WO2025167975A1

WO2025167975A1 - Crystalline cyclin-dependent kinase (cdk) 12 and/or cdk13 inhibitor and uses thereof

Info

Publication number: WO2025167975A1
Application number: PCT/CN2025/075983
Authority: WO
Inventors: Lijun Zhang; Qingshuo MENG; Xing LIANG; Hongfu LU; Feng Ren
Original assignee: InSilico Medicine IP Ltd
Current assignee: InSilico Medicine IP Ltd
Priority date: 2024-02-07
Filing date: 2025-02-06
Publication date: 2025-08-14
Anticipated expiration: 2026-08-07

Abstract

Described herein are crystalline forms of a small molecule cyclin-dependent kinase (cdk) 12 and/or cdk13 inhibitor, as well as pharmaceutical compositions thereof, and methods of use thereof in the treatment of cancer or neoplastic disease.

Description

CRYSTALLINE CYCLIN-DEPENDENT KINASE (CDK) 12 AND/OR CDK13 INHIBITOR AND USES THEREOF

CROSS REFERENCE TO RELATED APPLICATIONS

This patent application claims the benefit of International Application No. PCT/CN2024/076726, filed February 7, 2024, which is incorporated herein by reference in its entirety.

BACKGROUND

Cyclin-dependent kinases (CDKs) are a family of multifunctional enzymes that play important regulatory roles in proliferation, such as modifying various protein substrates involved in cell cycle progression. The discovery of selective inhibitors of CDK12 and/or CDK13 has been limited due to the high sequence and structural similarities of the kinase domain of CDK family members. Therefore, it is imperative to discover and develop selective CDK12 and/or CDK13 inhibitors.

SUMMARY

Disclosed herein is a solid state form of (R) -1- (4- (3- ( (4- (1-methyl-1H-pyrazol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) pyrrolidin-1-yl) -5, 8-dihydropyrido [3, 4-d] pyrimidin-7 (6H) -yl)prop-2-en-1-one: (Compound 1) or a pharmaceutically acceptable adduct thereof.

In some embodiments, the solid state form is an amorphous form.

In some embodiments, the solid state form is a crystalline form.

In some embodiments, the solid state form is crystalline Compound 1 as a freebase.

In some embodiments, the solid state form is crystalline Compound 1 freebase Type A.

In some embodiments, the solid state form is crystalline Compound 1 as a pharmaceutically acceptable adduct. In some embodiments, the adduct is a salt of Compound 1. In some embodiments, the adduct is a cocrystal of Compound 1. In some embodiments, the solid state form is a salt or a cocrystal.

In some embodiments, the solid state form is crystalline Compound 1 fumaric acid adduct Type A, Compound 1 succinic acid adduct Type A, or Compound 1 p-toluenesulfonate adduct Type A.

Also disclosed herein is a pharmaceutical composition comprising a crystalline form of Compound 1 disclosed herein and a pharmaceutically acceptable excipient. Also disclosed herein is a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form disclosed herein and a pharmaceutically acceptable excipient.

Also disclosed herein is a method of treating a disease or disorder in a subject, the method comprising administering to the subject a crystalline form disclosed herein or a pharmaceutical composition disclosed herein, wherein the disease or disorder is cancer or neoplastic disease.

BRIEF DESCRIPTION OF THE DRAWINGS

The features of the invention are set forth with particularity in the appended claims. A better understanding of the features of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

FIG. 1A shows the X-Ray Powder Diffraction (XRPD) pattern of Compound 1 Freebase Type A.

FIG. 1B shows the Differential Scanning Calorimetry (DSC) thermogram of Compound 1 Freebase Type A.

FIG. 1C shows the Thermogravimetric Analysis (TGA) thermogram of Compound 1 Freebase Type A.

FIG. 1D shows the Dynamic Vapor Sorption (DVS) plot of Compound 1 Freebase Type A.

FIG. 1E shows the X-Ray Powder Diffraction (XRPD) pattern of Compound 1 Freebase Type A with different water content.

FIG. 2A shows the X-Ray Powder Diffraction (XRPD) pattern ofCompound 1 Freebase amorphous solid state form.

FIG. 2B shows the Modulated Differential Scanning Calorimetry (mDSC) thermogram of Compound 1 Freebase amorphous solid state form.

FIG. 2C shows the Thermogravimetric Analysis (TGA) thermogram of Compound 1 Freebase amorphous solid state form.

FIG. 3A shows the X-Ray Powder Diffraction (XRPD) pattern of Compound 1 fumaric acid adduct Type A.

FIG. 3B shows the Differential Scanning Calorimetry (DSC) thermogram of Compound 1 fumaric acid adduct Type A.

FIG. 3C shows the Thermogravimetric Analysis (TGA) thermogram of Compound 1 fumaric acid adduct Type A.

FIG. 3D shows the Dynamic Vapor Sorption (DVS) plot of Compound 1 fumaric acid adduct Type A.

FIG. 4A shows the X-Ray Powder Diffraction (XRPD) pattern of Compound 1 succinic acid adduct Type A.

FIG. 4B shows the Differential Scanning Calorimetry (DSC) thermogram of Compound 1 succinic acid adduct Type A.

FIG. 4C shows the Thermogravimetric Analysis (TGA) thermogram of Compound 1 succinic acid adduct Type A.

FIG. 4D shows the Dynamic Vapor Sorption (DVS) plot of Compound 1 succinic acid adduct Type A.

FIG. 5A shows the X-Ray Powder Diffraction (XRPD) pattern of Compound 1 p-toluenesulfonate adduct Type A.

FIG. 5B shows the Differential Scanning Calorimetry (DSC) thermogram of Compound 1 p-toluenesulfonate adduct Type A.

FIG. 5C shows the Thermogravimetric Analysis (TGA) thermogram of Compound 1 p-toluenesulfonate adduct Type A.

FIG. 5D shows the Dynamic Vapor Sorption (DVS) plot of Compound 1 p-toluenesulfonate adduct Type A.

DETAILED DESCRIPTION

While small molecule inhibitors are often initially evaluated for their activity when dissolved in solution, solid state characteristics such as polymorphism are also important. Polymorphic forms of a drug substance can have different physical properties, including melting point, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can have a direct effect on the ability to process or manufacture a drug substance and the drug product. Moreover, differences in these properties can and often lead to different pharmacokinetics profiles for different polymorphic forms of a drug. Therefore, polymorphism is often an important factor under regulatory review of the ‘sameness’ of drug products from various manufacturers.
Compound 1

Compound 1 is (R) -1- (4- (3- ( (4- (1-methyl-1H-pyrazol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) pyrrolidin-1-yl) -5, 8-dihydropyrido [3, 4-d] pyrimidin-7 (6H) -yl) prop-2-en-1-one: (Compound 1) . In some embodiments, Compound 1 is in the form of a freebase. In some embodiments, Compound 1 is in the form of a pharmaceutically acceptable adduct. In some embodiments, Compound 1 is in the form of a pharmaceutically acceptable salt. In some embodiments, Compound 1 is in the form of a fumaric acid adduct. In some embodiments, Compound 1 is in the form of a fumaric acid salt. In some embodiments, Compound 1 is in the form of a fumaric acid cocrystal. In some embodiments, Compound 1 is in the form of a succinic acid adduct. In some embodiments, Compound 1 is in the form of a succinic acid salt. In some embodiments, Compound 1 is in the form of a succinic acid cocrystal. In some embodiments, Compound 1 is in the form of a succinic acid cocrystal. In some embodiments, Compound 1 is in the form of a p-toluenesulfonate adduct. In some embodiments, Compound 1 is in the form of a p-toluenesulfonate salt. In some embodiments, Compound 1 is in the form of a p-toluenesulfonate cocrystal.
Solid State Form of Compound 1

In one aspect, provided herein is a solid state form of (R) -1- (4- (3- ( (4- (1-methyl-1H-pyrazol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) pyrrolidin-1-yl) -5, 8-dihydropyrido [3, 4-d] pyrimidin-7 (6H) -yl) prop-2-en-1-one: (Compound 1) or a pharmaceutically acceptable adduct thereof.

In some embodiments, the solid state form is an amorphous form.

In some embodiments, the solid state form is a crystalline form.

In some embodiments, the solid state form is crystalline Compound 1 freebase. In some embodiments, the solid state form is crystalline Compound 1 freebase Type A. In some embodiments, the Compound 1 freebase Type A is hydrated.

