9.9 O.2 4.450 0.044 1OO 20.40.2 4.354 - 0.042 18 TABLE 7 20.6 - 0.2 4.318 O.042 28 20.8 O2 4.272, O.O41 52 Observed FT-IR peaks for 4-(5-Chloro-2-isopropylaminopyridin 21.5 + 0.2 4.122 O.O38 28 4-yl)-1H-pyrrole-2-carboxylic acid (1-(3-chlorophenyl)- 22.10.2 4.016 O.036 4 2-hydroxyethylamide Form C. 22.6 0.2 3.935 O.O34 28 22.7 O.2 3.923 O.O34 27 Position (cm) Intensity 23.50.2 3.785, O.O32 43 24.O. O.2 3704 O.O3O 29 68O O.O389 24.30.2 3.664 O.O3O 12 694 0.0737 24.50.2 3.634 O.O29 8 705 O.O2O3 24.90.2 3.573 0.028 56 723 O.O273 25.40.2 3.498 0.027 60 728 O.0245 25.7, 0.2 3.467 O.O27 37 742 O.O263 26.O. O.2 3.424 - 0.026 6 771 O.0449 US 2016/022 1987 A1 Aug. 4, 2016 31

TABLE 7-continued 1H-pyrrole-2-carboxylic acid 1-(3-chlorophenyl)-2-hy droxyethylamide Form A was formed as white solids/ Observed FT-IR peaks for 4-(5-Chloro-2-isopropylaminopyridin needles. 4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlorophenyl)- 2-hydroxyethylamide Form C. 0249. Alternatively, 4-(5-Chloro-2-isopropylaminopyri Position (cm) Intensity din-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlorophenyl)- 2-hydroxyethylamide Form C was prepared as a slurry in 785 0.0527 845 O.O479 ethanol resulting in a white Suspension. The ethanol slurry 865 O.O128 was maintained at ambient temperature for 7 days. 4-(5- 879 O.O232 Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-car 922 O.O112 boxylic acid 1-(3-chlorophenyl)-2-hydroxyethylamide 946 0.0275 958 O.O11 Form A was formed as white tiny specks. 985 O.O119 OOO O.O124 0250. The resulting 4-(5-Chloro-2-isopropylaminopyri O76 O.O649 din-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlorophenyl)- 107 O.O183 2-hydroxyethylamide Form A was analyzed by XRPD (FIG. 129 O.0245 141 O.O322 7). Peaks shown in FIG. 7 are listed in Table 8, prominent 177 O.018 peaks are listed in Table 9. 219 O.OSS4 246 O.O238 TABLE 8 282 O.O279 310 O.O342 324 O.O179 XRPD peaks observed for 4-(5-Chloro-2-isopropylaminopyridin 344 O.O144 4-yl)-1H-pyrrole-2-carboxylic acid (1-(3-chlorophenyl)- 376 O.O239 2-hydroxyethylamide Form A. 380 O.O24 389 O.O2O4 20 () d space (A) Intensity (%) 413 O.O196 436 O.O324 5.8 0.2 15.175 O.S21 2O 472 O.O279 5.9 O.2 14.9920.509 22 498 O.O2S4 