RU2792005C2 - Crystalline forms of the tlr7/tlr8 inhibitor - Google Patents

Abstract

FIELD: crystalline form of the compound.

SUBSTANCE: invention relates to a method for obtaining a crystalline form of the compound ( S ) -N- (4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4 ,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide, comprising the steps: a) suspension of the amorphous free form (S)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6 ,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide in a solvent mixture containing acetone, ethanol, methanol , isopropanol, isobutanol, tetrahydrofuran or acetonitrile and at least 2% by weight of water, to form a mixture in suspension, b) heating the mixture in suspension until dissolved to form a solution, c) cooling the solution to -10° C. to form a slurry, d) filtering the slurry to collect the crystalline form, wherein the compound is a hemiheptahydrate, the crystalline form is in free form and is characterized by one of the following: (i) an X-ray powder diffraction pattern containing characteristic peaks expressed as 2θ , at a value of °2θ , which is 6.6± 0.2, value °2θ , which is 16.0± 0.2 and a value of °2θ , which is 17.3± 0.2 measured at a temperature of approximately 25°Cand at an X-ray wavelength,λ , which is 1.5418

; (ii) an X-ray powder diffraction pattern containing four or more values of 2θ , selected from the group consisting of values °2θ , constituting 6.6±0.2°, 7.1±0.2°, 10.6±0.2°, 13.2±0.2°, 14.3±0.2°, 16.0±0.2°, 17.3±0.2°, 23.5±0.2°, 26.5±0.2° and 27.3±0.2° measured at a temperature of approximately 25°Cand at an X-ray wavelength, λ , which is 1.5418Å; and (iii) an X-ray powder diffraction pattern containing five or more values of 2θ , selected from the group consisting of values °2θ , constituting 6.6±0.2°, 7.1±0.2°, 10.6±0.2°, 13.2±0.2°, 14.3±0.2°, 16.0±0.2°, 17.3±0.2°, 23.5±0.2°, 26.5±0.2° and 27.3±0.2, measured at a temperature of approximately 25°C and at an X-ray wavelength,λ , which is 1.5418Å .The new method for obtaining a crystalline form (S) -N- (4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl- 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide, which is applicable in treatment of various autoimmune disease states associated with the activity of an endosomal Toll-like receptor selected from TLR7 and TLR8. The solid form of the active pharmaceutical ingredient (API) of a particular drug is often an important determinant of ease of formulation, hygroscopicity, stability, solubility, storage stability, ease of formulation, dissolution rate in gastrointestinal fluids, and in vivo bioavailability.

EFFECT: new method for obtaining a crystalline form has been developed.

3 cl, 6 dwg, 2 tbl, 2 ex

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

The present invention relates generally to the crystalline forms of ( S ) -N- (4-((5-(1,6-dimethyl- 1H -pyrazolo[3,4-b]pyridin-4-yl)-3-methyl- 4,5,6,7-tetrahydro- 1H -pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide. The present invention also generally relates to a pharmaceutical composition containing crystalline forms, as well as to methods of obtaining and methods of using crystalline forms in the treatment of specific autoimmune diseases associated with the activity of an endosomal Toll-like receptor selected from TLR7 and TLR8, and to methods for obtaining such crystalline forms.

BACKGROUND OF THE INVENTION

( S ) -N- (4-((5-(1,6-Dimethyl- 1H -pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7- tetrahydro- 1H- pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide was first disclosed as the HCl salt in WO2018/047081 , filed September 6, 2017, which is incorporated by reference in its entirety, and is a dual inhibitor of TLR7 and TLR8, characterized by the structure of formula I:

The compound of formula I is useful in the treatment of various autoimmune disease states associated with the activity of an endosomal Toll-like receptor selected from TLR7 and TLR8. Thus, a compound of formula I is therefore useful in the treatment of certain autoimmune diseases, including, for example, systemic lupus erythematosus, cutaneous lupus, discoid lupus, mixed connective tissue disease, primary biliary cirrhosis, immune thrombocytopenic purpura, suppurative hydradenitis, dermatomyositis , polymyositis, Sjögren's syndrome, arthritis, rheumatoid arthritis or psoriasis.

The solid form of the active pharmaceutical ingredient (API) of a particular drug is often an important determinant of ease of formulation, hygroscopicity, stability, solubility, storage stability, ease of formulation, dissolution rate in gastrointestinal fluids, and in vivo bioavailability. Crystal forms are observed when a substance of a similar composition crystallizes in different structural lattices, resulting in different thermodynamic properties and types of stability characteristic of a particular crystalline form. Crystalline forms may also include various hydrates or solvates of the same compound. In deciding which shape is preferred, a number of shape properties are compared and the preferred shape is selected based on a variety of variable physical properties. It is possible that one form may be preferred in some circumstances where certain aspects such as ease of preparation, stability, etc. are considered critical. In other situations, a different form may be preferred due to a faster dissolution rate and/or better bioavailability. It is not yet possible to predict whether a particular compound or salt of a compound will form polymorphs, whether any such polymorphs will be suitable for commercial use in a therapeutic composition, or which polymorphs will exhibit such desired properties.

SHORT DESCRIPTION

The present invention contemplates the crystalline forms of ( S ) -N- (4-((5-(1,6-dimethyl- 1H -pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4, 5,6,7-tetrahydro- 1H -pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide in free form (i.e., e. in non-salt form). In a specific embodiment, the free form further comprises water (referred to herein as a hydrate).

Thus, the present invention provides a crystalline form of ( S ) -N- (4-((5-(1,6-dimethyl- 1H -pyrazolo[3,4-b]pyridin-4-yl)-3-methyl -4,5,6,7-tetrahydro-1 H -pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide in free form .

The present invention further provides a crystalline form of ( S ) -N- (4-((5-(1,6-dimethyl- 1H -pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-) hydrate 4,5,6,7-tetrahydro- 1H -pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide.

Embodiments of such crystalline forms include those referred to herein as form A and form H _A . The names used herein to identify a particular form, such as "Form A" or "Form H _A ," should not be construed as limiting to any other substance having similar or identical physical and chemical characteristics, on the contrary, it should be understood that such designations are merely identifiers and should be interpreted in accordance with the performance information also provided in this document.

BRIEF DESCRIPTION OF GRAPHICS

In FIG. 1 shows an exemplary XRPD spectrum for the free form of a compound of formula I, herein designated form A, with the x-axis showing 2θ (2-theta) and the y-axis showing relative intensity.

In FIG. 2 shows exemplary DSC results for the free form of a compound of Formula I, herein designated Form A.

In FIG. 3 shows exemplary TGA results for the free form of a compound of formula I, herein designated Form A.

In FIG. 4 is an exemplary XRPD spectrum for the hydrated form of a compound of formula I, herein designated H _A form, with the x-axis showing 2θ (2-theta) and the y-axis showing relative intensity.

In FIG. 5 shows exemplary DSC results for the hydrated form of the compound of formula I, referred to herein as the H _A form.

In FIG. 6 shows illustrative TGA results for the hydrated form of the compound of formula I, referred to herein as form H _A .

More detailed listings of the XRPD peaks for each of Forms A and H _A are presented in Tables 1 and 2, respectively, below, which also show % relative intensity (I/I ₀ ×100) values. It should be understood that there is natural variability in powder x-ray diffraction spectra or powder x-ray diffraction patterns with respect to values measured in degrees 2θ (°2θ) as a result of, for example, instrument error (including differences between instruments). In this regard, it should be understood that there is a °2θ variability of up to ±0.2 in XRPD peak measurements, and yet such peak values will also be considered representative of the particular solid form of the crystalline materials described herein. It should also be understood that other measured values from XRPD experiments and DSC/TGA experiments, such as relative intensity and water content, may vary as a result of, for example, sample preparation and/or storage conditions and/or environment, and the measured values will also be considered specific to the particular solid form of the crystalline materials described herein.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the free-form crystalline form of ( S ) -N- (4-((5-(1,6-dimethyl- 1H- pyrazolo[3,4-b]pyridin-4-yl)-3-methyl- 4,5,6,7-tetrahydro-1 H -pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide (compounds of formula I ), which is described and whose properties are defined in this document.

The present invention also relates to the crystalline form of the hydrate ( S ) -N- (4-((5-(1,6-dimethyl-1 H -pyrazolo[3,4-b]pyridin-4-yl)-3-methyl- 4,5,6,7-tetrahydro- 1H -pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide. More specifically, the present invention relates to the crystalline form of ( S ) -N- (4-((5-(1,6-dimethyl- 1H -pyrazolo[3,4-b]pyridin-4-yl)-3- methyl-4,5,6,7-tetrahydro-1 H -pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide, which described and whose properties are defined in this document.