In some embodiments, the solid state form is an adduct. In some embodiments, the adduct is a salt. In some embodiments, the adduct is a cocrystal. In some embodiments, the solid state form is a salt. In some embodiments, the solid state form is a cocrystal. In some embodiments, the solid state form is Compound 1 fumaric acid adduct. In some embodiments, the solid state form is Compound 1 fumaric acid adduct Type A. In some embodiments, the solid state form is Compound 1 fumaric acid salt. In some embodiments, the solid state form is Compound 1 fumaric acid cocrystal. In some embodiments, the solid state form is Compound 1 succinic acid adduct. In some embodiments, the solid state form is Compound 1 succinic acid adduct Type A. In some embodiments, the solid state form is Compound 1 succinic acid salt. In some embodiments, the solid state form is Compound 1 succinic acid cocrystal. In some embodiments, the solid state form is Compound 1 p-toluenesulfonate adduct. In some embodiments, the solid state form is Compound 1 p-toluenesulfonate adduct Type A. In some embodiments, the solid state form is Compound 1 p-toluenesulfonate salt. In some embodiments, the solid state form is Compound 1 p-toluenesulfonate cocrystal.
Compound 1 Freebase Type A

Disclosed herein is Compound 1 freebase Type A. In some embodiments, the crystalline form is Compound 1 freebase characterized as having at least one of the following properties:
(a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG.
1A as measured using Cu Kα. radiation;
(b) an X-Ray powder diffraction (XRPD) pattern with at least one peak selected from 7.8 ±
0.2° 2θ, 17.2 ± 0.2° 2θ, and 23.2 ± 0.2° 2θ as measured using Cu Kα. radiation;
(c) an X-Ray powder diffraction (XRPD) pattern with three or more peaks (e.g., three, four,
five, or six peaks) selected from 7.8 ± 0.2° 2θ, 17.2 ± 0.2° 2θ, 18.9 ± 0.2° 2θ, 19.4 ± 0.2° 2θ, 22.3± 0.2° 2θ and 23.2 ± 0.2° 2θ as measured using Cu Kα. radiation;
(d) an X-Ray powder diffraction (XRPD) pattern with at least three, at least six, at least nine,
or all of the peaks selected from 7.8 ± 0.2° 2θ, 13.4 ± 0.2° 2θ, 16.0 ± 0.2° 2θ, 17.2 ± 0.2° 2θ, 18.9 ± 0.2° 2θ, 19.4 ± 0.2° 2θ, 22.3± 0.2° 2θ, 23.2 ± 0.2° 2θ and 27.2 ± 0.2° 2θ as measured using Cu Kα. radiation;
(e) a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown
in FIG. 1B;
(f) a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak
having a peak temperature at about 62℃;
(g) a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak
having a peak temperature at about 104℃;
(h) a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as
shown in FIG. 1C;
(i) a TGA thermogram exhibiting a mass loss of less than about 6.8%from the onset of
heating up to about 90 ℃;
(j) a water uptake of less than about 9 %wt between 0%and 20%Relative Humidity (RH)
as determined by Dynamic Vapor Sorption (DVS) ;
(k) a water uptake of about 7.5 %wt between 0%and 20%Relative Humidity (RH) as
determined by Dynamic Vapor Sorption (DVS) ; or
(l) combinations thereof.

In some embodiments, the crystalline form is Compound 1 freebase characterized as having at least one of the following properties:
(a) an X-Ray powder diffraction (XRPD) pattern with peaks at 7.8 ± 0.2° 2θ, 17.2 ± 0.2° 2θ,
and 23.2 ± 0.2° 2θ as measured using Cu Kα. radiation;
(b) a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak
having a peak temperature at about 62℃;
(c) a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak
having a peak temperature at about 104℃; or
(d) combinations thereof.

In some embodiments, the crystalline form is Compound 1 freebase characterized as having at least one of the following properties:
(a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG.
1A as measured using Cu Kα. radiation;
(b) an X-Ray powder diffraction (XRPD) pattern with peaks at 7.8 ± 0.2° 2θ, 17.2 ± 0.2° 2θ,
and 23.2 ± 0.2° 2θ as measured using Cu Kα. radiation;
(c) a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown
in FIG. 1B;
(d) a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as
shown in FIG. 1C; or
(e) combinations thereof.

In some embodiments of Compound 1 freebase, the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 1A as measured using Cu Kα.radiation.

In some embodiments of Compound 1 freebase, the crystalline form has an X-ray powder diffraction (XRPD) pattern with one or more peaks (e.g., one, two, three, four, five, six, seven, eight, nine, or all peaks) found in Table 1.1 or Table 1.2 as measured using Cu Kα. radiation. In some embodiments of Compound 1 freebase, the crystalline form has an X-ray powder diffraction (XRPD) pattern with one or more peaks (e.g., one, two, three, four, five, six, seven, eight, nine, or all peaks) found in Table 1.1 or Table 1.2 , ± 0.2° 2θ, as measured using Cu Kα. radiation.

In some embodiments of Compound 1 freebase, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, or all of the peaks found in Table 1.2, ± 0.2° 2θ, as measured using Cu Kα. radiation.

In some embodiments of Compound 1 freebase, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 7.8 ± 0.2° 2θ, 17.2 ± 0.2° 2θ, and 23.2 ± 0.2° 2θ as measured using Cu Kα. radiation.

In some embodiments of Compound 1 freebase, the X-ray powder diffraction (XRPD) pattern further comprises peaks at 18.9 ± 0.2° 2θ, 19.4 ± 0.2° 2θ, and 22.3± 0.2° 2θ as measured using Cu Kα. radiation.

In some embodiments of Compound 1 freebase, the X-ray powder diffraction (XRPD) pattern further comprises peaks at 13.4 ± 0.2° 2θ, 16.0 ± 0.2° 2θ, and 27.2 ± 0.2° 2θ as measured using Cu Kα. radiation.

In some embodiments of Compound 1 freebase, the X-ray powder diffraction (XRPD) pattern with peaks at 7.8 ± 0.2° 2θ, 17.2 ± 0.2° 2θ, 18.9 ± 0.2° 2θ, 19.4 ± 0.2° 2θ, 22.3± 0.2° 2θ and 23.2 ± 0.2° 2θas measured using Cu Kα. radiation.

In some embodiments of Compound 1 freebase, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 7.8 ± 0.2° 2θ, 13.4 ± 0.2° 2θ, 16.0 ± 0.2° 2θ, 17.2 ± 0.2° 2θ, 18.9 ± 0.2° 2θ, 19.4 ± 0.2° 2θ, 22.3± 0.2° 2θ, 23.2 ± 0.2° 2θ and 27.2 ± 0.2° 2θ as measured using Cu Kα. radiation.

In some embodiments of Compound 1 freebase, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or all of the peaks selected from 7.8 ± 0.2° 2θ, 13.4 ± 0.2° 2θ, 16.0 ± 0.2° 2θ, 17.2 ± 0.2° 2θ, 18.9 ± 0.2° 2θ, 19.4 ± 0.2° 2θ, 22.3± 0.2° 2θ, 23.2 ± 0.2° 2θ and 27.2 ± 0.2° 2θ as measured using Cu Kα. radiation.

In some embodiments of Compound 1 freebase, the Differential Scanning Calorimetry (DSC) thermogram is substantially the same as shown in FIG. 1B.

In some embodiments of Compound 1 freebase, the Differential Scanning Calorimetry (DSC) thermogram has an endothermic peak having a peak temperature at about 62℃.

In some embodiments of Compound 1 freebase, the Differential Scanning Calorimetry (DSC) thermogram has an endothermic peak having a peak temperature at 104℃.

In some embodiments of Compound 1 freebase, the Thermogravimetric Thermal Analysis (TGA) thermogram is substantially the same as shown in FIG. 1C.

In some embodiments of Compound 1 freebase, the crystalline form is a hydrate. In some embodiments, the crystalline is a hydrate with about 4%to about 18 %by weight of water. In some embodiments, the crystalline is a hydrate with about 5%to about 9 %by weight of water.

In some embodiments of Compound 1 freebase, the crystalline form is stable.

In some embodiments of Compound 1 freebase, the crystalline form is chemically stable.

In some embodiments of Compound 1 freebase, the crystalline form is thermodynamically stable.

In some embodiments of Compound 1 freebase, the crystalline form is substantially pure. In another embodiment, the crystalline form has a purity of at least 80wt%, at least 85wt%, at least 86wt%, at least 87wt%, at least 88wt%, at least 89wt%, at least 90wt%, at least 91wt%, at least 92wt%, at least 93wt%, at least 94wt%, at least 95wt%, at least 96wt%, at least 97wt%, at least 98wt%, or at least 99wt%.
Table 1.1 XRPD peaks table of Compound 1 freebase Type A

Table 1.2 XRPD peaks table of Compound 1 freebase Type A

Compound 1 freebase amorphous solid state form

Disclosed herein is Compound 1 amorphous solid state form. In some embodiments, the amorphous solid state form is freebase characterized as having at least one of the following properties:
(a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG.
2A as measured using Cu Kα. radiation;
(b) a Modulated Differential Scanning Calorimetry (mDSC) thermogram substantially the
same as shown in FIG. 2B;
(c) a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as
shown in FIG. 2C; or
(d) combinations thereof.
Compound 1 fumaric acid adduct Type A

Disclosed herein is Compound 1 fumaric acid adduct (such as salt or cocrystal) . Further, disclosed herein is Compound 1 fumaric acid adduct (such as salt or cocrystal) Type A. In some embodiments, the crystalline form is Compound 1 fumaric acid adduct characterized as having at least one of the following properties:
(a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG.
3A as measured using Cu Kα. radiation;
(b) an X-Ray powder diffraction (XRPD) pattern with at least one peak selected from 12.0 ±
0.2° 2θ, 19.3 ± 0.2° 2θ, and 25.1 ± 0.2° 2θ as measured using Cu Kα. radiation;
(c) an X-Ray powder diffraction (XRPD) pattern with three or more peaks (e.g., three, four,
five, or six peaks) selected from 12.0 ± 0.2° 2θ, 19.3 ± 0.2° 2θ, 23.3 ± 0.2° 2θ, 25.1 ± 0.2° 2θ, 25.7± 0.2° 2θ, and 29.4 ± 0.2° 2θ as measured using Cu Kα. radiation;
(d) an X-Ray powder diffraction (XRPD) pattern with at least three, at least six, at least nine,
or all of the peaks selected from 10.8 ± 0.2° 2θ, 12.0 ± 0.2° 2θ, 19.3 ± 0.2° 2θ, 21.1 ± 0.2° 2θ, 21.9 ± 0.2° 2θ, 23.3 ± 0.2° 2θ, 25.1 ± 0.2° 2θ, 25.7± 0.2° 2θ, and 29.4 ± 0.2° 2θ as measured using Cu Kα. radiation;
(e) a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown
in FIG. 3B;
(f) a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak
having a peak temperature at about 149 ℃;
(g) a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as
shown in FIG. 3C;
(h) a TGA thermogram exhibiting a mass loss of less than about 0.8 %from the onset of
heating up to about 150 ℃;
(i) a water uptake of less than about 5 %wt between 0%and 90 %Relative Humidity (RH)
as determined by Dynamic Vapor Sorption (DVS) ;
(j) a water uptake of about 3 %wt between 0%and 90%Relative Humidity (RH) as
determined by Dynamic Vapor Sorption (DVS) ; or
(k) combinations thereof.