6.2. O.2 14.250 0.459 76 523 O.0543 10.5 O.2 8.418 it 0.160 1OO 551 O.O27 11.7 O2 7.571 - 0.129 6 574 O.O371 610 O.O697 11.8 O2 7.474. O.126 11 643 O.O865 12.4 - 0.2 7.114 O. 114 2O 2952 O.O153 15.3 - 0.2 S.772 0.075 7 2977 O.O167 15.90.2 S.S87, O.O70 17 3057 O.O15 16.1 O.2 5.506 O.O68 9 31.78 O.O147 16.30.2 5.440 OO66 6 3229 O.O162 16.40.2 5.393 0.06S 5 3.294 O.O171 17.6 O.2 S.048 0.057 49 3369 O.O161 17.8 O2 4.98O, O.OS6 21 18.7 O2 4.74O O.OSO 9 0246 DSC was performed on a sample of Form C as 19.8 O2 4.478 O.045 6 2O.O. O.2 4.427 O.044 25 described in Example 1 (FIG. 6) and showed a prominent 20.4 0.2 4.345 0.042 10 endotherm having an onset temperature of approximately 20.7 - 0.2 4.291 O.O41 8 2399 C. 2O.90.2 4.249 O.040 7 21.1 - 0.2 4.209 O.O39 11 Example 4 214 - 0.2 4.153 O.O38 23 21.90.2 4.OS2 O.O37 17 Preparation of 4-(5-Chloro-2-isopropylaminopyri 22.4 - 0.2 3.963 O.O3S 82 23.10.2 3.854 O.O33 11 din-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlo 23.50.2 3.790 O.O32 7 rophenyl)-2-hydroxyethylamide Form A 24.O. O.2 3.702 0.030 47 0247 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H 24.2 0.2 3.677 0.030 23 24.90.2 3.570 0.028 1OO pyrrole-2-carboxylic acid 1-(3-chlorophenyl)-2-hydroxy 25.30.2 3.523 O.O27 19 ethylamide Form C was dissolved in methanol at 60° C. 25.7 O2 3.47O O.O27 27 resulting in a clear Solution. The sample was slow cooled 26.40.2 3.370 O.O2S 10 from 60°C. to ambient temperature followed by fast evapo 26.90.2 3.317 O.O24 17 ration. 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyr 26.90.2 3.307 O.O24 16 role-2-carboxylic acid 1-(3-chlorophenyl)-2-hydroxyethyl 27.2 0.2 3.281 O.O24 13 amide Form A was formed as white solids/needles. 27.3 - 0.2 3.260 O.O23 11 27.8 O2 3.208 O.O23 9 0248 Alternatively, 4-(5-Chloro-2-isopropylaminopyri 28.10.2 3.178 O.O22 29 din-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlorophenyl)- 28.50.2 3.130 O.O22 43 2-hydroxyethylamide Form C was dissolved in ethanol at 29.0 O2 3.082, O.O21 9 60° C. resulting in a clear solution. The sample was slow 29.8 O2 2.999, O.O2O 32 cooled from 60° C. to ambient temperature followed by fast evaporation. 4-(5-Chloro-2-isopropylaminopyridin-4-yl)- US 2016/022 1987 A1 Aug. 4, 2016 32