In one embodiment, the present invention provides a free-form crystalline form of ( S ) -N- (4-((5-(1,6-dimethyl- 1H -pyrazolo[3,4-b]pyridin-4-yl)- 3-methyl-4,5,6,7-tetrahydro-1 H -pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide (Form A) characterized by an X-ray powder diffraction (XRPD) pattern containing a characteristic peak expressed in °2θ at a °2θ value of 18.6 ± 0.2, measured at a temperature of approximately 25°C. In another embodiment, the XRPD pattern further comprises one or more additional exemplary peaks at values selected from a °2θ value of 4.1 ± 0.2 and a °2θ value of 16.3 ± 0.2. In one aspect of the previous embodiment, the XRPD pattern further comprises one or more additional characteristic peaks at values selected from a °2θ value of 18.2 ± 0.2 and a °2θ value of 19.8 ± 0.2 measured at temperature of approximately 25°C. Accordingly, an XRPD diffraction pattern for a crystalline form of the free form of a compound of formula I may contain one, two, three, or four characteristic peaks at values selected from a °2θ value of 18.6 ± 0.2, a °2θ value of 4.1 ± 0.2, °2θ values of 16.3 ± 0.2, °2θ values of 18.2 ± 0.2, and °2θ values of 19.8 ± 0.2, measured at a temperature of approximately 25°C. In another embodiment, the crystalline form of the free form of the compound of formula I is characterized by an XRPD pattern, which may additionally contain one or more additional characteristic peaks at values selected from a °2θ value of 8.2 ± 0.2, a °2θ value of 15, 2 ± 0.2 and a °2θ value of 16.9 ± 0.2, measured at a temperature of approximately 25°C. Thus, an XRPD diffraction pattern for a crystalline form of the free form of a compound of formula I may contain one, two, three, four, five, or six characteristic peaks at values selected from a °2θ value of 18.6 ± 0.2, a °2θ value, of 4.1 ± 0.2, °2θ values of 16.3 ± 0.2, °2θ values of 18.2 ± 0.2, °2θ values of 19.8 ± 0.2, °2θ values of 2θ value of 8.2 ± 0.2, °2θ value of 15.2 ± 0.2, and °2θ value of 16.9 ± 0.2 measured at a temperature of approximately 25°C. An XRPD diffraction pattern for a crystalline form of the free form of a compound of formula I may contain one, two, three, four, five, or six characteristic peaks selected from the peaks disclosed in Table 1 and measured at a temperature of approximately 25°C.

), выбранных из группы, состоящей из значений 4,1±0,2°, 8,2±0,2°, 15,2 ± 0,2°, 16,3 ± 0,2°, 16,9 ± 0,2°, 18,2 ± 0,2°, 18,6 ± 0,2°, 19,8 ± 0,2°и 20,4 ± 0,2°, измеренных при температуре, составляющей приблизительно 25°C.In another aspect of the above embodiment, the crystalline form of the free form of the compound of formula I is characterized by an X-ray powder diffraction pattern containing four or more 2θ values (CuKα λ=1.54184

) selected from the group consisting of values 4.1±0.2°, 8.2±0.2°, 15.2±0.2°, 16.3±0.2°, 16.9±0 .2°, 18.2 ± 0.2°, 18.6 ± 0.2°, 19.8 ± 0.2° and 20.4 ± 0.2° measured at approximately 25°C.

), выбранных из группы, состоящей из значений 4,1 ± 0,2°, 8,2 ± 0,2°, 15,2 ± 0,2°, 16,3 ± 0,2°, 16,9 ± 0,2°, 18,2 ± 0,2°, 18,6 ± 0,2°, 19,8 ± 0,2°и 20,4 ± 0,2°, измеренных при температуре, составляющей приблизительно 25°C.In another aspect of the above embodiment, the free-form crystalline form of the compound of formula I is characterized by an X-ray powder diffraction pattern containing five or more 2θ values (CuKα λ=1.54184

) selected from the group consisting of values 4.1 ± 0.2°, 8.2 ± 0.2°, 15.2 ± 0.2°, 16.3 ± 0.2°, 16.9 ± 0 .2°, 18.2 ± 0.2°, 18.6 ± 0.2°, 19.8 ± 0.2° and 20.4 ± 0.2° measured at approximately 25°C.

In yet another aspect of the above embodiment, the free form crystalline form of the compound of formula I has an XRPD pattern that is essentially as shown in FIG. 1. It should be understood that the water content of form A can range from about 0% to about 1.5%, and is still considered to be a crystalline form characterized by an XRPD pattern containing one, two, three, four, five, or six the characteristic peaks described above or in Table 1. The water content determined using the Karl Fischer titration method for form A is 0.9%.

Properties of the free form crystal form ( S ) -N- (4-((5-(1,6-dimethyl- 1H -pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5 ,6,7-tetrahydro- 1H -pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide can be determined by thermal analysis . In one embodiment, the crystalline form of the free form of the compound of formula I is characterized by a thermal profile measured using differential scanning calorimetry (DSC) with a heating rate of 10°C/min, containing a single endothermic peak that begins at approximately 182.7°C, with an enthalpy ΔH 65 J/g.

In another embodiment, the free form crystalline form of the compound of formula I has a DSC thermogram that is essentially as shown in FIG. 2. It should be understood that different thermograms (in terms of peak shape and profile) may be obtained for hydrated forms depending on the parameters of the instrument, thus a similar substance may have thermograms that look essentially different from each other if the data is obtained on two different devices.

In another embodiment, the free-form crystalline form of the compound of formula I is characterized by a thermogravimetric analysis (TGA) chart that is essentially as shown in FIG. 3. Weight loss with TGA is approximately 0.4% at 182°C.

In yet another embodiment, crystalline form A is essentially a pure phase.

In another embodiment, the present invention relates to a process for the preparation of crystalline form A of the compound ( S ) -N- (4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl )-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholin-3- carboxamide, wherein said method includes the steps

a) suspending the amorphous free form (S)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4.5 ,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide in acetone or isopropanol to form a mixture in in the form of a suspension

b) heating the slurry mixture to a temperature of approximately 50°C, until dissolved to form a solution,

c) cooling the solution to approx. 15°C for a period of approximately 4 hours, with the formation of a mixture in the form of a suspension,

d) optionally repeating steps b) and c) once or twice,

e) heating the slurry mixture to approximately 50°C and adding dropwise heptane,

f) stirring the mixture at 50°C for approx. 1 hour,

g) cooling the solution to approximately 15°C for a period of approximately 4 hours, with the formation of a mixture in the form of a suspension,

h) stirring the mixture in the form of suspension at 15°C for 1 hour and

i) filtering the suspension to collect crystalline Form A.

The present invention further provides a crystalline form of ( S ) -N- (4-((5-(1,6-dimethyl- 1H -pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-) hydrate 4,5,6,7-tetrahydro- 1H -pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide (form H _A ) characterized by an X-ray powder diffraction (XRPD) pattern containing a characteristic peak expressed in °2θ at a °2θ value of 14.3 ± 0.2, measured at a temperature of approximately 25°C. In another embodiment, the XRPD pattern further comprises one or more additional characteristic peaks at values selected from a °2θ value of 6.6 ± 0.2, a °2θ value of 16.0 ± 0.2, and a °2θ value, of 17.3 ± 0.2, measured at a temperature of approximately 25°C.

Alternatively, an XRPD pattern for a crystalline form of said hydrate of a compound of formula I may contain one, two, three, or four characteristic peaks at values selected from a °2θ value of 14.3 ± 0.2, a °2θ value of 6, 6 ± 0.2, a °2θ value of 16.0 ± 0.2, and a °2θ value of 17.3 ± 0.2, measured at a temperature of approximately 25°C.

In another embodiment, the crystalline form of said hydrate of the compound of formula I is characterized by an XRPD pattern which may further contain one or more additional characteristic peaks at values selected from a °2θ value of 23.5 ± 0.2, a °2θ value of 26, 5 ± 0.2, °2θ value of 27.3 ± 0.2. Thus, an XRPD pattern for a crystalline form of said hydrate of a compound of formula I may contain one, two, three, four, five, or six characteristic peaks at values selected from a °2θ value of 14.3 ± 0.2, a °2θ value, of 6.6 ± 0.2, °2θ values of 16.0 ± 0.2, °2θ values of 17.3 ± 0.2, °2θ values of 23.5 ± 0.2, °2θ values of 2θ of 26.5 ± 0.2 and °2θ of 27.3 ± 0.2 or selected from the peaks disclosed in Table 2 measured at a temperature of approximately 25°C.

), выбранных из группы, состоящей из значений °2θ, составляющих 6,6 ± 0,2°, 7,1 ± 0,2°, 10,6 ± 0,2°, 13,2 ± 0,2°, 14,3 ± 0,2°, 16,0 ± 0,2°, 17,3 ± 0,2°, 23,5 ± 0,2°, 26,5 ± 0,2° и 27,3 ± 0,2°, измеренных при температуре, составляющей приблизительно 25°C.In another embodiment, said hydrate form is characterized by an X-ray powder diffraction pattern containing four or more 2θ values (CuKα λ=1.54184

) selected from the group consisting of °2θ values of 6.6 ± 0.2°, 7.1 ± 0.2°, 10.6 ± 0.2°, 13.2 ± 0.2°, 14 .3 ± 0.2°, 16.0 ± 0.2°, 17.3 ± 0.2°, 23.5 ± 0.2°, 26.5 ± 0.2° and 27.3 ± 0, 2° measured at a temperature of approximately 25°C.