In some embodiments, the crystalline form is Compound 1 fumaric acid adduct characterized as having at least one of the following properties:
(a) an X-Ray powder diffraction (XRPD) pattern with peaks at 12.0 ± 0.2° 2θ, 19.3 ± 0.2°
2θ, and 25.1 ± 0.2° 2θ as measured using Cu Kα. radiation;
(b) a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak
having a peak temperature at about 149 ℃;
(c) a TGA thermogram exhibiting a mass loss of less than about 0.8 %from the onset of
heating up to about 150 ℃; or
(d) combinations thereof.

In some embodiments, the crystalline form is Compound 1 fumaric acid adduct characterized as having at least one of the following properties:
(a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG.
3A as measured using Cu Kα. radiation;
(b) an X-Ray powder diffraction (XRPD) pattern with peaks at 12.0 ± 0.2° 2θ, 19.3 ± 0.2°
2θ, and 25.1 ± 0.2° 2θ as measured using Cu Kα. radiation;
(c) a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown
in FIG. 3B;
(d) a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as
shown in FIG. 3C; or
(e) combinations thereof.

In some embodiments of Compound 1 fumaric acid adduct, the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 3A as measured using Cu Kα. radiation.

In some embodiments of Compound 1 fumaric acid adduct, the crystalline form has an X-ray powder diffraction (XRPD) pattern with one or more peaks (e.g., one, two, three, four, five, six, seven, eight, nine, or all peaks) found in Table 2.1 or Table 2.2 as measured using Cu Kα. radiation. In some embodiments of Compound 1 fumaric acid adduct, the crystalline form has an X-ray powder diffraction (XRPD) pattern with one or more peaks (e.g., one, two, three, four, five, six, seven, eight, nine, or all peaks) found in Table 2.1 or Table 2.2, ± 0.2° 2θ, as measured using Cu Kα. radiation.

In some embodiments of Compound 1 fumaric acid adduct, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, or all of the peaks found in Table 2.2, ± 0.2° 2θ, as measured using Cu Kα. radiation.

In some embodiments of Compound 1 fumaric acid adduct, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 12.0 ± 0.2° 2θ, 19.3 ± 0.2° 2θ, and 25.1 ± 0.2° 2θ as measured using Cu Kα. radiation.

In some embodiments of Compound 1 fumaric acid adduct, the X-ray powder diffraction (XRPD) pattern further comprises peaks at 23.3 ± 0.2° 2θ, 25.7± 0.2° 2θ, and 29.4 ± 0.2° 2θ as measured using Cu Kα. radiation.

In some embodiments of Compound 1 fumaric acid adduct, the X-ray powder diffraction (XRPD) pattern further comprises peaks at 10.8 ± 0.2° 2θ, 21.1 ± 0.2° 2θ, and 21.9 ± 0.2° 2θ as measured using Cu Kα. radiation.

In some embodiments of Compound 1 fumaric acid adduct, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 12.0 ± 0.2° 2θ, 19.3 ± 0.2° 2θ, 23.3 ± 0.2° 2θ, 25.1 ± 0.2° 2θ, 25.7± 0.2° 2θ, and 29.4 ± 0.2° 2θ as measured using Cu Kα. radiation.

In some embodiments of Compound 1 fumaric acid adduct, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 10.8 ± 0.2° 2θ, 12.0 ± 0.2° 2θ, 19.3 ± 0.2° 2θ, 21.1 ± 0.2° 2θ, 21.9 ± 0.2° 2θ, 23.3 ± 0.2° 2θ, 25.1 ± 0.2° 2θ, 25.7± 0.2° 2θ, and 29.4 ± 0.2° 2θ as measured using Cu Kα. radiation.

In some embodiments of Compound 1 fumaric acid adduct, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or all of the peaks selected from 10.8 ± 0.2° 2θ, 12.0 ± 0.2° 2θ, 19.3 ± 0.2° 2θ, 21.1 ± 0.2° 2θ, 21.9 ± 0.2° 2θ, 23.3 ± 0.2° 2θ, 25.1 ± 0.2° 2θ, 25.7± 0.2° 2θ, and 29.4 ± 0.2° 2θ as measured using Cu Kα. radiation.

In some embodiments of Compound 1 fumaric acid adduct, the Differential Scanning Calorimetry (DSC) thermogram is substantially the same as shown in FIG. 3B.

In some embodiments of Compound 1 fumaric acid adduct, a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak having a peak temperature at about 149 ℃.

In some embodiments of Compound 1 fumaric acid adduct, the Thermogravimetric Thermal Analysis (TGA) thermogram is substantially the same as shown in FIG. 3C.

In some embodiments of Compound 1 fumaric acid adduct, a TGA thermogram exhibiting a mass loss of less than about 0.8 %from the onset of heating up to about 150 ℃.

In some embodiments of Compound 1 fumaric acid adduct, the mole ratio of Compound 1 to fumaric acid is about 1: (0.9-1.1) . In some embodiments, the mole ratio of Compound 1 to fumaric acid is about 1: 1.

In some embodiments of Compound 1 fumaric acid adduct, the crystalline form is anhydrate.

In some embodiments of Compound 1 fumaric acid adduct, the crystalline form is stable.

In some embodiments of Compound 1 fumaric acid adduct, the crystalline form is chemically stable.

In some embodiments of Compound 1 fumaric acid adduct, the crystalline form is thermodynamically stable.

In some embodiments of Compound 1 fumaric acid adduct, the crystalline form is substantially pure. In another embodiment, the crystalline form has a purity of at least 80wt%, at least 85wt%, at least 86wt%, at least 87wt%, at least 88wt%, at least 89wt%, at least 90wt%, at least 91wt%, at least 92wt%, at least 93wt%, at least 94wt%, at least 95wt%, at least 96wt%, at least 97wt%, at least 98wt%, or at least 99wt%.
Table 2.1 XRPD peaks table of Compound 1 fumaric acid adduct Type A

Table 2.2 XRPD peaks table of Compound 1 fumaric acid adduct Type A

Compound 1 succinic acid adduct Type A

Disclosed herein is Compound 1 succinic adduct (such as salt or cocrystal) . Further, disclosed herein is Compound 1 succinic acid adduct (such as salt or cocrystal) Type A. In some embodiments, the crystalline form is Compound 1 succinic acid adduct characterized as having at least one of the following properties:
(a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG.
4A as measured using Cu Kα. radiation;
(b) an X-Ray powder diffraction (XRPD) pattern with at least one peak selected from 12.2 ±
0.2° 2θ, 23.1 ± 0.2° 2θ, and 25.9 ± 0.2° 2θ as measured using Cu Kα. radiation;
(c) an X-Ray powder diffraction (XRPD) pattern with three or more peaks (e.g., three, four,
five, or six peaks) selected from 12.2 ± 0.2° 2θ, 16.1 ± 0.2° 2θ, 19.5 ± 0.2° 2θ, 22.0 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, and 25.9 ± 0.2° 2θ as measured using Cu Kα. radiation;
(d) an X-Ray powder diffraction (XRPD) pattern with at least three, at least six, at least
nine, or all of the peaks selected from 12.2 ± 0.2° 2θ, 16.1 ± 0.2° 2θ, 17.5 ± 0.2° 2θ, 18.9 ± 0.2° 2θ, 19.5 ± 0.2° 2θ, 21.3 ± 0.2° 2θ, 22.0 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, and 25.9 ± 0.2° 2θas measured using Cu Kα. radiation;
(e) a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown
in FIG. 4B;
(f) a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak
having a peak temperature at about 140 ℃;
(g) a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as
shown in FIG. 4C;
(h) a TGA thermogram exhibiting a mass loss of about 0.4 %from the onset of heating up to
about 130 ℃; or
(i) combinations thereof.

In some embodiments, the crystalline form is Compound 1 succinic acid adduct characterized as having at least one of the following properties:
(a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG.
4A as measured using Cu Kα. radiation;
(b) an X-Ray powder diffraction (XRPD) pattern with peaks at 12.2 ± 0.2° 2θ, 23.1 ± 0.2°
2θ, and 25.9 ± 0.2° 2θ as measured using Cu Kα. radiation;
(c) a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak
having a peak temperature at about 140 ℃;
(d) a TGA thermogram exhibiting a mass loss of about 0.4 %from the onset of heating up to
about 130 ℃; or
(e) combinations thereof.