TABLE 9 TABLE 10-continued Prominent XRPD peaks for 4-(5-Chloro-2-isopropylaminopyridin Observed FT-IR peaks for 4-(5-Chloro-2-isopropylaminopyridin 4-yl)-1H-pyrrole-2-carboxylic acid (1-(3-chlorophenyl)- 4-yl)-1H-pyrrole-2-carboxylic acid (1-(3-chlorophenyl)- 2-hydroxyethylamide Form A. 2-hydroxyethylamide Form A. 20 () d space (A) Intensity (%) Position (cm) Intensity 5.8 O2 15.175 - O.S21 2O 309 O.O387 5.9 O.2 14.9920.509 22 6.2. O.2 14.2SO - 0.459 76 329 O.O3O8 10.5 + 0.2 8.418. O.160 1OO 345 O.O262 11.8 O2 7.474 - 0.126 1 383 O.O214 12.40.2 7.1140.114 2O 394 O.O227 15.90.2 S.S87 O.O70 7 428 O.0288 17.6 O.2 S.048 0.057 49 452 O.O369 17.8 O2 4.98O, O.OS6 21 462 O.O366 2O.O. O.2 4.427 O.044 25 471 O.O374 20.40.2 4.345 0.042 O 500 O.0496 21.10.2 4.209 O.O39 1 537 O.O473 21.4 - 0.2 4.153 O.O38 23 573 O.064 21.90.2 4.OS2 O.O37 7 22.40.2 3.963 O.O3S 82 599 O.O412 23.10.2 3.854 - O.O33 1 613 O.O86 24.O. O.2 3.702 0.030 47 631 O.O909 24.2 0.2 3.677 0.030 23 648 O.069 24.90.2 3.570 0.028 1OO 823 O.OOS2 25.30.2 3.523 O.O27 9 2734 O.O193 25.7, 0.2 3.470 - 0.027 27 2939 O.O157 26.40.2 3.370 O.O2S O 2972 O.O182 26.90.2 3.317 O.O24 7 26.90.2 3.307 O.O24 6 3124 O.O184 27.2 0.2 3.281 O.O24 3 316S O.019 27.30.2 3.260 O.O23 1 3250 O.O184 28.10.2 3.178 O.O22 29 28.50.2 3.130 O.O22 43 29.8 O2 2.999, O.O2O 32 0252. DSC was performed on a sample of Form A as described in Example 1 (FIG.9) and showed four endother 0251 FT-IR was performed on a sample of Form A as mic events: melting of water at 0°C., followed by two broad described in Example 1 (FIG. 8). Observed peaks from FIG. events having peak maxima attemperatures of approximately 8 are listed in Table 10. 61° C. and 136° C. with weight losses of 3.0% and 1.9%, respectively and, finally, an endotherm having an onset tem TABLE 10 perature of approximately 201° C. Observed FT-IR peaks for 4-(5-Chloro-2-isopropylaminopyridin 4-yl)-1H-pyrrole-2-carboxylic acid (1-(3-chlorophenyl)- Example 5 2-hydroxyethylamide Form A. Position (cm) Intensity Preparation of 4-(5-Chloro-2-isopropylaminopyri 679 O.O296 din-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlo 687 O.0661 rophenyl)-2-hydroxyethylamide Form D 689 O.0658 712 O.0619 729 O.O227 0253) A vessel containing 4-(5-Chloro-2-isopropylami 742 O.O2O2 nopyridin-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlo 787 O.O614 rophenyl)-2-hydroxyethylamide Form A was purged with 790 O.O458 827 O.04 dry nitrogen and relative humidity was monitored. After 833 O.O371 about 73 minutes the relative humidity had decreased from 84.4 O.O446 36.9% to 1.0%. The resulting material was analyzed and was 868 O.O259 877 O.O224 determined to be a new form, designated Form D. 892 O.018 920 O.O14 0254. In a related experiment, a sample of 4-(5-Chloro-2- 946 O.O385 isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid 979 O.O103 1-(3-chlorophenyl)-2-hydroxyethylamide Form D was, 1001 O.OO98 1042 O.0228 uponsorption of water, observed to be Form A. This led to the 1068 O.O248 conclusion that Forms A and D interconvert reversibly as a 1094 O.O269 function of relative humidity. 1122 O.O195 1163 O.OS64 0255. A sample of 4-(5-Chloro-2-isopropylaminopyridin 1.192 O.O176 4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlorophenyl)-2- 1215 O.O443 1237 O.0651 hydroxyethylamide Form D was analyzed by XRPD (FIG. 1284 O.O295 10). Peaks shown in FIG. 10 are listed in Table 11, prominent peaks are listed in Table 12.