), выбранных из группы, состоящей из значений °2θ, составляющих 6,6 ± 0,2°, 7,1 ± 0,2°, 10,6 ± 0,2°, 13,2 ± 0,2°, 14,3 ± 0,2°, 16,0 ± 0,2°, 17,3 ± 0,2°, 23,5 ± 0,2°, 26,5 ± 0,2° и 27,3 ± 0,2°, измеренных при температуре, составляющей приблизительно 25°C.In another embodiment, said hydrate form is characterized by an X-ray powder diffraction pattern containing five or more 2θ values (CuKα λ=1.54184

) selected from the group consisting of °2θ values of 6.6 ± 0.2°, 7.1 ± 0.2°, 10.6 ± 0.2°, 13.2 ± 0.2°, 14 .3 ± 0.2°, 16.0 ± 0.2°, 17.3 ± 0.2°, 23.5 ± 0.2°, 26.5 ± 0.2° and 27.3 ± 0, 2° measured at a temperature of approximately 25°C.

In another embodiment, the crystalline form of the hydrate of the compound of formula I is characterized by an XRPD pattern that is essentially as shown in FIG. 4. It should be understood that the water content of the _HA form can range from about 9% to about 12% and is still considered to be a hydrate characterized by an XRPD pattern containing one, two, three, four, five, or six characteristic peaks. described above. The water content, determined using the Karl Fischer titration method, for form H _A is 10.6%.

Properties of the crystalline form of the hydrate ( S ) - N - (4- ((5- (1,6-dimethyl-1 H -pyrazolo[3,4-b] pyridin-4-yl) -3-methyl-4,5, 6,7-tetrahydro- 1H- pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide can be determined by thermal analysis. In one embodiment, the crystalline form of a hydrate of a compound of formula I is characterized by a differential thermogravimetry profile containing an endothermic peak that starts at about 54.2° C., with an ΔH enthalpy of 284 J/g (corresponding to dehydration) and an endothermic peak that starts at about 130 ,6°C, with an enthalpy ΔH of 24 J/g (corresponding to melting).

In another embodiment, the crystalline form of the hydrate of the compound of formula I is characterized by a DSC thermogram that is essentially as shown in FIG. 5. It should be understood that different thermograms (in terms of peak shape and profile) may be obtained for hydrated forms depending on the parameters of the instrument, thus a similar substance may have thermograms that look essentially different from each other if the data is obtained on two different devices.

In another embodiment, the crystalline form of the hydrate of the compound of formula I is characterized by a thermogravimetric analysis (TGA) diagram that is essentially as shown in FIG. 6. Weight loss with TGA is approximately 9.9% at 96°C.

In yet another embodiment, the crystalline form of H _A described above is the hemiheptahydrate form.

In yet another embodiment, the _HA crystalline form is essentially a pure phase.

In yet another embodiment, the present invention relates to a process for preparing the crystalline form H _A of the compound ( S ) -N- (4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4- yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholin-3 -carboxamide, wherein said method includes the steps

a) suspending the amorphous free form (S)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4.5 ,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide in a solvent mixture containing at least about 2% by weight of water, to form a mixture in suspension,

b) heating the slurry mixture to a certain temperature until dissolved to form a solution,

c) cooling the solution to approx. -10°C with the formation of a suspension,

d) filtering the suspension to collect the crystalline form of H _A .

In a specific aspect of the above embodiment, the present invention relates to a process for preparing crystalline Form A, wherein the solvent mixture in step a) contains acetone, alcohol, tetrahydrofuran or acetonitrile.

In yet another aspect of the previous embodiment, the present invention relates to a process for preparing crystalline Form A, wherein the solvent mixture in step a) is selected from acetone/water 98:2 (w/w) and isopropanol/water 95:5 (w/w). ).

In another embodiment, the present invention relates to a pharmaceutical composition containing a therapeutically effective amount of a crystalline form (S)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholin-3-carboxamide (Form A or Form H_Aor their combinations) and at least one pharmaceutically acceptable carrier, diluent or excipient. In a specific embodiment, the present invention relates to a pharmaceutical composition containing crystalline form A and one or more pharmaceutically acceptable carriers, diluents or excipients. In another aspect, the present invention relates to a pharmaceutical composition containing the crystalline Form A in a substantially pure phase. In yet another embodiment, the present invention relates to a pharmaceutical composition containing crystalline form A and additionally containing at least one other solid form 5(S)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide. In one aspect of this embodiment, the other solid form is the crystalline form H_A. In another embodiment, the other solid form is an amorphous form (S)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide.

In a particular embodiment, the present invention relates to a pharmaceutical composition comprising a crystalline form of _HA and one or more pharmaceutically acceptable carriers, diluents or excipients. In yet another aspect, the present invention relates to a pharmaceutical composition containing a crystalline form of _HA in a substantially pure phase. In yet another embodiment, the present invention relates to a pharmaceutical composition comprising a crystalline form of H _A and further comprising at least one other solid form of 5( S ) -N- (4-((5-(1,6-dimethyl-1 H -pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1 H -pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo [2.2.2]octan-1-yl)morpholine-3-carboxamide. In one aspect of this embodiment, the other solid form is the crystalline form A. In yet another embodiment, the other solid form is the amorphous form ( S ) -N- (4-((5-(1,6-dimethyl-1 H- pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1 H -pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[ 2.2.2]octan-1-yl)morpholine-3-carboxamide.

In other embodiments, the present invention relates to combinations, in particular pharmaceutical combinations, containing a therapeutically effective amount of the crystalline form ( S ) -N -(4-((5-(1,6-dimethyl-1 H -pyrazolo[3,4- b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1 H -pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octane- 1-yl)morpholine-3-carboxamide (Form A, Form H _A , or combinations thereof) and one or more therapeutic agents.

In a specific embodiment, the present invention relates to a pharmaceutical combination containing crystalline Form A and one or more therapeutic agents. In another aspect, the present invention relates to a pharmaceutical combination containing the crystalline Form A in essentially pure phase and one or more therapeutic agents. In another embodiment, the present invention relates to a pharmaceutical combination containing crystalline form A and additionally containing at least one other solid form 5( S ) -N -(4-((5-(1,6-dimethyl-1 H - pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1 H -pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[ 2.2.2]octan-1-yl)morpholine-3-carboxamide. In one aspect of this embodiment, the other solid form is the _HA crystalline form. In yet another embodiment, the other solid form is the amorphous form ( S ) -N- (4-((5-(1,6-dimethyl- 1H- pyrazolo[3,4-b]pyridin-4-yl)- 3-methyl-4,5,6,7-tetrahydro-1 H -pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide .

In a specific embodiment, the present invention relates to a pharmaceutical combination containing a crystalline form of _HA and one or more therapeutic agents. In yet another aspect, the present invention provides a pharmaceutical combination comprising a crystalline form of _HA in substantially pure phase and one or more therapeutic agents. In yet another embodiment, the present invention relates to a pharmaceutical combination containing a crystalline form of H _A and additionally containing at least one other solid form of 5( S ) - N - (4- ((5- (1,6-dimethyl-1 H -pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1 H -pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo [2.2.2]octan-1-yl)morpholine-3-carboxamide. In one aspect of this embodiment, the other solid form is the crystalline form A. In yet another embodiment, the other solid form is the amorphous form ( S ) -N- (4-((5-(1,6-dimethyl-1 H- pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1 H -pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[ 2.2.2]octan-1-yl)morpholine-3-carboxamide.

In another embodiment, the present invention provides the pharmaceutical combinations described above, wherein the second agent is independently selected from the group consisting of anti-inflammatory agents, immunomodulatory agents, immunosuppressive agents, cytokines, nonsteroidal anti-inflammatory drugs (NSAIDs), antimalarial compounds, antirheumatic compounds, inhibitors B-cell activating factor (BAFF), inhibitors of B-lymphocyte stimulator (BLyS) and steroid hormones.

In one embodiment, the present invention relates to a method of treating an autoimmune disease in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of the crystalline form ( S ) -N- (4-((5-(1 ,6-dimethyl-1 H -pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1 H -pyrazolo[4,3-c]pyridine- 1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide (Form A, Form H _A or combinations thereof) alone or in combination with one or more therapeutic agents.

In another embodiment, the present invention relates to a method of treating an autoimmune disease in a subject in need thereof, comprising administering to said subject a pharmaceutical composition as described above, alone or in combination with one or more therapeutic agents.

In another embodiment, the present invention relates to a method of treating an autoimmune disease in a subject in need thereof, comprising administering to said subject a pharmaceutical combination as described above.

In one embodiment, the present invention relates to the use of the crystalline form ( S ) -N- (4-((5-(1,6-dimethyl-1 H -pyrazolo[3,4-b]pyridin-4-yl)-3 -methyl-4,5,6,7-tetrahydro-1 H -pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide ( Form A, Form H _A , or combinations thereof) alone or in combination with one or more therapeutic agents for the treatment of an autoimmune disease.