In some embodiments, the crystalline form is Compound 1 succinic acid adduct characterized as having at least one of the following properties:
(f) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG.
4A as measured using Cu Kα. radiation;
(g) an X-Ray powder diffraction (XRPD) pattern with peaks at 12.2 ± 0.2° 2θ, 23.1 ± 0.2°
2θ, and 25.9 ± 0.2° 2θ as measured using Cu Kα. radiation;
(h) a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown
in FIG. 4B;
(i) a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as
shown in FIG. 4C;
(j) combinations thereof.

In some embodiments of Compound 1 succinic acid adduct, the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 4A as measured using Cu Kα. radiation.

In some embodiments of Compound 1 succinic acid adduct, the crystalline form has an X-ray powder diffraction (XRPD) pattern with one or more peaks (e.g., one, two, three, four, five, six, seven, eight, nine, or all peaks) found in Table 3.1 or Table 3.2 as measured using Cu Kα. radiation. In some embodiments of Compound 1 succinic acid adduct, the crystalline form has an X-ray powder diffraction (XRPD) pattern with one or more peaks (e.g., one, two, three, four, five, six, seven, eight, nine, or all peaks) found in Table 3.1 or Table 3.2, ± 0.2° 2θ, as measured using Cu Kα. radiation.

In some embodiments of Compound 1 succinic acid adduct, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, or all of the peaks found in Table 3.2, ± 0.2° 2θ, as measured using Cu Kα. radiation.

In some embodiments of Compound 1 succinic acid adduct, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 12.2 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, and 25.9 ± 0.2° 2θ as measured using Cu Kα. radiation.

In some embodiments of Compound 1 succinic acid adduct, the X-ray powder diffraction (XRPD) pattern further comprises peaks at 16.1 ± 0.2° 2θ, 19.5 ± 0.2° 2θ, and 22.0 ± 0.2° 2θ as measured using Cu Kα. radiation.

In some embodiments of Compound 1 succinic acid adduct, the X-ray powder diffraction (XRPD) pattern further comprises peaks at 17.5 ± 0.2° 2θ, 18.9 ± 0.2° 2θ, and 21.3 ± 0.2° 2θ as measured using Cu Kα. radiation.

In some embodiments of Compound 1 succinic acid adduct, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 12.2 ± 0.2° 2θ, 16.1 ± 0.2° 2θ, 19.5 ± 0.2° 2θ, 22.0 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, and 25.9 ± 0.2° 2θ as measured using Cu Kα. radiation.

In some embodiments of Compound 1 succinic acid adduct, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks selected from 12.2 ± 0.2° 2θ, 16.1 ± 0.2° 2θ, 17.5 ± 0.2°2θ, 18.9 ± 0.2° 2θ, 19.5 ± 0.2° 2θ, 21.3 ± 0.2° 2θ, 22.0 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, and 25.9 ± 0.2° 2θ as measured using Cu Kα. radiation.

In some embodiments of Compound 1 succinic acid adduct, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or all of the peaks selected from 12.2 ± 0.2° 2θ, 16.1 ± 0.2° 2θ, 17.5 ± 0.2° 2θ, 18.9 ± 0.2° 2θ, 19.5 ± 0.2° 2θ, 21.3 ± 0.2° 2θ, 22.0 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, and 25.9 ± 0.2° 2θ as measured using Cu Kα. radiation.

In some embodiments of Compound 1 succinic acid adduct, the Differential Scanning Calorimetry (DSC) thermogram is substantially the same as shown in FIG. 4B.

In some embodiments of Compound 1 succinic acid adduct, a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak having a peak temperature at about 140 ℃.

In some embodiments of Compound 1 succinic acid adduct, the Thermogravimetric Thermal Analysis (TGA) thermogram is substantially the same as shown in FIG. 4C.

In some embodiments of Compound 1 succinic acid adduct, a TGA thermogram exhibiting a mass loss of about 0.4 %from the onset of heating up to about 130 ℃.

In some embodiments of Compound 1 succinic acid adduct, the mole ratio of Compound 1 to succinic acid is about 1: (0.9-1.1) . In some embodiments, the mole ratio of Compound 1 to succinic acid is about 1: 1.

In some embodiments of Compound 1 succinic acid adduct, the crystalline form is anhydrate.

In some embodiments of Compound 1 succinic acid adduct, the crystalline form is stable.

In some embodiments of Compound 1 succinic acid adduct, the crystalline form is chemically stable.

In some embodiments of Compound 1 succinic acid adduct, the crystalline form is thermodynamically stable.

In some embodiments of Compound 1 succinic acid adduct, the crystalline form is substantially pure. In another embodiment, the crystalline form has a purity of at least 80wt%, at least 85wt%, at least 86wt%, at least 87wt%, at least 88wt%, at least 89wt%, at least 90wt%, at least 91wt%, at least 92wt%, at least 93wt%, at least 94wt%, at least 95wt%, at least 96wt%, at least 97wt%, at least 98wt%, or at least 99wt%.
Table 3.1 XRPD peaks table of Compound 1 succinic acid adduct Type A

Table 3.2 XRPD peaks table of Compound 1 succinic acid adduct Type A

Compound 1 p-toluenesulfonate adduct Type A

Disclosed herein is Compound 1 p-toluenesulfonate adduct (such as salt or cocrystal) . Further, disclosed herein is Compound 1 p-toluenesulfonate adduct (such as salt or cocrystal) Type A. In some embodiments, the crystalline form is Compound 1 p-toluenesulfonate adduct characterized as having at least one of the following properties:
(a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG.
5A as measured using Cu Kα. radiation;
(b) an X-Ray powder diffraction (XRPD) pattern with at least one peak selected from 7.5 ±
0.2° 2θ, 18.7 ± 0.2° 2θ, and 23.1 ± 0.2° 2θ as measured using Cu Kα. radiation;
(c) an X-Ray powder diffraction (XRPD) pattern with three or more peaks (e.g., three, four,
five, or six peaks) selected from 7.5 ± 0.2° 2θ, 14.2 ± 0.2° 2θ, 18.7 ± 0.2° 2θ, 20.2 ± 0.2° 2θ, 21.5 ± 0.2° 2θ, and 23.1 ± 0.2° 2θ as measured using Cu Kα. radiation;
(d) an X-Ray powder diffraction (XRPD) pattern with at least three, at least six, at least nine,
or all of the peaks selected from 7.5 ± 0.2° 2θ, 11.2 ± 0.2° 2θ, 14.2 ± 0.2° 2θ, 18.7 ± 0.2° 2θ, 20.2 ± 0.2° 2θ, 21.5 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, 23.8 ± 0.2° 2θ and 26.2 ± 0.2° 2θ as measured using Cu Kα. radiation;
(e) a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown
in FIG. 5B;
(f) a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak
having a peak temperature at about 44 ℃;
(g) a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak
having a peak temperature at about 156 ℃;
(h) a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as
shown in FIG. 5C;
(i) a TGA thermogram exhibiting a mass loss of less than about 2.5 %from the onset of
heating up to about 82 ℃;
(j) a water uptake of less than about 10 %wt between 0%and 90 %Relative Humidity
(RH) as determined by Dynamic Vapor Sorption (DVS) ;
(k) a water uptake of about 7.7 %wt between 0%and 90%Relative Humidity (RH) as
determined by Dynamic Vapor Sorption (DVS) ; or
(l) combinations thereof.

In some embodiments, the crystalline form is Compound 1 p-toluenesulfonate adduct characterized as having at least one of the following properties:
(a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG.
5A as measured using Cu Kα. radiation;
(b) an X-Ray powder diffraction (XRPD) pattern with peaks at 7.5 ± 0.2° 2θ, 18.7 ± 0.2° 2θ,
and 23.1 ± 0.2° 2θ as measured using Cu Kα. radiation;
(c) a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak
having a peak temperature at about 44 ℃;
(d) a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak
having a peak temperature at about 156 ℃;
(e) a TGA thermogram exhibiting a mass loss of less than about 2.5 %from the onset of
heating up to about 82 ℃; or
(f) combinations thereof.

In some embodiments, the crystalline form is Compound 1 p-toluenesulfonate adduct characterized as having at least one of the following properties:
(a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG.
5A as measured using Cu Kα. radiation;
(b) an X-Ray powder diffraction (XRPD) pattern with peaks at 7.5 ± 0.2° 2θ, 18.7 ± 0.2° 2θ,
and 23.1 ± 0.2° 2θ as measured using Cu Kα. radiation;
(c) a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown
in FIG. 5B;
(d) a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as
shown in FIG. 5C; or
(e) combinations thereof.

In some embodiments of Compound 1 p-toluenesulfonate adduct, the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 5A as measured using Cu Kα. radiation.

In some embodiments of Compound 1 p-toluenesulfonate adduct, the crystalline form has an X-ray powder diffraction (XRPD) pattern with one or more peaks (e.g., one, two, three, four, five, six, seven, eight, nine, or all peaks) found in Table 4.1 or Table 4.2 as measured using Cu Kα. radiation. In some embodiments of Compound 1 p-toluenesulfonate adduct, the crystalline form has an X-ray powder diffraction (XRPD) pattern with one or more peaks (e.g., one, two, three, four, five, six, seven, eight, nine, or all peaks) found in Table 4.1 or Table 4.2, ± 0.2° 2θ, as measured using Cu Kα. radiation.