US 2016/022 1987 A1 Aug. 4, 2016 34

TABLE 13-continued 0268 7. The United States Pharmacopeia-National For mulary, The United States Pharmacopeial Convention, Observed FT-IR peaks for 4-(5-Chloro-2-isopropylaminopyridin 4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlorophenyl)- Rockville, Md. 2-hydroxyethylamide Form D. All documents cited in this application are hereby incorpo rated by reference as if recited in full herein. Position (cm) Intensity What is claimed is: 31.63 O.O111 3248 O.0109 1. Crystalline 4-(5-Chloro-2-isopropylaminopyridin-4- yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlorophenyl)-2-hy 0257 DSC was performed on a sample of Form D as droxyethylamide. described in Example 1 (FIG. 12) and showed endotherms 2. Crystalline free base 4-(5-Chloro-2-isopropylaminopy having peak maxima at temperatures of approximately 156 ridin-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlorophe and 204°C., respectively. The DSC is consistent with that of nyl)-2-hydroxyethylamide. Form A, except that the first two endotherms related to the 3. A crystalline free base of a compound of formula: melting and loss of water are not present in the DSC trace of Form D. Thus, the DSC is consistent with the conclusion that Form D is dehydrated Form A. Example 6 Comparison of 4-(5-Chloro-2-isopropylaminopyri din-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlo rophenyl)-2-hydroxyethylamide Forms A and C by C Raman Spectroscopy 0258 Samples of each of 4-(5-Chloro-2-isopropylami nopyridin-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlo rophenyl)-2-hydroxyethylamide Forms A and C were pre pared at 60 mg/mlinaethanol:methanol:isopropanol (90:5:5) mixture at 24° C. Raman spectroscopy was performed on having an X-ray powder diffraction (XRPD) pattern com each sample and on the solvent alone as described in Example prising a characteristic peak at about 19.5° 20. 1 4. A crystalline free base of a compound of formula: 0259 Results for a scan of wavelengths 1000-1600 cm are shown in FIG. 13. A clear characteristic peak at about 1165 cm was observed for Form A. 0260 Results for a scan of wavelengths 950-1030 cm are shown in FIG. 14. A characteristic peak at about 983 cm was observed for Form A and a characteristic peak at about 987 cm was observed for Form C. 0261 Although illustrative embodiments of the present invention have been described herein, it should be understood C that the invention is not limited to those described, and that various other changes or modifications may be made by one skilled in the art without departing from the scope or spirit of the invention. having an XRPD pattern comprising characteristic peaks at CITED REFERENCES about 9.1 and 19.5° 20. 0262. 1. Kohno M. Pouyssegur J. (2006) Targeting the 5. A crystalline free base of a compound of formula: ERK signaling pathway in cancer therapy. Ann Med 38:

200-211 0263. 2. Kuby, J., Immunology, 3rd Ed., W.H. Freeman & Co., New York. 0264 3. Lee D C, Webb M L (2003) Pharmaceutical Analysis. John Wiley & Sons, Inc., New York: 255-257. 0265. 4. Peterson ML, Hickey MB, Zaworotko MJ and Almarsson O (2006) Expanding the Scope of Crystal Form Evaluation in Pharmaceutical Science. J Pharm Pharma C ceut Sci9(3):317-326. 0266 5. Pierce Catalog and Handbook, 1994-1995; Pierce Chemical Co., Rockford, Ill. 0267 6. Remington, The Science and Practice of Phar macy (21st Edition, Lippincott Williams and Wilkins, having an XRPD pattern comprising characteristic peaks at Philadelphia, Pa. about 9.1, 15.4, 19.5 and 21.4° 20. US 2016/022 1987 A1 Aug. 4, 2016 35

6. A crystalline free base of a compound of formula: 14. A method of treating a cancer in a Subject in need thereof comprising administering to the Subject an effective amount of a crystalline compound according to claim 1. 15. The method according to claim 14, wherein the subject is a mammal. 16. The method according to claim 15, wherein the mam mal is selected from the group consisting of humans, pri mates, farm animals, and domestic animals. 17. The method according to claim 15, wherein the mam C mal is a human. 18. The method according to claim 14 further comprising administering to the Subject at least one additional anti-cancer agent. 19. A method of treating a cancer in a subject in need thereof comprising administering to the Subject an effective having one or more XRPD 20-reflections () selected from amount of a pharmaceutical composition according to claim the group consisting of about 9.1, 12.5, 15.2, 15.4, 19.2, 13. 19.5, 20.3, 20.5, 21.4, 21.7, 21.9, 23.1, 23.3, 23.6, and 20. The method according to claim 19, wherein the subject 24.3. is a mammal. 7. A crystalline free base of a compound of formula: 21. The method according to claim 20, wherein the mam mal is selected from the group consisting of humans, pri