In yet another embodiment, the present invention relates to the crystalline form of ( S ) -N- (4-((5-(1,6-dimethyl-1 H -pyrazolo[3,4-b]pyridin-4-yl)-3 -methyl-4,5,6,7-tetrahydro-1 H -pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide ( form A, form H _A , or combinations thereof) for use in the treatment of an autoimmune disease.

In another embodiment, the present invention relates to a combination of the crystalline form ( S ) -N- (4-((5-(1,6-dimethyl-1 H -pyrazolo[3,4-b]pyridin-4-yl)- 3-methyl-4,5,6,7-tetrahydro-1 H -pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide (Form A, Form H _A , or combinations thereof) and one or more therapeutic agents for use in the treatment of an autoimmune disease.

In one embodiment, the present invention relates to a method of treatment, use, compound for use, or combination of uses described above, wherein the autoimmune disease is associated with the activity of an endosomal Toll-like receptor selected from TLR7 and TLR8. In one aspect of this embodiment, the autoimmune disease associated with endosomal Toll-like receptor activity selected from TLR7 and TLR8 is selected from systemic lupus erythematosus, cutaneous lupus, discoid lupus, mixed connective tissue disease, primary biliary cirrhosis, immune thrombocytopenic purpura, suppurative hidradenitis, dermatomyositis, polymyositis, Sjögren's syndrome, arthritis, rheumatoid arthritis and psoriasis.

In one embodiment, the present invention relates to a method, use, or combination for use according to the above embodiment, wherein the therapeutic agent is co-administered in one composition or administered separately in two or more different composition forms.

In one embodiment, the present invention relates to a method, use, or combination of uses described above, wherein the therapeutic agent is administered concurrently with the crystalline form of ( S ) -N- (4-((5-(1,6-dimethyl-1 H- pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1 H -pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[ 2.2.2]octan-1-yl)morpholine-3-carboxamide, before or after it.

The crystalline forms described herein have been found to have advantageous properties. The selection criteria are toxicological factors, crystallinity, melting point, hygroscopicity, bulk stability, compatibility with excipients, aqueous pH, solubility in water and aqueous media, morphology, handling and polymorphic behavior. The free form A and the hydrated form _HA showed better behaviors, in particular compared to the HCl salt which was previously known and described in WO2018/047081. The HCl salt was found to be hygroscopic above 70% RH and also had potential corrosivity.

Crystal form A is the anhydrous form ( S ) -N- (4-((5-(1,6-dimethyl- 1H -pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4 ,5,6,7-tetrahydro-1 H -pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide, which is a highly crystalline a substance consisting of thin lamellar particles. It is slightly hygroscopic at no more than 70%RH with an absorption of 1.3% moisture, however at higher humidity values (i.e. above 70%RH) it hydrates to the _HA crystalline form.

The crystalline form of _HA is the hydrated form of ( S ) -N- (4-((5-(1,6-dimethyl- 1H -pyrazolo[3,4-b]pyridin-4-yl)-3-methyl- 4,5,6,7-tetrahydro- 1H -pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide. TGA and DVS data indicate that it is a hemiheptahydrate. The crystalline form of H _A is slightly hygroscopic at humidity values above 30%RH. Below 20%RH, it dehydrates to form an uncharacterized anhydrate form, which rehydrates back to the hydrated form _HA once the humidity reaches 30%RH.

Solvent stability

Conducted competitive equilibrium tests to investigate the relative stability of Forms A and H_A in experiments on the competitive establishment of equilibrium in the solvent. 1:1 mix of form A and form H_A obtained and suspended in various solvents or their mixtures at temperatures from 25°C to 50°C for seven days. The resulting suspension was filtered and analyzed by XRPD/DVS. Competitive equilibration experiments and data indicate that there is a conversion of form A to form H_A at low water content. The results demonstrated that the conversion of Form A to Form H_A occurs when water activity is approximately a_w=0.25.

Solid state stability in bulk and with mixtures of excipients

Form A and form H _A were studied for stability and compatibility with the excipient. Both forms were subjected to various test conditions, described below.

Bulk test conditions: 1 week in sealed container at 80°C 50°C 80°C-75%RH or 50^oC-75%RH.

Test conditions with mixtures of excipients (EM):

a. 1% form A or form H_A in EM1 for 2 weeks at 50°C;

b. 1% form A or form H_A in EM2 for 2 weeks at 50°C;

c. 10% form A or form H_A crushed hard gelatin capsule (HGC) for 2 weeks at 50°C;

d. 10% form A or form H_A in crushed hydroxypropyl methylcellulose (HMPC) for 2 weeks at 50°C;

e. 1% form A or form H_A in EM1 for 2 weeks at 50°C and 75%RH;

f. 1% form A or form H_A in EM2 for 2 weeks at 50°C and 75%RH;

g. 10% form A or form H_A in crushed HGC for 2 weeks at 50°C and 75%RH;

h. 10% form A or form H_A in crushed HMPC for 2 weeks at 50°C and 75%RH.

EM1: Excipient Blend 1: Spray-dried lactose (53%), microcrystalline cellulose (MCC) PH102 (40%), crospovidone XL (5%), Aerosil (0.5%), magnesium stearate (1.5%).

EM2: Excipient Blend 2: DC Mannitol (68%), MCC PH102 (26%), Ac-Di-Sol (4%), Aerosil (0.5%), Magnesium Stearate (1.5%).

Breakdown products were analyzed by HPLC and the sample was analyzed by XPRD to detect any change in solid state.

Under the test conditions described above, both Form A and Form H _A showed good stability in bulk and with excipients.

Optional both form A and form H_A showed good physical and chemical stability under exposure to light (exposure to 1200 klux at 25°C).

Physical stability

Press behavior . The physical stability of each crystalline form (Form A or Form H _A ) was also evaluated.

100 mg of the crystalline form was pressed for 5 minutes at 10 tons using a hydraulic press (tablet diameter 8 mm). Sample properties were then determined using XRPD to detect any change in the solid state.

No crystal form change was observed for crystal form A and crystal form H _A by XRPD. Thus, the crystalline forms A and H _A have been shown to have good physical stability properties.

Behavior when experimenting with granulation simulation. Physical stability of crystalline forms A and H_A also evaluated in granulation simulation experiments. In such experiments, to the crystalline form A or H_A granulation solvent was added dropwise until the solid was sufficiently moistened. The mixture was then vortexed between each addition at 25°C. Alternatively, dry grinding was carried out. The crystallinity of the material (after milling) was reassessed by XRPD and/or DSC. Under dry milling conditions, no shape change was found after milling the crystalline form H_A. In granulation using ethanol and water as the granulation solvent, the XRPD results also showed no shape change.

Modification A was also stable under dry grinding conditions, but partially changed during granulation with water into the crystalline form H _A .

Solubility

Form A is highly soluble at pH values of 4.7 and below (solubility above 2 mg/ml), however, at higher pH levels, formation of the less soluble form _HA results in lower solubility values.

Form H _A exhibits a solubility in aqueous buffers in appropriate biological media of approximately 0.004 mg/mL.

In conclusion, the crystalline form of _HA has shown chemical and physical stability in both dissolved and solid states, but exhibits lower solubility. The _HA crystalline form is stable over a wide range of humidity values and is highly crystalline. Crystal form A is a highly crystalline and anhydrous form. It has been shown to be chemically and physically stable in the solid state, but converts to form H _A in a low water solvent. Form A is more soluble.

DEFINITION

As used herein, the terms "approximately" and "substantially" indicate, with respect to features such as endotherms, endothermic peak, exotherms, baseline shifts, etc., that that their values may change. With respect to the position of X-ray diffraction peaks, "approximately" or "essentially" means that the typical variability in peak position and intensity is taken into account. For example, one skilled in the art will appreciate that peak positions (2θ) will exhibit some variability between devices, typically up to 0.2°. Sometimes the variability can be more than 0.2° depending on differences in device calibration. In addition, one skilled in the art will appreciate that relative peak intensity values will exhibit some variability between devices as well as variability due to degree of crystallinity, preferred orientation obtained by the sample surface, and other factors known to those skilled in the art, and should be considered. only as a quality measure. For DSC, the change in observed temperatures will depend on the rate of temperature change, as well as the method of obtaining the sample and the specific instrument used. Thus, the endotherm/melting point values reported herein for DSC/TGA thermograms may vary by ±2°C (and are also considered to be representative of the particular crystal form described herein). When used in the context of other indications, such as, for example, percentage by weight (% by weight), the term "about" indicates a change of ± 3%.

As used herein, the term "polymorph" refers to crystalline forms having a similar chemical composition but different spatial arrangements of the molecules, atoms and/or ions that form the crystal.

As used herein, the term "amorphous" refers to the solid form of a molecule, atom, and/or ions that is not crystalline. Amorphous solids do not show a definite x-ray diffraction pattern.