In some embodiments of Compound 1 p-toluenesulfonate adduct, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, or all of the peaks found in Table 4.2, ± 0.2° 2θ, as measured using Cu Kα. radiation.

In some embodiments of Compound 1 p-toluenesulfonate adduct, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 7.5 ± 0.2° 2θ, 18.7 ± 0.2° 2θ, and 23.1 ± 0.2° 2θ as measured using Cu Kα. radiation.

In some embodiments of Compound 1 p-toluenesulfonate adduct, the X-ray powder diffraction (XRPD) pattern further comprises peaks at 14.2 ± 0.2° 2θ, 20.2 ± 0.2° 2θ, and 21.5 ± 0.2° 2θ as measured using Cu Kα. radiation.

In some embodiments of Compound 1 p-toluenesulfonate adduct, the X-ray powder diffraction (XRPD) pattern further comprises peaks at 11.2 ± 0.2° 2θ, 23.8 ± 0.2° 2θ and 26.2 ± 0.2° 2θ as measured using Cu Kα. radiation.

In some embodiments of Compound 1 p-toluenesulfonate adduct, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 7.5 ± 0.2° 2θ, 14.2 ± 0.2° 2θ, 18.7 ± 0.2° 2θ, 20.2 ± 0.2° 2θ, 21.5 ± 0.2° 2θ, and 23.1 ± 0.2° 2θ as measured using Cu Kα. radiation.

In some embodiments of Compound 1 p-toluenesulfonate adduct, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 7.5 ± 0.2° 2θ, 11.2 ± 0.2° 2θ, 14.2 ± 0.2° 2θ, 18.7 ± 0.2° 2θ, 20.2 ± 0.2° 2θ, 21.5 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, 23.8 ± 0.2° 2θ and 26.2 ± 0.2° 2θ as measured using Cu Kα. radiation.

In some embodiments of Compound 1 p-toluenesulfonate adduct, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or all of the peaks selected from 7.5 ± 0.2° 2θ, 11.2 ± 0.2°2θ, 14.2 ± 0.2° 2θ, 18.7 ± 0.2° 2θ, 20.2 ± 0.2° 2θ, 21.5 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, 23.8 ± 0.2° 2θ and 26.2 ± 0.2° 2θ as measured using Cu Kα. radiation.

In some embodiments of Compound 1 p-toluenesulfonate adduct, the Differential Scanning Calorimetry (DSC) thermogram is substantially the same as shown in FIG. 5B.

In some embodiments of Compound 1 p-toluenesulfonate adduct, the Thermogravimetric Thermal Analysis (TGA) thermogram is substantially the same as shown in FIG. 5C.

In some embodiments of Compound 1 p-toluenesulfonate adduct, the mole ratio of Compound 1 to p-toluenesulfonate is about 1: (0.9-1.1) . In some embodiments, the mole ratio of Compound 1 to p-toluenesulfonate is about 1: 1.

In some embodiments of Compound 1 p-toluenesulfonate adduct, the crystalline form is a hydrate. In some embodiments of Compound 1 p-toluenesulfonate adduct, the crystalline form is a monohydrate. In some embodiments, the crystalline is a hydrate with about 2%to about 3 %by weight of water. In some embodiments, the crystalline is a hydrate with about 2.3%to about 2.7 %by weight of water. In some embodiments, the crystalline is a hydrate with about 2.5%.

In some embodiments of Compound 1 p-toluenesulfonate adduct, the crystalline form is stable.

In some embodiments of Compound 1 p-toluenesulfonate adduct, the crystalline form is chemically stable.

In some embodiments of Compound 1 p-toluenesulfonate adduct, the crystalline form is thermodynamically stable.

In some embodiments of Compound 1 p-toluenesulfonate adduct, the crystalline form is substantially pure. In another embodiment, the crystalline form has a purity of at least 80wt%, at least 85wt%, at least 86wt%, at least 87wt%, at least 88wt%, at least 89wt%, at least 90wt%, at least 91wt%, at least 92wt%, at least 93wt%, at least 94wt%, at least 95wt%, at least 96wt%, at least 97wt%, at least 98wt%, or at least 99wt%.
Table 4.1 XRPD peaks table of Compound 1 p-toluenesulfonate adduct Type A

Table 4.2 XRPD peaks table of Compound 1 p-toluenesulfonate adduct Type A

Method of Treatment

Disclosed herein is a method of treating a disease or disorder in a subject, the method comprising administering to the subject a crystalline form disclosed herein, wherein the disease or disorder is cancer or neoplastic disease. In some embodiments, the cancer is breast cancer, triple-negative breast cancer (TNBC) , colorectal cancer, ovarian cancer, pancreatic cancer, prostate cancer, or lung cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is triple-negative breast cancer (TNBC) .
Dosing

In certain embodiments, the compositions containing the compound (s) described herein are administered for prophylactic and/or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
Routes of Administration

Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
Pharmaceutical Compositions/Formulations

The compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In one embodiment, the compounds of this invention may be administered to animals. The compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and topical routes of administration.

In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995) ; Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N. Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins1999) , herein incorporated by reference for such disclosure.
Definitions

In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to. ” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

As used herein, the term “apharmaceutically acceptable adduct” covers both pharmaceutically acceptable salts and pharmaceutically acceptable cocrystals of a compound.

As used herein, the term “apharmaceutically acceptable salt” is to be understood to include acid addition salts and basic addition salts. The acid includes inorganic or organic acid, including but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2] oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4, 4’ -methylenebis- (3-hydroxy-2-ene-1 -carboxylic acid) , 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. The base includes inorganic or organic base, including but not limited to an amine (primary, secondary or tertiary) , hydroxide, carbonate, bicarbonate, sulfate of an alkali metal or alkaline earth metal, or the like. Representative bases include, for example, amino acids, such as L-glycine, L-lysine, and L-arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as hydroxyethylpyrrolidine, piperidine, morpholine, piperazine, sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, and the like.

The term “cocrystal” is to be understood to refer to solids that are crystalline single-phase materials composed of a compound and at least one other molecular and/or ionic compound, herein referred to as a co-former, generally in a stoichiometric ratio. Generally speaking, if a compound and its co-former have a ΔpKa (pKa (base) -pKa (acid) ) > 3, there will be substantial proton transfer resulting in ionization and potential formation of a salt as opposed to a co-crystal. On the other hand, if a compound and its co-former have a ΔpKa (pKa (base) -pKa (acid) ) < 3, there will be less than substantial proton transfer and the compound-co-former entity should be classified as a cocrystal. In a cocrystal, the compound and co-former molecules interact by hydrogen bonding and possibly other non-covalent interactions. It may be noted that a cocrystal may itself form solvates, including hydrates.

As used herein, the terms “crystal form” , “crystalline form” and “Form” interchangeably refer to a crystal structure (or polymorph) having a particular molecular packing arrangement in the crystal lattice. Crystalline forms can be identified and distinguished from each other by one or more characterization techniques including, for example, X-ray powder diffraction (XRPD) , single crystal X-ray diffraction, differential scanning calorimetry (DSC) , thermogravimetric analysis (TGA) , and/or dynamic vapor sorption (DVS) . Accordingly, as used herein, the term “crystalline Form [X] of Compound (I) ” refers to unique crystalline forms that can be identified and distinguished from each other by one or more characterization techniques including, for example, X-ray powder diffraction (XRPD) , single crystal X-ray diffraction, differential scanning calorimetry (DSC) , thermogravimetric analysis (TGA) , and/or dynamic vapor sorption (DVS) . In some embodiments, the novel crystalline forms are characterized by an X-ray powder diffractogram having one or more signals at one or more specified two-theta values (° 2θ) .

As used herein, the term “solvate” refers to a crystal form comprising one or more molecules of the compound of the present disclosure and, incorporated into the crystal lattice, one or more molecules of a solvent or solvents in stoichiometric or nonstoichiometric amounts. When the solvent is water, the solvate is referred to as a “hydrate. ”

As used herein, the term “XRPD” refers to the analytical characterization method of X-ray powder diffraction. As used herein, the terms “X-ray powder diffractogram” , “X-ray powder diffraction pattern” , “XRPD pattern” interchangeably refer to an experimentally obtained pattern plotting signal positions (on the abscissa) versus signal intensities (on the ordinate) . For an amorphous material, an X-ray powder diffractogram may include one or more broad signals; and for a crystalline material, an X-ray powder diffractogram may include one or more signals, each identified by its angular value as measured in degrees 2θ (° 2θ) , depicted on the abscissa of an X-ray powder diffractogram.

A “peak” as used herein refers to a point in the XRPD pattern where the intensity as measured in counts is at a local maximum. One of ordinary skill in the art would recognize that one or more signals (or peaks) in an XRPD pattern may overlap and may, for example, not be apparent to the naked eye. Indeed, one of ordinary skill in the art would recognize that some art-recognized methods are capable of and suitable for determining whether a signal exists in a pattern, such as Rietveld refinement.

The repeatability of the measured angular values is in the range of ±0.2° 2θ, i.e., the angular value can be at the recited angular value + 0.2 degrees two-theta, the angular value -0.2 degrees two-theta, or any value between those two end points (angular value +0.2 degrees two-theta and angular value -0.2 degrees two-theta) . In some embodiments, the repeatability of the measured angular values is in the range of ±0.1° 2θ.

The term “peak intensities” refers to relative signal intensities within a given X-ray powder diffractogram. Factors that can affect the relative signal or peak intensities include sample thickness and preferred orientation (e.g., the crystalline particles are not distributed randomly) .