mates, farm animals, and domestic animals. 22. The method according to claim 20, wherein the mam mal is a human. 23. The method according to claim 19 further comprising administering to the Subject at least one additional anti-cancer agent. 24. Crystalline 4-(5-Chloro-2-isopropylaminopyridin-4- C yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlorophenyl)-2-hy droxyethylamide mono HC1. 25. A crystalline hydrochloride salt of a compound of formula:

having an XRPD pattern substantially as shown in FIG. 1. 8. Crystalline free base 4-(5-Chloro-2-isopropylaminopy ridin-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlorophe nyl)-2-hydroxyethylamide mono HCl according to claim 2 having a Fourier transform infrared spectroscopy (FT-IR) spectrum comprising one or more peaks at about 1603, 1533, 1487, 1080, 857, and 681 cm. 9. Crystalline free base 4-(5-Chloro-2-isopropylaminopy C ridin-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlorophe nyl)-2-hydroxyethylamide mono HCl according to claim 2 having an FT-IR spectrum substantially as shown in FIG. 2. 10. Crystalline free base 4-(5-Chloro-2-isopropylami having an X-ray powder diffraction (XRPD) pattern com nopyridin-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlo prising a characteristic peak at about 6.7° 20. rophenyl)-2-hydroxyethylamide mono HCl according to 26. A crystalline hydrochloride salt of a compound of claim 2 having (i) an XRPD pattern comprising one or more formula: peaks at about 9. 1, 15.4, 19.5 and 21.4° 20; and (ii) a FT-IR spectrum comprising one or more peaks at about 1603, 1533, 1487, 1080, 857, and 681 cm. 11. Crystalline free base 4-(5-Chloro-2-isopropylami nopyridin-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlo rophenyl)-2-hydroxyethylamide mono HCl according to claim 2 having a DSC thermogram with an endotherm having an onset temperature of approximately 184°C. 12. Crystalline free base 4-(5-Chloro-2-isopropylami C nopyridin-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlo rophenyl)-2-hydroxyethylamide mono HCl according to claim 2 having a DSC thermogram Substantially as shown in FIG. 3. 13. A pharmaceutical composition comprising a crystalline having an XRPD pattern comprising characteristic peaks at compound according to claim 1. about 6.7 and 11.0° 20. US 2016/022 1987 A1 Aug. 4, 2016 36

27. A crystalline hydrochloride salt of a compound of nyl)-2-hydroxyethylamide mono HCl according to claim 24 formula: having (i) an XRPD pattern comprising one or more peaks at about 6.7, 11.0, 17.6, and 19.9°20; and (ii) a FT-IR spectrum comprising one or more peaks at about 1610, 1523, 1219, 1141, 1076, and 845 cm. 33. Form C crystalline 4-(5-Chloro-2-isopropylaminopy ridin-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlorophe nyl)-2-hydroxyethylamide mono HCl according to claim 24 having a DSC thermogram with an endotherm having an onset temperature of approximately 239°C. C 34. Form C crystalline 4-(5-Chloro-2-isopropylaminopy ridin-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlorophe nyl)-2-hydroxyethylamide mono HCl according to claim 24 having a DSC thermogram substantially as shown in FIG. 6. 35. A pharmaceutical composition comprising a crystalline having an XRPD pattern comprising characteristic peaks at compound according to claim 24. about 6.7, 11.0, 17.6 and 19.9° 20. 36. A method of treating a cancer in a subject in need 28. A crystalline hydrochloride salt of a compound of thereof comprising administering to the Subject an effective formula: amount of a crystalline compound according to claim 24. 37. The method according to claim 36, wherein the subject is a mammal. 38. The method according to claim 37, wherein the mam mal is selected from the group consisting of humans, pri mates, farm animals, and domestic animals. 39. The method according to claim 37, wherein the mam mal is a human. 40. The method according to claim 36 further comprising C administering to the Subject at least one additional anti-cancer agent. 41. A method of treating a cancer in a subject in need thereof comprising administering to the Subject an effective amount of a pharmaceutical composition according to claim having one or more XRPD 20-reflections () selected from 35. the group consisting of about 6.1, 6.7, 11.0, 12.1, 13.7, 42. The method according to claim 41, wherein the subject 15.2, 16.5, 17.6, 17.9, 18.4, 18.7, 19.6, 19.9, and 20.4. is a mammal. 29. A crystalline hydrochloride salt of a compound of 43. The method according to claim 42, wherein the mam formula: mal is selected from the group consisting of humans, pri mates, farm animals, and domestic animals.