As used herein, "substantially pure phase", when used in relation to any crystalline form of a compound of Formula I, means a compound having a phase purity of greater than about 90% by weight, including greater than about 90.91. 92, 93, 94, 95, 96, 97, 98 and about 99% by weight, and also including equal to about 100% by weight of the compound of formula I, based on the weight of the compound on an anhydrous basis. The term "pure phase" or "phase purity" as used herein refers to the homogeneity of the phase with respect to a particular solid form of a compound of Formula I and does not necessarily imply a high degree of chemical purity unless explicitly stated to do so. Phase purity can be determined according to methods known in the art, for example using XRPD, to perform quantitative phase analysis using one or more approaches known in the art, for example using an external standard method, direct comparisons of linear ( peak) characteristics that refer to different phases in specific spectra, or using an internal standard method. However, quantification of phase purity by XRPD can be complicated by the presence of amorphous material. Accordingly, other methods that can be used to determine the purity of the phase include, for example, solid state NMR spectroscopy, Raman spectroscopy and/or infrared spectroscopy. One skilled in the art will readily understand such methods and how to use such additional (or alternative) methods to determine phase purity.

As used herein, "substantially chemically pure", when used in relation to any crystalline form of a compound of formula I, means a compound having a chemical purity of greater than about 90% by weight, including greater than about 90, 91, 92, 93, 94, 95, 96, 97, 98 and about 99% by weight, and also including equal to about 100% by weight of the compound of formula I, based on the weight of the salt (on an anhydrous basis). The remaining material generally contains other compounds, such as, for example, other stereoisomers of the compound of formula I, impurities resulting from the reaction, starting materials, reagents, by-products and/or other impurities resulting from processing, resulting from the preparation, and /or isolation and/or purification of a specific crystalline form. For example, a crystalline form of a compound of formula I may be considered to be substantially chemically pure if it has been determined to have a chemical purity of greater than about 90% by weight, as measured by standard and conventional methods known in the art, where the remainder is less than about 10% by weight are other substances, such as other stereoisomers of the compound of formula I, impurities resulting from the reaction, starting materials, reagents, by-products and/or impurities resulting from processing. Chemical purity can be determined according to methods known in the art, such as high performance liquid chromatography (HPLC), LC-MS (liquid chromatography with mass spectrometry), nuclear magnetic resonance (NMR) spectroscopy, or infrared spectroscopy. One of skill in the art will readily understand such methods and how to use such additional (or alternative) methods to determine chemical purity.

The term "therapeutically effective amount" of a compound of the present invention refers to an amount of a compound of the present invention that will elicit a biological or medical response in a subject, such as reducing or inhibiting enzyme or protein activity, or lessening the severity of symptoms, alleviating conditions, or slowing or arresting the progression of diseases, etc. In one non-limiting embodiment, the term "therapeutically effective amount" refers to the amount of a compound of the present invention, which, when administered to a subject, is effective in relation to (1) at least partially alleviate, suppress and/or reduce the severity of the condition, or a disorder or disease (i) associated with TLR7 and/or TLR8 activity or (ii) characterized by activity (normal or abnormal) of TLR7 and/or TLR8 receptors; or (2) reducing or suppressing the activity of TLR7 and/or TLR8 receptors. In another non-limiting embodiment, the term "therapeutically effective amount" refers to the amount of a compound of the present invention which, when administered to a cell or tissue or non-cellular biological material or medium, is effective to at least partially reduce or suppress TLR7 activity and/ or TLR8 or at least partially reduce or suppress the expression of TLR7 and/or TLR8 receptors.

As used herein, the term "subject" refers to an animal. Preferably the animal is a mammal. The subject refers to, for example, primates (eg, humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In a preferred embodiment, the subject is a human.

As used herein, terms in the singular form and similar terms used in the context of the present invention (in particular, in the context of the claims) should be construed as covering both the singular and plural forms, unless otherwise indicated in this document. or there is no apparent contradiction in context.

All of the methods described herein may be performed in any suitable order unless otherwise indicated herein or otherwise expressly conflicted by context. Use of all possible examples or illustrative style of presentation (for example, "such as") provided herein is only intended to better illuminate the present invention and is not intended to limit the scope of the present invention as otherwise claimed.

As used herein, the terms "suppress", "inhibit", or "suppressive" means a reduction or amelioration of a given condition, symptom, or disorder, or disease, or a significant reduction in baseline activity in relation to a biological activity or process.

As used herein, the terms "treat," "treat," or "treat" any disease or disorder, in one embodiment, refer to reducing the severity of the disease or disorder (i.e., slowing, or stopping, or reducing the development of a disease or at least one of its clinical symptoms). In another embodiment, "treat", "treating", or "treatment" refers to alleviating or reducing the severity of at least one physical parameter, including those that may not be apparent to the patient. In yet another embodiment, "treating", "administering treatment", or "treatment" refers to modulating a disease or disorder in a physical way (e.g., by stabilizing an overt symptom) or physiologically (for example, by stabilizing a physical parameter) or by using both. In one embodiment, "treat" or "treatment" refers to delaying the progression of a disease or disorder.

As used herein, the term "prevent", "prevent" or "prevention" of any disease or disorder means prophylactically treating the disease or disorder or delaying the onset of the disease or disorder.

The term "autoimmune disease" or "autoimmune disorder" as used herein refers to diseases where cells uncontrollably attack the body's own tissues and organs (autoimmune response), causing inflammatory reactions and other serious symptoms and diseases. Non-limiting examples of autoimmune diseases include idiopathic thrombocytopenic purpura, hemolytic anemia, systemic lupus erythematosus, cutaneous lupus, discoid lupus, rheumatoid arthritis (RA), multiple sclerosis (MS), systemic sclerosis, immune-mediated or type 1 diabetes mellitus, immune-mediated glomerulonephritis, scleroderma , pernicious anemia, alopecia, pemphigus, pemphigus vulgaris, myasthenia gravis, inflammatory bowel disease, Crohn's disease, Graves' disease, psoriasis, autoimmune thyroid disease, Hashimoto's disease, Hashimoto's thyroiditis, polymyositis, dermatomyositis, CREST syndrome, Goodpasture's syndrome, mixed disease connective tissue, pseudoparalytic myasthenia gravis, sympathetic ophthalmia, phacogenic uveitis, chronic aggressive hepatitis, primary biliary cirrhosis, autoimmune hemolytic anemia, Werlhof's disease, vitiligo vulgaris, Behcet's disease, collagen disease, uveitis, III syndrome egrena, autoimmune myocarditis, autoimmune liver disease, autoimmune gastritis, pemphigus, Guillain-Barré syndrome, atherosclerosis, inflammatory bowel disease, ankylosing spondylitis, idiopathic thrombocytopenia, polyarteritis nodosa, primary biliary sclerosis, sarcoidosis, sclerosing cholangitis, granulomatous arteritis, Takayasu's arteritis Wegener and HTLV-1-associated myelopathy.

As used herein, the term "combination" refers to either a fixed combination in a single unit dosage form or combination administration, where the crystalline form of a compound of Formula I and the combination partner (i.e., the immunotherapeutic agent) can be administered independently in the same at the same time or separately at intervals, in particular when these intervals allow the partners in the combination to demonstrate a cooperative, for example, synergistic effect. The individual components may be packaged in a kit or placed separately. One or both components (eg, powders or liquids) may be reconstituted or diluted to the desired dose prior to administration.

The terms "co-administration" or "combination administration" or the like, as used herein, are understood to encompass the administration of a selected combination partner to a single subject in need (e.g., a patient) and is intended to include treatment regimens in which the agents are optionally administered by the same route of administration or at the same time.

As used herein, the terms "pharmaceutical combination" and "combination product" are used interchangeably and refer to either a fixed combination in a single unit dosage form, or a non-fixed combination or set of parts for combined administration, where two or more therapeutic agents can be administered independently in at the same time or separately within time intervals, in particular when such time intervals allow the cooperative, eg synergistic, effect of the combination partners to be demonstrated. The term "fixed combination" means that both the crystalline form of the compound of formula I and the combination partner (ie, the immunotherapeutic agent) are administered to the patient simultaneously in the form of a single entity or dose. The term "non-fixed combination" means that both the crystalline form of the compound of formula I and the combination partner (i.e., the immunotherapeutic agent) are administered to the patient as separate entities, either simultaneously, in parallel, or sequentially without specific time limits, such administration provides effective therapeutic levels of the two compounds in the patient's body. The latter also applies to "cocktail therapy", for example, the administration of three or more therapeutic agents. In a preferred embodiment, the pharmaceutical combination is a non-fixed combination.

The term "combination therapy" refers to the administration of two or more therapeutic agents for the treatment of an autoimmune disorder described in the present invention. Such administration encompasses the co-administration of these therapeutic agents substantially simultaneously, for example in a single capsule having a fixed ratio of active ingredients. Alternatively, such administration encompasses co-administration in multiple or separate containers (eg tablets, capsules, powders and liquids) for each active ingredient. Powders and/or liquids may be reconstituted or diluted to the desired dose prior to administration. In addition, such administration also encompasses the use of each type of therapeutic agent in a sequential manner, either at approximately the same time or at different times. In any event, the treatment regimen will provide the beneficial effects of the combination of drugs in the treatment of the conditions or disorders described herein.