As used herein, the term “amorphous” refers to a solid form of a molecule, atom, and/or ions that is not crystalline. An amorphous solid does not display a definitive X-ray diffraction pattern.

As used herein, “substantially pure, ” when used in reference to a form, means a compound having a purity greater than 90 weight %, including greater than 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99 weight %, and also including equal to about 100 weight %of Compound I, based on the weight of the compound. The remaining material comprises other form (s) of the compound, and/or reaction impurities and/or processing impurities arising from its preparation. For example, a crystalline form of Compound (I) may be deemed substantially pure in that it has a purity greater than 90 weight %, as measured by means that are at this time known and generally accepted in the art, where the remaining less than 10 weight %of material comprises other form (s) of Compound (I) and/or reaction impurities and/or processing impurities.

As used herein, the term “pharmaceutical composition” refers to a formulation containing the compound or solid forms thereof provided herein in a form suitable for administration to a subject.

As used herein, the term “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable excipient” as used herein includes both one and more than one such excipient. The term “pharmaceutically acceptable excipient” also encompasses “pharmaceutically acceptable carrier” and “pharmaceutically acceptable diluent” .

Unless otherwise stated, the following terms used in this application have the definitions given below. The use of the term “including” as well as other forms, such as “include, ” “includes, ” and “included, ” is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

The term “acceptable” with respect to a formulation, composition, or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

The terms “administer, ” “administering, ” “administration, ” and the like, as used herein, refer to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion) , topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

The terms “effective amount” or “therapeutically effective amount, ” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.

The terms “enhance” or “enhancing, ” as used herein, means to increase, or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An “enhancing-effective amount, ” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.

The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

The terms “treat, ” “treating” or “treatment, ” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.

The term “about” means within a statistically meaningful range of a value, such as a stated concentration range, time frame, molecular weight, particle size, temperature, or pH, etc. Such a range can be within an order of magnitude, typically within 10%, more typically within 5%, and even more typically within 3%of the indicated value or range. Sometimes, such a range can be within the experimental error typical of standard methods used for the measurement and/or determination of a given value or range. The allowable variation encompassed by the term “about” will depend upon the particular system under study, and can be readily appreciated by one of ordinary skill in the art. Whenever a range is recited within this application, every whole number integer within the range is also contemplated as an embodiment of the disclosure.

If multiple diffraction patterns are available, then assessments of particle statistics (PS) and/or preferred orientation (PO) are possible. Consistency of relative intensity among XRPD patterns from multiple diffractometers indicates good orientation statistics. Alternatively, the observed XRPD pattern may be compared with a calculated XRPD pattern based upon a single crystal structure, if available. Two-dimensional scattering patterns using area detectors can also be used to evaluate PS/PO. If the effects of both PS and PO are determined to be negligible, then the XRPD pattern is representative of the powder average intensity for the sample and prominent peaks may be identified as “Representative Peaks. ” In general, the more data collected to determine Representative Peaks, the more confident one can be of the classification of those peaks.

“Characteristic peaks, ” to the extent they exist, are a subset of representative peaks and are used to differentiate one crystalline polymorph from another crystalline polymorph (polymorphs being crystalline forms having the same chemical composition) . Characteristic peaks are determined by evaluating which representative peaks, if any, are present in one crystalline polymorph of a compound against all other known crystalline polymorphs of that compound to within ±0.2 °2Θ. Not all crystalline polymorphs of a compound necessarily have at least one characteristic peak.

The term “preferred orientation” as used herein refers to an extreme case of non-random distribution of the crystallites of a solid state form. In XRPD, the ideal sample is homogenous and the crystallites are randomly distributed in the bulk solid. In a truly random sample, each possible reflection from a given set of planes will have and equal number of crystallites contributing to it. However, when the solid state form is in a preferred orientation this is not the case. Accordingly, comparing the intensity between a randomly oriented diffraction pattern and a preferred oriented diffraction pattern can look entirely different. Quantitative analysis depending on intensity ratios are greatly distorted by preferred orientation. Careful sample preparation is important for decreasing the incidence of a preferred orientation.

The term “substantially the same, ” as used herein to reference a figure is intended to mean that the figure is considered representative of the type and kind of characteristic data that is obtained by a skilled artisan in view of deviations acceptable in the art. Such deviations may be caused by factors related to sample size, sample preparation, particular instrument used, operation conditions, and other experimental condition variations known in the art. For example, one skilled in the art can appreciate that the endotherm onset and peak temperatures as measured by differential scanning calorimetry (DSC) may vary significantly from experiment to experiment. For example, one skilled in the art can readily identify whether two X-ray diffraction patterns or two DSC thermograms are substantially the same. In some embodiments, when characteristic peaks of two X-ray diffraction patterns do not vary more than ± 0.2° 2-θ, it is deemed that the X-ray diffraction patterns are substantially the same.
EXAMPLES

The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.
Example A: Preparation of Compound 1 amorphous free base

To a solution of 1-1 (460 mg, 2.12 mmol) and DIEA (820 mg, 6.36 mmol) in THF (10 mL) at 0 ℃ was added tert-butyl (R) -3-aminopyrrolidine-1-carboxylate (395 mg, 2.12 mmol) . After the addition, the reaction mixture was stirred at 25℃ for 2 h. Then the mixture was poured into ice water (50 mL) . After extraction with EtOAc (30 mL x 3) , the combined organic layers were washed with brine (50 mL) , dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with ethyl acetate (from 0%to 20%) in petroleum ether to give compound 1-2 (600 mg, 77.2%yield) . LC-MS (ESI+) : m/z 367.3 [M+H] ⁺.

To a solution of 1-2 (500 mg, 1.36 mmol) , 1-methyl-3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (426 mg, 2.05 mmol) and K₂CO₃ (565 mg, 4.08 mmol) in 1, 4-dioxane-H₂O (6 mL, 5: 1 ) was added Pd (dppf) Cl₂ (200 mg, 0.27 mmol) at 25 ℃. The mixture was stirred at 100 ℃ under N₂ for 12 h. After cooling to 25 ℃, the reaction mixture was poured into ice water (50 mL) and extracted with EtOAc (30 mL x 3) . The organic layers were washed with brine (50 mL) , dried over Na₂SO₄, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford 1-3 (507 mg, 90.2%yield) . LC-MS (ESI+) : m/z 413.3 (M+H) ⁺.

To a solution of 1-3 (507 mg, 1.22 mmol) in DCM (6 mL) were added HCl (3 mL, 4M in dioxane) . The mixture was stirred at 25 ℃ for 1 h, then concentrated and dried under vacuum to afford 1-4 (383 mg, 99.8%yield) , which was directly used in the next step without further purification. LC-MS (ESI+) : m/z 313.3 (M+H) ⁺.

To a solution of 1-4 (757 mg, 2.42 mmol) ) in ACN (7 mL) were added tert-butyl 4-chloro-5, 8-dihydropyrido [3, 4-d] pyrimidine-7 (6H) -carboxylate (719 mg, 2.67 mmol) and DIEA (1.20 mL, 7.27 mmol) . The reaction mixture was stirred at 25 ℃ for 18 h, then added ice-water (100 mL) and extracted with EtOAc (50 mL x 3) . The organic layers were washed with brine (50 mL) , dried over Na₂SO₄, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford 1-5 (842 mg, 63.7%yield) . LC-MS (ESI+) : m/z 546.3 (M+H) ⁺.

To a solution of 1-5 (842 mg, 1.54 mmol) in DCM (7 mL) were added HCl (3 mL, 4 M in dioxane) . The reaction mixture was stirred at 25 ℃ for 1 h, then concentrated and dried under vacuum to afford 1-6 (687 mg, 99.9%yield) , which was directly used in the next step without further purification. LC-MS (ESI+) : m/z 446.3 (M+H) ⁺.

To a solution of 1-6 (587 mg, 1.32 mmol) and DIEA (0.87 mL, 5.27 mmol) in DCM (7 mL) was dropwise added acrylic anhydride (166 mg, 1.30 mmol) at 0 ℃. The reaction mixture was stirred at 25 ℃for 0.5 h, then concentrated under reduced pressure. The resulting residue was purified by Prep-HPLC. Solid sample was obtained by lyophilization to afford Compound 1 amorphous free base. LC-MS (ESI+) : m/z 500.2 (M+H) ⁺. ¹H NMR (400 MHz, Methanol-d₄) δ 8.58 (s, 1H) , 8.27 (s, 1H) , 7.64 (d, J = 2.4 Hz, 1H) , 6.93 -6.69 (m, 2H) , 6.26 (dd, J = 16.7, 1.9 Hz, 1H) , 5.80 (d, J = 10.4 Hz, 1H) , 4.75 -4.57 (m, 3H) , 4.16 -3.65 (m, 9H) , 3.09 -2.91 (m, 2H) , 2.36 -2.23 (m, 1H) , 2.18 -2.04 (m, 1H) . Samples were collected for XRPD, DSC and TGA test.

The XRPD pattern of Compound 1 is shown in FIG. 2A. mDSC result of Compound 1 is shown in FIG. 2B. TGA result of Compound 1 is shown in FIG. 2C.

Example B: The objective of this experiment was to assess the potential inhibitory effect of compounds on CDK12/CyclinK kinase.

1. Procedure for CDK12/CyclinK assay:
Table 5. Materials and reagents used in this experiment

Table 6. Consumables and instrument used in this experiment

2.1. Compound preparation:

Testing compounds were dissolved to 10 mM by adding fresh DMSO.