44. The method according to claim 42, wherein the mam mal is a human. 45. The method according to claim 41 further comprising administering to the Subject at least one additional anti-cancer agent. 46. Crystalline 4-(5-Chloro-2-isopropylaminopyridin-4- yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlorophenyl)-2-hy C droxyethylamide HCl hydrate. 47. A crystalline hydrochloride salt of a compound of formula:

having an XRPD pattern substantially as shown in FIG. 4. 30. Form C crystalline 4-(5-Chloro-2-isopropylaminopy ridin-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlorophe nyl)-2-hydroxyethylamide mono HCl according to claim 24 having a Fourier transform infrared spectroscopy (FT-IR) spectrum comprising one or more peaks at about 1610, 1523, 1219, 1141, 1076, and 845 cm. C 31. Form C crystalline 4-(5-Chloro-2-isopropylaminopy ridin-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlorophe nyl)-2-hydroxyethylamide mono HCl according to claim 24 having an FT-IR spectrum substantially as shown in FIG. 5. 32. Form C crystalline 4-(5-Chloro-2-isopropylaminopy having an X-ray powder diffraction (XRPD) pattern com ridin-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlorophe prising a characteristic peak at about 10.5° 20. US 2016/022 1987 A1 Aug. 4, 2016 37

48. A crystalline hydrochloride salt of a compound of 51. A crystalline hydrochloride salt of a compound of formula: formula:

C C

having an XRPD pattern substantially as shown in FIG. 7. 52. Form A crystalline 4-(5-Chloro-2-isopropylaminopy ridin-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlorophe having an XRPD pattern comprising characteristic peaks at nyl)-2-hydroxyethylamide HCl hydrate according to claim about 6.2 and 10.5° 20. 46 having a Fourier transform infrared spectroscopy (FT-IR) 49. A crystalline hydrochloride salt of a compound of spectrum comprising one or more peaks at about 1573, 1237. formula: 1163,946, and 790 cm. 53. Form A crystalline 4-(5-Chloro-2-isopropylaminopy ridin-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlorophe nyl)-2-hydroxyethylamide HCl hydrate according to claim 46 having an FT-IR spectrum substantially as shown in FIG.

8. 54. Form A crystalline 4-(5-Chloro-2-isopropylaminopy ridin-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlorophe nyl)-2-hydroxyethylamide HCl hydrate according to claim 46 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 spec trum comprising one or more peaks at about 1573, 1237, C 1163,946, and 790 cm. 55. Form A crystalline 4-(5-Chloro-2-isopropylaminopy ridin-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlorophe nyl)-2-hydroxyethylamide HCl hydrate according to claim 46 having a DSC thermogram substantially as shown in FIG. 9. 56. A pharmaceutical composition comprising a crystalline compound according to claim 46. having an XRPD pattern comprising characteristic peaks at 57. A method of treating a cancer in a subject in need about 6.2, 10.5, 22.4 and 28.5° 20. thereof comprising administering to the Subject an effective amount of a crystalline compound according to claim 46. 50. A crystalline hydrochloride salt of a compound of 58. The method according to claim 57, wherein the subject formula: is a mammal. 59. The method according to claim 58, wherein the mam