Pharmaceutical composition, combination, dosage and administration

In some embodiments, the crystalline forms of ( S ) -N- (4-((5-(1,6-dimethyl- 1H -pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4, 5,6,7-tetrahydro-1 H -pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide described herein, may be used alone or they may be formulated into a pharmaceutical composition which also contains at least one pharmaceutically acceptable excipient and often contains at least two or more pharmaceutically acceptable excipients. Some suitable excipients are disclosed in this document. Other adjuvants that are known in the art may be used without departing from the spirit and scope of this application.

In some embodiments, the present invention employs a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient. The pharmaceutical composition may be formulated for specific administration routes such as oral administration, parenteral administration and rectal administration, etc. In addition, the pharmaceutical compositions of the present invention may be prepared in solid form (including, without limitation, capsules, tablets, pills). , granules, powders or suppositories) or in liquid form (including, without limitation, solutions, suspensions or emulsions). Pharmaceutical compositions may be subjected to conventional pharmaceutical processing steps such as sterilization and/or may contain conventional inert diluents, lubricants, carriers or buffers, as well as adjuvants such as diluents, preservatives, stabilizers, wetting agents, emulsifiers and bulking agents. funds, etc.

As a rule, pharmaceutical compositions are tablets or capsules containing the active ingredient together with at least one excipient, for example:

a) diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine;

b) lubricants, for example silica, talc, stearic acid, its magnesium or calcium salt and/or polyethylene glycol; in the case of tablets also with

c) binders, for example, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if necessary;

d) carriers such as an aqueous carrier medium containing a co-solvent such as captisol, PEG, glycerol, cyclodextrin or the like;

e) disintegrators, for example starches, agar, alginic acid or its sodium salt or effervescent mixtures; and/or

f) absorbents, colorants, flavors and sweeteners.

Tablets can be either film-coated or enteric-coated according to methods known in the art.

Preferably, the compound or composition is prepared for oral administration, eg in the form of a tablet or eg a capsule, and is optionally packaged in a multi-dose form suitable for storing and/or dispensing single doses of a pharmaceutical product. Examples of suitable packaging include, but are not limited to, sealed foils, single dose containers (eg, vials), blister packs, and blister packs.

The tablets may contain the active ingredient in admixture with non-toxic, pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. Such excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch or alginic acid; binders, for example starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. The tablets are uncoated or coated by known techniques to slow down disintegration and absorption in the gastrointestinal tract and thereby provide sustained action over a longer period. For example, a delayed release material such as glyceryl monostearate or glyceryl distearate may be used. Formulations for oral administration may be presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules where the active ingredient is mixed with water or an oily vehicle, for example , with peanut butter, liquid paraffin or olive oil.

The present invention further provides anhydrous pharmaceutical compositions and dosage forms containing the compounds of the present invention as active ingredients, since water may assist in the degradation of some compounds.

Anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low moisture ingredients and low moisture or low humidity conditions. The anhydrous pharmaceutical composition can be prepared and stored in such a way that its anhydrous nature is maintained. Accordingly, anhydrous compositions are preferably packaged using materials known to prevent exposure to water so that they can be included in suitable formulation kits. Examples of suitable packaging include, but are not limited to, sealed foils, plastic materials, single dose containers (e.g. vials), blister packs and contour packs.

The present invention further provides pharmaceutical compositions and dosage forms that contain one or more agents that reduce the rate at which the compound of the present invention as an active ingredient will degrade. Such agents, which are referred to herein as "stabilizers", include, without limitation, antioxidants such as ascorbic acid, pH buffers or saline buffers, and the like.

The pharmaceutical composition or combination of the present invention may be presented in a single dosage of about 1-1000 mg of the active ingredient(s) for a subject weighing about 50-70 kg, or about 1-500 mg, or about 1-250 mg , or about 1-150 mg, or about 0.5-100 mg, or about 1-50 mg of the active ingredients. A therapeutically effective dose of a compound, pharmaceutical composition, or combinations thereof will depend upon the type of subject, body weight, age, and individual condition, disorder, or disease being treated, or their severity. A skilled physician, clinician or veterinarian can easily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progression of the disorder or disease.

The above dosage parameters are evident in the testsin vitroAndin vivousing predominantly mammals, for example, mice, rats, dogs, non-human apes or isolated organs, tissues and preparations thereof. The compounds of the present invention can be usedin vitroin the form of solutions, for example, preferably aqueous solutions, andin vivoeither enterally or parenterally, preferably intravenously, for example, in the form of a suspension or aqueous solution. Dosein vitromay range in molar concentration from about 10^-3 mol/l up to 10^-9 mol/l. Therapeutically effective amountin vivo depending on the route of administration may be in the range of about 0.1-500 mg/kg or about 1-100 mg/kg.

In other embodiments, a pharmaceutical composition is provided that contains at least one compound according to the embodiments above and at least one carrier.

Crystal forms ( S ) -N- (4-((5-(1,6-dimethyl- 1H -pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6, 7-tetrahydro-1 H -pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide described herein are also applicable in as active pharmaceutical ingredients (API), as well as materials for the preparation of compositions that include one or more pharmaceutically acceptable excipients and are suitable for administration to human subjects.

As used herein, the term "pharmaceutically acceptable excipients" includes any and all solvents, carriers, diluents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterials, antifungals, antioxidants), isotonic agents. absorption delaying agents, salts, drug stabilizers, binders, additives, bulking agents, disintegrating agents, lubricants, sweeteners, flavoring agents, coloring agents, and the like. and combinations thereof, which will be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). It should be understood that if the conventional excipient is incompatible with the active ingredient, then this application contemplates the use of any conventional excipient in any therapeutic or pharmaceutical compositions.

Accordingly, in one embodiment, the present invention provides a crystalline form of ( S ) -N- (4-((5-(1,6-dimethyl-1 H -pyrazolo[3,4-b]pyridin-4-yl)-3 -methyl-4,5,6,7-tetrahydro-1 H -pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide ( form A or form H _A ) in the form of a substantially pure phase. This crystalline form is ( S ) -N- (4-((5-(1,6-dimethyl- 1H -pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6 ,7-tetrahydro-1 H -pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide (form A or form H _A ) in form essentially pure phase can be used to obtain pharmaceutical compositions, which may additionally contain one or more pharmaceutically acceptable excipients. In some embodiments, the crystalline form of ( S ) -N- (4-((5-(1,6-dimethyl- 1H -pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4, 5,6,7-tetrahydro-1 H -pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide may not retain its crystallinity in pharmaceutical composition. For example, in some embodiments, the implementation of the crystalline Form A or H _A can be used in a method for obtaining a pharmaceutical composition, which, for example, includes spray drying or wet granulation; thus, it is possible that a small amount of crystalline form A or H _A will be detected in the resulting pharmaceutical composition or it will not be detected.

Therapy kits

In one embodiment, the present invention provides a kit containing two or more separate pharmaceutical compositions, at least one of which contains the crystalline form of the compounds of formula (I) (Form A or Form H _A ). In one embodiment, the kit contains means for keeping said compositions separate, such as a container, a split bottle, or a split foil pouch. An example of such a kit is a blister pack, typically used for packaging tablets, capsules, and the like.

The kit of the present invention can be used to administer various dosage forms, for example, for oral and parenteral use, to administer individual compositions at different intervals between doses, or to titrate individual compositions against one another. In order to facilitate adherence to a treatment regimen, the kit of the present invention typically contains instructions for administration.

In the combination therapies of the present invention, the crystalline form of the compound of formula (I) (i.e. Form A or Form H_A) and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Moreover, a crystalline form of a compound of formula (I) and another therapeutic agent can be combined in a combination therapy: (i) before the combination product reaches physicians (e.g., in the case of a kit containing a crystalline form of a compound of formula (I) and another therapeutic agent); (ii) by physicians themselves (or under the supervision of a physician) shortly before administration; (iii) in the patients themselves, for example, during sequential administration of a crystalline form of a compound of formula (I) and another therapeutic agent.

Accordingly, the present invention contemplates the use of the crystalline form described herein (ie Form A or Form H _A ) for the treatment of autoimmune diseases wherein the drug is formulated to be administered with another therapeutic agent. The present invention also contemplates the use of a therapeutic agent for the treatment of autoimmune diseases, wherein the drug is administered with a crystalline form of the compound of formula (I).

The present invention also provides a crystalline form of a compound of formula (I) (ie Form A or Form _HA ) for use in a method of treating autoimmune diseases, wherein the crystalline form of a compound of formula (I) is prepared for administration with another therapeutic agent. The present invention also provides another immunotherapeutic agent for use in a method of treating autoimmune diseases, wherein the other therapeutic agent is formulated to be administered with a crystalline form of a compound of formula (I). The present invention also provides a crystalline form of the compound of formula (I) for use in a method of treating autoimmune diseases, wherein the crystalline form of the compound of formula (I) is administered with another therapeutic agent. The present invention also provides another therapeutic agent for use in a method of treating autoimmune diseases, wherein the other therapeutic agent is administered with a crystalline form of a compound of formula (I).