2.2. Assay Procedure:

Echo655 was used to transfer the compound dilution (50 nl for CDK12/CyclinK) to each well of the assay plate (784075, Greiner) . The final concentration of DMSO was 1%. The assay plate was sealed, and the compound plates were centrifuged at 1000g for 1 min. 1 × kinase buffer was prepared by mixing 1 volume of 5x kinase buffer with 4 volumes of distilled water; 1.5 mM DTT. 2 × kinase solution (5 ng/μL for CDK12/CyclinK) was prepared in 1× kinase buffer. 2.5 μL 2× kinase solution was added into the assay plate, and the plates were centrifuged at 1000 g for 1 min and incubated at room temperature for 10 min. 2× substrates (160 uM pS7-CTD peptide) and ATP (40 μM) mixture in 1× kinase buffer were prepared. The reaction was started by adding 2.5 μL 2× substrates and ATP mixture (as prepared above) . The plates were centrifuged at 1000 g for 1 min. The assay plates were sealed and incubated at room temperature for 120 min. 4 μL ADP-Glo reagents were added. The plate was centrifuged at 1000 g for 1 min and incubated at room temperature for 40 min. 8 μL kinase detection reagents were added. The plate was centrifuged at 1000 g for 1 min and incubated at room temperature for 40 min. The plate was centrifuged at 1000 g for 1 min. The luminescence signal was read on Envision 2104 plate reader.

3. Data analysis

1) %Inhibition was calculated as follow:

Signal _{Ave_PC}: The average for the positive controls across the plate.
Signal _{Ave_VC}: The average for the negative controls across the plate.

2) Calculation of IC₅₀ and Plot effect-dose curve of compounds.

IC₅₀ was calculated by fitting %Inhibition values and log of compound concentrations to nonlinear regression (dose response –variable slope) with Graphpad:
Y = Bottom + (Top-Bottom) / (1+10^ ( (LogIC₅₀-X) *HillSlope) )
X: log of Inhibitor concentration; Y: %Inhibition.

Quality control

Z’ >0.5, Reference data was in the historic range (3 ～ 5-fold) .

The results for exemplary compounds of the present application are illustrated in Table 7.
Table 7. IC₅₀ values of exemplary compounds

CDK12 IC₅₀ (nM) : 25 nM <B≤ 100 nM;

Examples C: Pharmacokinetic profile evaluation

Species and strain: CD-1 mice of SPF. Source: Sino-British SIPPR/BK Lab Animal Ltd, Shanghai. Three mice were intravenously administrated with given compound 1 (Formulation: 5%DMSO + 10%Solutol + 85%Saline) or orally gavage administrated with given compound 1 (Formulation: 5%DMSO + 10%Solutol + 85%Saline) . The blood samples were taken via cephalic vein at timepoints 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after intravenous (iv) administration or at timepoints 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6h, 8 h, and 24 h after oral gavage administration, 30 μL/time point. Blood samples were placed in tubes containing K2-EDTA and stored on ice until centrifuged. The blood samples were centrifuged at 6800 g for 6 minutes at 2-8 ℃ within 1 h after collected and stored frozen at approximately -80 ℃. An aliquot of 20 μL plasma samples were protein precipitated with 400 μL MeOH in which contains 100 ng/mL Verapamil (IS) . The mixture was vortexed for 1 min and centrifuged at 18000 g for 10 min. Transfer 400 μL supernatant to 96 well plates. An aliquot of 5 μL supernatant was injected for LC-MS/MS analysis by LC-MS/MS-27 (TQ6500+) instrument. The analytical results were confirmed using quality control samples for intra-assay variation. The accuracy of >66.7%of the quality control samples should be between 80 -120%of the known value (s) . Standard set of parameters including Area Under the Curve (AUC _(0-t) and AUC _(0-∞) ) , elimination half-life (T_1/2) , maximum plasma concentration (C_max) , oral bioavailability (F) will be calculated using noncompartmental analysis modules in FDA certified pharmacokinetic program Phoenix WinNonlin 7.0 (Pharsight, USA) .

The data for Example C is shown in Table 8 and Table 9
Table 8. Mouse PK profile after iv administration at 1 mg/kg.

Table 9. Mouse PK profile after oral administration at 5 mg/kg

Example 1 Preparation of Compound 1 Freebase Type A

About 50mg of Compound 1 amorphous free base was dissolved in 0.04mL of acetonitrile /water (50: 50, v: v) at 50℃. After stirring at 50℃ for about 10min. The clear solution was cooled to 5℃ at 0.1℃ /min and kept stirring at 5℃ for 6 hours. Another 0.4mL of 0.2mL of acetonitrile /water (50: 50, v: v) was added to improve the mobility and kept stirring at 5℃ for 18 hours, respectively. Precipitates were collected by centrifugation filtration through a 0.45μm nylon membrane filter at 14,000 rpm. Free base type A was obtained. Sample of the solid were collected for XRPD, DSC, TGA, and DVS test.

The XRPD pattern of Free base Type A of Compound 1 is shown in FIG. 1A. DSC result is shown in FIG. 1B. TGA result is shown in FIG. 1C. DVS result is shown in FIG. 1D. Compound 1 Freebase Type A is a hydrate with 4.1%-17.6%water by weight (measured by Karl Fischer method) , as shown in FIG. 1E.

Example 2 Preparation of Compound 1 fumaric acid adduct Type A

About 50mg of the Compound 1 amorphous free base and 1.05 equiv. of fumaric acid were added into 0.5mL of ethyl acetate in a 2mL glass vial. After stirring at 50℃ for a while, a hazy suspension was obtained. 10μL of water was added into above hazy suspension and kept stirred at 50℃for about 2 hours. The hazy suspension was cooled to 25℃ by natural cooling and kept stirring at 25℃for 1 day. The hazy suspension was cooled to 5℃ to precipitate solids and kept stirring at 5℃ for 6 days. A suspension was obtained. Solids were collected by centrifugation filtration and then dried at 50℃under vacuum for about 2 hours. Fumaric acid adduct type A was obtained as an off-white solid. Samples of the solid were collected for XRPD, DSC, TGA, and DVS test.

The XRPD pattern of fumaric acid adduct of Compound 1 is shown in FIG. 3A. DSC result is shown in FIG. 3B. TGA result is shown in FIG. 3C. DVS result is shown in FIG. 3D.

Example 3 Preparation of Compound 1 succinic acid adduct Type A

About 50mg of the Compound 1 amorphous free base and 1.05 equiv. of succinic acid were added into 0.5mL of ethyl acetate at 50℃ in a 2mL glass vial. After stirring at 50℃ for a while, a hazy suspension was obtained. After stirring at 50℃ for about 2 hours, the hazy suspension was cooled to 25℃ by natural cooling and kept stirring at 25℃ for 1 day. The hazy suspension was cooled to 5℃ to precipitate solids and kept stirring for 6 days. A suspension was obtained. Solids were collected by centrifugation filtration and then dried at 50℃ under vacuum for about 2 hours. Succinic acid adduct type A was obtained as an off-white solid. Samples of the solid were collected for XRPD, DSC, TGA, and DVS test.

The XRPD pattern of succinic acid adduct Type A of Compound 1 is shown in FIG. 4A. DSC result is shown in FIG. 4B. TGA result is shown in FIG. 4C. DVS result is shown in FIG. 4D.

Example 4 Preparation of Compound 1 p-toluenesulfonate adduct Type A

About 300 mg of the Compound 1 amorphous free base was totally dissolved in 2 mL acetonitrile. 103.4mg of the p-toluenesulfonic acid (～1.0 equivalent by molar ratio) was totally dissolved in 1 mL acetonitrile. The clear solution of p-toluenesulfonic acid was added into the clear solution of free base. About 2mg crystal seeds were added into the clear solution. The clear solution converted into a suspension. After stirring at 50℃ for about 2h, the suspension was cooled to 25℃ and kept stirring at 25℃ for about 2 days. 0.15mL water was added into the suspension. 1mg crystal seeds were added into the hazy suspension. After stirring at 25℃ for about 3h, the hazy suspension was cooled to 5℃ by natural cooling. After stirring at 5℃ for 0.5h, more precipitation was obtained. Then the suspension was transferred to 25℃ and kept stirring overnight. Solids were collected by filtration through a 0.45μm nylon membrane filter by centrifugation and then dried at 50℃ under vacuum for about 2 hours. 132mg of the p-toluenesulfonate adduct type A was obtained. Sample of the solid were collected for XRPD, DSC, TGA, and DVS test.

The XRPD pattern of p-toluenesulfonate adduct Type A of Compound 1 is shown in FIG. 5A. DSC result is shown in FIG. 5B. TGA result is shown in FIG. 5C. DVS result is shown in FIG. 5D.

It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. A person of skill would understand that although the above diffractometer and/or diffractometer parameters were used in the examples, other types of diffractometers or parameters can also be used. Furthermore, other wavelengths can be used and converted to the Cu Kα. In some embodiments, Synchrotron Radiation X-Ray Powder Diffraction (SR-XRPD) can be used to characterize the crystalline forms.