mal is selected from the group consisting of humans, pri mates, farm animals, and domestic animals. 60. The method according to claim 58, wherein the mam mal is a human. 61. The method according to claim 57 further comprising administering to the Subject at least one additional anti-cancer agent. C 62. A method of treating a cancer in a Subject in need thereof comprising administering to the Subject an effective amount of a pharmaceutical composition according to claim 56. 63. The method according to claim 62, wherein the subject is a mammal. 64. The method according to claim 63, wherein the mam having one or more XRPD 20-reflections () selected from mal is selected from the group consisting of humans, pri the group consisting of about 5.8, 5.9, 6.2, 10.5, 11.8, mates, farm animals, and domestic animals. 12.4, 15.9, 17.6, 17.8, 20.0, 20.4, 21.1, 21.4, 21.9, 22.4, 65. The method according to claim 63, wherein the mam 23.1, 24.0, 24.2, 24.9, and 25.3. mal is a human. US 2016/022 1987 A1 Aug. 4, 2016

66. The method according to claim 62 further comprising 70. A crystalline hydrochloride salt of a compound of administering to the Subject at least one additional anti-cancer formula: agent.

67. A crystalline hydrochloride salt of a compound of formula:

C having one or more XRPD 20-reflections () selected from the group consisting of about 6.0, 6.3, 10.7, 12.0, 12.7, 15.6, 16.2, 16.3, 16.7, 17.9, 18.1, and 21.4. 71. A crystalline hydrochloride salt of a compound of formula:

having an X-ray powder diffraction (XRPD) pattern com prising a characteristic peak at about 10.7° 20. 68. A crystalline hydrochloride salt of a compound of formula:

having an XRPD pattern substantially as shown in FIG. 10. 72. Form D crystalline 4-(5-Chloro-2-isopropylaminopy ridin-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlorophe C nyl)-2-hydroxyethylamide HCl according to claim 24 hav ing a Fourier transform infrared spectroscopy (FT-IR) spectrum comprising one or more peaks at about 1537, 1471, 1239, 1163, 1067, and 946 cm. 73. Form D crystalline 4-(5-Chloro-2-isopropylaminopy ridin-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlorophe nyl)-2-hydroxyethylamide HCl according to claim 24 hav ing an FT-IR spectrum substantially as shown in FIG. 11. having an XRPD pattern comprising characteristic peaks at 74. Form D crystalline 4-(5-Chloro-2-isopropylaminopy about 10.7 and 18.1° 20. ridin-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlorophe nyl)-2-hydroxyethylamide HCl according to claim 24 hav 69. A crystalline hydrochloride salt of a compound of ing (i) an XRPD pattern comprising one or more peaks at formula: 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. 75. Form D crystalline 4-(5-Chloro-2-isopropylaminopy ridin-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chlorophe nyl)-2-hydroxyethylamide HCl according to claim 24 hav ing a DSC thermogram substantially as shown in FIG. 12. 76. A pharmaceutical composition comprising a crystalline compound according to claim 67. C 77. A method of treating a cancer in a subject in need thereof comprising administering to the Subject an effective amount of a crystalline compound according to claim 67. 78. The method according to claim 77, wherein the subject is a mammal. 79. The method according to claim 78, wherein the mam having an XRPD pattern comprising characteristic peaks at mal is selected from the group consisting of humans, pri about 6.0, 10.7, 12.7, and 18.1° 20. mates, farm animals, and domestic animals. US 2016/022 1987 A1 Aug. 4, 2016 39

80. The method according to claim 78, wherein the mam mal is a human. 81. The method according to claim 77 further comprising administering to the Subject at least one additional anti-cancer agent. 82. A method of treating a cancer in a Subject in need thereof comprising administering to the Subject an effective amount of a pharmaceutical composition according to claim 76. 83. The method according to claim 82, wherein the subject is a mammal. 84. The method according to claim 83, wherein the mam mal is selected from the group consisting of humans, pri mates, farm animals, and domestic animals. 85. The method according to claim 83, wherein the mam mal is a human. 86. The method according to claim 82 further comprising administering to the Subject at least one additional anti-cancer agent.