The present invention also contemplates the use of a crystalline form of a compound of formula (I) for the treatment of autoimmune diseases where the patient has previously (e.g., within 24 hours) was treated with another therapeutic agent. The present invention also contemplates the use of another therapeutic agent for the treatment of autoimmune diseases where the patient has previously (for example, within 24 hours) was treated with a crystalline form of the compound of formula (I).

Combination

Additional therapeutic agents used in combination with the crystalline form of the present invention include, without limitation, anti-inflammatory agents, immunomodulatory agents, immunosuppressive agents, cytokines, non-steroidal anti-inflammatory drugs (NSAIDs), antimalarial compounds, antirheumatic compounds, inhibitors of B-cell activating factor (BAFF ), B-lymphocyte stimulator (BLyS) inhibitors, and steroid hormones.

Non-steroidal anti-inflammatory drugs (NSAIDs) used in combination with the compounds of the present invention include, but are not limited to, salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin, sulindac, etodolac, mefenamic acid, meclofenamate sodium, tolmetin, ketorolac, diclofenac, ibuprofen, naproxen, naproxen sodium, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam, tenoxicam, nabumetone, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, apazone and nimesulide.

The antirheumatic compound used in combination with the compounds of the present invention includes, without limitation, methotrexate.

The antimalarial compound used in combination with the compounds of the present invention includes, without limitation, chloroquine and hydroxychloroquine.

B-cell activating factor (BAFF) inhibitors, also known as B-lymphocyte stimulator (BLyS) inhibitors, used in combination with the compounds of the present invention include, but are not limited to, belimumab (Benlysta®), blisibimod, and BR3-Fc.

Immunosuppressive agents useful in combination with the compounds of the present invention include, but are not limited to, mycophenolate mofetil (MMF), mycophenolic acid, cyclophosphamide, azathioprine, and laquinimod (5-chloro-N-ethyl-4-hydroxy-1-methyl-2-oxo- N-phenyl-1,2-dihydroquinoline-3-carboxamide).

Steroid hormones used in combination with the compounds of the present invention include, without limitation, dehydroepiandrosterone (DHEA).

Preparation of the crystalline form ( S ) -N- (4-((5-(1,6-dimethyl-1 H -pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6 ,7-tetrahydro-1 H -pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide

Crystalline forms can be obtained by various methods, including, for example, crystallization or recrystallization from a suitable solvent, sublimation, melt growth, solid state transformation from another phase, crystallization from a supercritical fluid, and jet spraying. Methods for crystallizing or recrystallizing crystalline forms from a solvent mixture include, for example, evaporating the solvent, lowering the temperature of the solvent mixture, seeding crystals with a supersaturated solution of a molecule and/or salt in the solvent mixture, freeze-drying the solvent mixture, and adding anti-solvents (anti-solvents) to the solvent mixture. Exemplary methods for preparing the crystalline forms described herein are detailed below.

Drug crystals, including polymorphs, methods for preparing and characterizing drug crystals are reviewed in Solid-State Chemistry of Drugs , SR Byrn, RR Pfeiffer, and JG Stowell, ^2nd Edition, SSCI, West Lafayette, Indiana (1999).

In the case of crystallization procedures that use solvents, the choice of solvent or solvents generally depends on one or more factors such as the solubility of the compound, the crystallization procedure, and the vapor pressure of the solvent. Combinations of solvents may be used, for example, the compound may be solubilized in a first solvent to form a solution, followed by the addition of an anti-solvent to reduce the compound's solubility in the solution to allow crystals to form. An antisolvent is a solvent in which the compound has low solubility.

In one method of obtaining crystals, the compound is suspended and/or stirred in a suitable solvent to form a slurry which can be heated to induce dissolution. Used in this document, the term "slurry" means a saturated solution of the compounds, which may also contain additional compounds to obtain a heterogeneous mixture of compound and solvent at a given temperature. This may also be referred to as a suspension.

Seed crystals can be added to any crystallization mixture to promote crystallization. Seeding can be used to control the growth of a particular polymorph or to control the particle size distribution of the crystalline product. Accordingly, the calculation of the required amount of seed crystals depends on the seed crystal size available and the average particle size of the product required, as described, for example, in "Programmed Cooling of Batch Crystallizers," JW Mullin and J. Nyvlt, Chemical Engineering Science, 1971,26, 369 -377. Typically, small seed crystals are needed to effectively control the growth of crystals in a batch. A small seed crystal can be obtained by sieving, grinding, or micronizing large crystals, or by microcrystallizing solutions. Care should be taken that milling or micronizing the crystals does not result in any change in the crystal form of the desired crystal shape (ie, change to an amorphous state or another polymorph).

The cooled crystallization mixture can be filtered under vacuum and the isolated solids can be washed with a suitable solvent such as cold recrystallization solvent and dried under a nitrogen purge to obtain the desired crystalline form. The isolated solids can be analyzed using a suitable spectroscopic or analytical technique, such as solid state nuclear magnetic resonance, differential scanning calorimetry, powder x-ray diffraction, or the like, to ensure the formation of the preferred crystalline form of the product. Typically, the resulting crystalline form is obtained in an amount corresponding to a practical yield of more than about 70 wt. %, preferably a practical yield of more than 90 wt. %, based on the weight of the compound originally used in the crystallization procedure. The product can be co-milled or passed through a sieve to remove lumps of product if necessary.

Alternatively, crystalline forms can be obtained directly from the reaction medium from the final preparation of ( S ) -N- (4-((5-(1,6-dimethyl- 1H -pyrazolo[3,4-b]pyridine-4 -yl)-3-methyl-4,5,6,7-tetrahydro-1 H -pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine -3-carboxamide. This can be achieved, for example, by using at the end of the process a solvent or mixture of solvents from which ( S ) -N- (4-((5-(1,6-dimethyl- 1H -pyrazolo[3,4 -b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1 H -pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octane -1-yl)morpholine-3-carboxamide. In addition, crystalline forms can be obtained by distillation or solvent addition techniques.

In addition to the methods briefly discussed below, it should be understood that various analytical methods can be used to characterize any of the substances described herein.

The following non-limiting examples illustrate the present invention.

EXAMPLES

Reduction:

DIPEA: N,N-Diisopropylethylamine

HATU: O-(7-Azobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

DCM: Dichloromethane

THF: Tetrahydrofuran

Example 1 Preparation of Crystal Form A

(S)-4-(tert-Butoxycarbonyl)morpholine-3-carboxylic acid (637 g, 2.75 mol) was dissolved in THF (1.1 L), DIPEA (508 g, 3.9 mol) was added, HATU ( 1097 g, 2.9 mol) and 4-((5-(1,6-dimethyl-1 H -pyrazolo[3,4- b ]pyridin-4-yl)-3-methyl-4,5,6, 7-tetrahydro- 1H- pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octane-1-amine ( 1a , 1.1 kg, 2.6 mol, as described in WO 2018/047081), the mixture was stirred until the yellow suspension turned into a yellow solution for 16 h, HPLC indicated that the reaction was complete, the mixture was quenched with water (7.4 kg), extracted with DCM (14.6 kg), layer based on DCM was washed with 0.5 M HCl solution (5.5 kg, with complete removal of DIPEA) and sat. NaCl solution (5.5 kg), the DCM-based layer was separated.

Water (5.3 kg) and 31% HCl solution (1.2 kg) were added to this DCM-based layer. The mixture was stirred at 35°C for 16 h, HPLC indicated that the deprotection reaction was complete. The reaction mixture was cooled to room temperature, separated and the organic layer was discarded. DCM (14.6 kg) was added to the aqueous phase and 20% NaOH solution (~3.2 kg) was added with stirring until pH >8. The organic layer was separated and washed with 5% NaOH (5.5 kg*2, with complete removal of HPF ₆ ), then washed with water (5.5 kg*3), the organic layer was dried with Mg ₂ SO ₄ and filtered, then concentrated under reduced pressure to give ( S ) -N- (4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4.5 ,6,7-Tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide as free base ( 1b ).

Recrystallization step

The above material ( 1b ) was taken up in acetone (8.7 kg*3) and heated to an internal temperature of 50°C, then cooled to 15°C over a period of 4 hours. The heating/cooling cycle was repeated twice to form a white suspension . The white suspension was heated to 50°C, heptane (15.6 kg) was added dropwise, the suspension was stirred at an internal temperature of 50°C for 1 hour, then cooled to an internal temperature of 15°C over a period of 4 hours. at 15° C. for 1 hour, filtered, washed with acetone/heptane (0.87 kg/1.56 kg) and dried at 50° C. for 16 hours to give 890 g of a white solid. The white solid was analyzed by XRPD, DSC and TGA (FIGS. 1-3, respectively).