All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

A solid state form of (R) -1- (4- (3- ( (4- (1-methyl-1H-pyrazol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) pyrrolidin-1-yl) -5, 8-dihydropyrido [3, 4-d] pyrimidin-7 (6H) -yl) prop-2-en-1-one:

or a pharmaceutically acceptable adduct thereof.
The solid state form of claim 1, wherein the solid state form is a crystalline form.
The solid state form of claim 1 or 2, wherein the solid state form is crystalline Compound 1 as a freebase.
The solid state form of claim 3, wherein the solid state form is crystalline Compound 1 Freebase Type A.
The solid state form of claim 2, wherein the crystalline form is Compound 1 freebase characterized as having at least one of the following properties:

(a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 1A as measured using Cu Kα. radiation;

(b) an X-Ray powder diffraction (XRPD) pattern with peaks at 7.8 ± 0.2° 2θ, 17.2 ± 0.2° 2θ, and 23.2 ± 0.2° 2θ as measured using Cu Kα. radiation;

(c) a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown in FIG. 1B;

(d) a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as shown in FIG. 1C; or

(e) combinations thereof.
The solid state form of claim 5, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 1A as measured using Cu Kα. radiation.
The solid state form of claim 5 or 6, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with one or more peaks found in Table 1.1 or Table 1.2 as measured using Cu Kα. radiation.
The solid state form of any one of claims 5-7, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 7.8 ± 0.2° 2θ, 17.2 ± 0.2° 2θ, and 23.2 ± 0.2° 2θ as measured using Cu Kα. radiation.
The solid state form of any one of claims 5-8, wherein the X-ray powder diffraction (XRPD) pattern further comprises peaks at 18.9 ± 0.2° 2θ, 19.4 ± 0.2° 2θ, and 22.3± 0.2° 2θ as measured using Cu Kα. radiation.
The solid state form of any one of claims 5-9, wherein the X-ray powder diffraction (XRPD) pattern further comprises peaks at 13.4 ± 0.2° 2θ, 16.0 ± 0.2° 2θ, and 27.2 ± 0.2° 2θ as measured using Cu Kα. radiation.
The solid state form of any one of claims 5-10, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 7.8 ± 0.2° 2θ, 13.4 ± 0.2° 2θ, 16.0 ± 0.2° 2θ, 17.2 ± 0.2° 2θ, 18.9 ± 0.2° 2θ, 19.4 ± 0.2° 2θ, 22.3± 0.2° 2θ, 23.2 ± 0.2° 2θ and 27.2 ± 0.2° 2θ as measured using Cu Kα. radiation.
The solid state form of any one of claims 4-11, wherein the crystalline form is a hydrate.
The solid state form of any one of claims 4-12, wherein the crystalline is a hydrate with about 4 %to about 18 %by weight of water.
The solid state form of any one of claims 4-13, wherein the crystalline is a hydrate with about 5 to about 9 %by weight of water.
The solid state form of claim 1 or 2, wherein the solid state form is crystalline Compound 1 as a adduct.
The solid state form of claim 15, wherein the solid state form is crystalline Compound 1 fumaric acid adduct Type A.
The solid state form of claim 15 or 16, wherein the crystalline form is Compound 1 fumaric acid adduct characterized as having at least one of the following properties:

(a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 3A as measured using Cu Kα. radiation;

(b) an X-Ray powder diffraction (XRPD) pattern with peaks at 12.0 ± 0.2° 2θ, 19.3 ± 0.2° 2θ, and 25.1 ± 0.2° 2θ as measured using Cu Kα. radiation;

(c) a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown in FIG. 3B;

(d) a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as shown in FIG. 3C; or

(e) combinations thereof.
The solid state form of claim 17, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 3A as measured using Cu Kα. radiation.
The solid state form of claim 17 or 18, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with one or more peaks found in Table 2.1 or Table 2.2 as measured using Cu Kα. radiation.
The solid state form of any one of claims 17-19, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 12.0 ± 0.2° 2θ, 19.3 ± 0.2° 2θ, and 25.1 ± 0.2° 2θ as measured using Cu Kα. radiation.
The solid state form of any one of claims 17-20, wherein the X-ray powder diffraction (XRPD) pattern further comprises peaks at 23.3 ± 0.2° 2θ, 25.7± 0.2° 2θ, and 29.4 ± 0.2° 2θ as measured using Cu Kα. radiation.
The solid state form of any one of claims 17-21, wherein the X-ray powder diffraction (XRPD) pattern further comprises peaks at 10.8 ± 0.2° 2θ, 21.1 ± 0.2° 2θ, and 21.9 ± 0.2° 2θ as measured using Cu Kα. radiation.
The solid state form of any one of claims 17-22, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 10.8 ± 0.2° 2θ, 12.0 ± 0.2° 2θ, 19.3 ± 0.2° 2θ, 21.1 ± 0.2° 2θ, 21.9 ± 0.2° 2θ, 23.3 ± 0.2° 2θ, 25.1 ± 0.2° 2θ, 25.7± 0.2° 2θ, and 29.4 ± 0.2° 2θ as measured using Cu Kα. radiation.
The solid state form of any one of claims 16-23, wherein the mole ratio of Compound 1 to fumaric acid is about 1: 1.
The solid state form of claim 15, wherein the solid state form is crystalline Compound 1 succinic acid adduct Type A.
The solid state form of claim 25, wherein the crystalline form is Compound 1 succinic acid adduct characterized as having at least one of the following properties:

(a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 4A as measured using Cu Kα. radiation;

(b) an X-Ray powder diffraction (XRPD) pattern with peaks at 12.2 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, and 25.9 ± 0.2° 2θ as measured using Cu Kα. radiation;

(c) a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown in FIG. 4B;

(d) a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as shown in FIG. 4C;

(e) combinations thereof.
The solid state form of claim 26, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 4A as measured using Cu Kα. radiation.
The solid state form of claim 26 or 27, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with one or more peaks found in Table 3.1 or Table 3.2 as measured using Cu Kα. radiation.
The solid state form of any one of claims 26-28, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 12.2 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, and 25.9 ± 0.2° 2θ as measured using Cu Kα. radiation.
The solid state form of any one of claims 26-29, wherein the X-ray powder diffraction (XRPD) pattern further comprises peaks at 16.1 ± 0.2° 2θ, 19.5 ± 0.2° 2θ, and 22.0 ± 0.2° 2θ as measured using Cu Kα. radiation.
The solid state form of any one of claims 26-30, wherein the X-ray powder diffraction (XRPD) pattern further comprises peaks at 17.5 ± 0.2° 2θ, 18.9 ± 0.2° 2θ, and 21.3 ± 0.2° 2θ as measured using Cu Kα. radiation.
The solid state form of any one of claims 26-31, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 12.2 ± 0.2° 2θ, 16.1 ± 0.2° 2θ, 17.5 ± 0.2° 2θ, 18.9 ± 0.2° 2θ, 19.5 ± 0.2° 2θ, 21.3 ± 0.2° 2θ, 22.0 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, and 25.9 ± 0.2° 2θ as measured using Cu Kα. radiation.
The solid state form of any one of claims 25-32, wherein the mole ratio of Compound 1 to succinic acid is about 1: 1.
The solid state form of claim 15, wherein the solid state form is crystalline Compound 1 p-toluenesulfonate adduct Type A.
The solid state form of claim 34, wherein the crystalline form is Compound 1 p-toluenesulfonate adduct characterized as having at least one of the following properties:

(f) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 5A as measured using Cu Kα. radiation;

(g) an X-Ray powder diffraction (XRPD) pattern with peaks at 7.5 ± 0.2° 2θ, 18.7 ± 0.2° 2θ, and 23.1 ± 0.2° 2θ as measured using Cu Kα. radiation;

(h) a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown in FIG. 5B;

(i) a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as shown in FIG. 5C; or

(j) combinations thereof.
The solid state form of claim 35, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 5A as measured using Cu Kα. radiation.
The solid state form of claim 35 or 36, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with one or more peaks found in Table 4.1 or Table 4.2 as measured using Cu Kα. radiation.
The solid state form any one of claims 35-37, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 7.5 ± 0.2° 2θ, 18.7 ± 0.2° 2θ, and 23.1 ± 0.2° 2θ as measured using Cu Kα. radiation.
The solid state form of any one of claims 35-38, wherein the X-ray powder diffraction (XRPD) pattern further comprises peaks at 14.2 ± 0.2° 2θ, 20.2 ± 0.2° 2θ, and 21.5 ± 0.2° 2θ as measured using Cu Kα. radiation.
The solid state form of any one of claims 35-39, wherein the X-ray powder diffraction (XRPD) pattern further comprises peaks at 11.2 ± 0.2° 2θ, 23.8 ± 0.2° 2θ, and 26.2 ± 0.2° 2θ as measured using Cu Kα. radiation.
The solid state form of any one of claims 35-40, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 7.5 ± 0.2° 2θ, 11.2 ± 0.2° 2θ, 14.2 ± 0.2° 2θ, 18.7 ± 0.2° 2θ, 20.2 ± 0.2° 2θ, 21.5 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, 23.8 ± 0.2° 2θ and 26.2 ± 0.2° 2θ as measured using Cu Kα. radiation.
The solid state form of any one of claims 34-41, wherein the mole ratio of Compound 1 to p-toluenesulfonate is about 1: 1.
A pharmaceutical composition comprising a solid state form of any one of claims 1-42 and a pharmaceutically acceptable excipient.
A method of treating a disease or disorder in a subject, the method comprising administering to the subject a solid state form of any one of claims 1-42, or a pharmaceutical composition of claim 43, wherein the disease or disorder is cancer or neoplastic disease.