Example 2 Preparation of Hydrate Crystalline Form H _A

To a mixture of ( 3S )-4-(tert-butoxycarbonyl)morpholine-3-carboxylic acid (6.06 g, 26.2 mmol) and 4-methylmorpholine (3.62 g, 35.8 mmol) in 125 ml dichloromethane 4-{[5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4] was added ,3-c]pyridin-1-yl]methyl}bicyclo[2.2.2]octan-1-amine ( 1a , 10.0 g, 23.8 mmol, as described in WO 2018/047081) in 25 ml dichloromethane, HATU (10.9 g, 28.6 mmol) was added, then the mixture was stirred at room temperature for 16 hours. After completion of the conversion, the reaction mixture was washed with an aqueous sodium hydroxide solution and an aqueous sodium chloride solution. The separated organic layer was concentrated and treated with a solution of 2-propanol hydrochloride in t -butyl methyl ether. The resulting suspension was filtered and washed with tert -butyl methyl ether and the product, tert -butyl-(3S)-3-[(4-{[5-(1,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-4 -yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl]methyl}bicyclo[2.2.2]octan-1-yl)carbamoyl] morpholine-4-carboxylate ( 2a ) was isolated and dried as the hydrochloride salt.

To the product mixture, tert -butyl-(3S)-3-[(4-{[5-(1,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-methyl- 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl]methyl}bicyclo[2.2.2]octan-1-yl)carbamoyl]morpholine-4-carboxylate ( 2a , 7.56 g, 11.3 mmol), 50 ml of dichloromethane was added to 70 ml of water, then a 31% hydrochloride aqueous solution (4.65 g, 39.5 mmol) was added and the mixture was stirred at 37° C. for 16 hours. After completion of the conversion, the dichloromethane phase was separated and the aqueous layer was washed with t -butyl methyl ether. The pH of the aqueous phase was adjusted to 7-8 with 16% aqueous sodium hydroxide, 25 ml of 2-propanol was added and the pH was further adjusted to 8-9 with 16% aqueous sodium hydroxide. The pH of the mixture was further adjusted to >12 with 16% aqueous sodium hydroxide solution. The resulting suspension was filtered and suspended in 2-propanol/water (70 ml/5 ml), the solid was collected by filtration and washed with water/2-propanol (50 ml/3 ml) and the product, (S) -N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholin-3-carboxamide ( 2b ) was isolated and dried as a free form.

Recrystallization step

( S ) -N- (4-((5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro -1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholin-3-carboxamide ( 2b , described above) was suspended in acetone/water 98: 2 (weight:weight) and heated to 50°C with the dissolution of the entire amount of the substance. After filtration to obtain a clear product, water was added to the solution to obtain a mixture of acetone/water 95:5 (wt:wt). The solution was seeded at 45°C. Then the suspension was cooled to -10°C. The product was isolated and washed with acetone/water 95:5 (w:w), filtered and carefully dried under vacuum.

Drying can also be carried out in the presence of water.

Alternatively, ( S ) -N- (4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6 ,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholin-3-carboxamide ( 2b as described above) was suspended in isopropanol :water 95:5 (w:w) and heated to 50°C to dissolve the entire amount of the substance. After filtration to obtain a clear product, the solution was cooled to 25°C and seeded. Additional water was added and cooled to -10°C. The product was isolated and gently dried under vacuum.

Drying can also be carried out in the presence of water.

Other solvents that can be used in the process described above, which leads to the formation of a hydrate of the crystalline form _HA (always in combination with water), are other alcohols such as ethanol, methanol and isobutanol; THF or acetonitrile.

Powder x-ray diffraction

). Данные собирали для 2-тета 2-40° со временем выдерживания образца по меньшей мере 300 секунд.X-ray powder diffraction (XRPD) data were obtained using a Bruker Discovery D8 with a LynxEye detector. The powder samples were placed on the Si sample holder without background noise. The radiation was Cu Kα (l=1.5418

). Data was collected for 2-theta 2-40° with a sample holding time of at least 300 seconds.

Table 1

Powder X-ray diffraction data for crystalline form A

Corner d value Intensity °2-theta angstrom % 4.06 21.744 38 8.17 10.810 9 15.20 5.823 15 16.33 5.424 48 16.92 5.235 16 18.20 4,871 27 18.67 4,750 100 19.82 4.477 29 20.46 4.338 18 21.61 4.108 25 23.08 3.851 10 24.60 3.616 14 24.43 3.641 14 26.22 3.397 14

table 2

Powder X-ray diffraction data for the crystalline hydrate form H _A

Corner d value Intensity °2-theta angstrom % 6.59 13.412 14 7.12 12.404 3 10.61 8.330 6 13.24 6.682 6 14.28 6.196 100 14.87 5.953 14 15.63 5.666 8 15.99 5.539 23 17.36 5.105 21 18.55 4.781 7 18.87 4,700 15 21.46 4.138 14 22.23 3.996 10 22.84 3,890 10 23.53 3.778 10 25.30 3.517 7 26.47 3.365 8 27.36 3.257 8

Thermal Analysis (TA)

Crystalline forms were analyzed using the Discovery instrument from TA instrument (DSC) and thermogravimetric analysis (TGA): Discovery (DSC) and Discovery (TGA) with aluminum crucible (T150603); heating rate 10°C/min, temperature range: 30-300°C.

DSC

Differential scanning calorimetry was performed for each crystal form using an instrument from TA Instruments, Model Discovery. For each assay, the DSC cell was purged with 50 ml/min of ultrapure nitrogen gas. The instrument was calibrated against high-purity indium. The heating rate was 10°C per minute in the temperature range from 30 to 300°C. The dependence of the heat flux, which was normalized by the weight of the sample, on the measured temperature of the sample was built on the graph. Temperature values are given in degrees Celsius (°C) and enthalpy values are given in Joules per gram (J/g). On the graphs, endothermic peaks are shown in a downward direction. The endothermic melting peak (melting point) was determined from the extrapolated melting onset temperature. The accuracy of the sample temperature measured by this method is approximately ±1°C, and the specific heat of fusion can be measured with a relative error of approximately ±5%.

Exemplary DSC profiles obtained using crystalline forms A and H _A are shown in FIG. 2 and 4, respectively.

Form A: melting endotherm: T _start =182.7 ^° C, ΔH=65 J/g

Form H _A : melting endotherm: T _start =54.2°C with enthalpy ΔH 284 J/g, and T _start =130.6°C with enthalpy ΔH 24 J/g

TGA

The instrument from TGA instruments used for testing crystal forms was a model Q5000 from TA Instruments. 10-20 milligrams of samples were analyzed at a heating rate 10°C/min in the temperature range from 25°C to 300°C at a constant flow of 20 ml/min of ultrapure nitrogen gas. A plot of weight loss versus measured sample temperature was plotted. Temperature values are given in degrees Celsius (°C) and weight loss is given in %.

Exemplary TGA profiles obtained using crystalline Forms A and H _A are shown in FIG. 3 and 6, respectively.

Claims (11)

1. Method for obtaining the crystalline form of the compound ( S ) -N- (4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4, 5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide, comprising the steps a) suspending the amorphous free form (S)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4.5 ,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide in a solvent mixture containing acetone, ethanol , methanol, isopropanol, isobutanol, tetrahydrofuran or acetonitrile and at least 2% by weight of water, to form a mixture in the form of a suspension, b) heating the slurry mixture until dissolved to form a solution, c) cooling the solution to -10°C with the formation of a suspension, d) filtering the suspension to collect the crystalline form, where the compound is a hemiheptahydrate, the crystalline form is in free form and is characterized by one of the following characteristics: (i) an X-ray powder diffraction pattern containing characteristic peaks expressed in 2θ at a °2θ value of 6.6 ± 0.2, a °2θ value of 16.0 ± 0.2 and a °2θ value of 17, 3 ± 0.2, measured at a temperature of approximately 25°C and an X-ray wavelength, λ, of 1.5418

; (ii) an X-ray powder diffraction pattern containing four or more 2θ values selected from the group consisting of °2θ values of 6.6 ± 0.2°, 7.1 ± 0.2°, 10.6 ± 0.2 °, 13.2 ± 0.2°, 14.3 ± 0.2°, 16.0 ± 0.2°, 17.3 ± 0.2°, 23.5 ± 0.2°, 26.5 ± 0.2° and 27.3 ± 0.2° measured at a temperature of approximately 25°C and an X-ray wavelength, λ, of 1.5418

; And (iii) an X-ray powder diffraction pattern containing five or more 2θ values selected from the group consisting of °2θ values of 6.6 ± 0.2°, 7.1 ± 0.2°, 10.6 ± 0.2 °, 13.2 ± 0.2°, 14.3 ± 0.2°, 16.0 ± 0.2°, 17.3 ± 0.2°, 23.5 ± 0.2°, 26.5 ± 0.2° and 27.3 ± 0.2, measured at a temperature of approximately 25°C and an X-ray wavelength, λ, of 1.5418

. 2. The method according to claim 1, wherein the crystalline form has a differential scanning calorimetry (DSC) thermogram obtained by heating from 30 to 300°C at a rate of 10°C per minute, which shows melting endotherms at T _onset = 54.2°C with an enthalpy ΔH of 284 J/g and at T _onset = 130.6°C with an enthalpy of ΔH of 24 J/g. 3. The method according to claim 1 or 2, wherein the crystalline form has a thermogravimetric analysis (TGA) chart obtained by heating from 30 to 300°C at a rate of 10°C per minute, which shows a weight loss of 9.9% at 96°C .

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