阅读说明：本技术 固体形式的brd4抑制剂化合物及其制备方法与应用 (Solid BRD4 inhibitor compound and preparation method and application thereof ) 是由 沈春莉 刘勇 卞桓钰 吴成德 吴家虎 于 2020-03-23 设计创作，主要内容包括：一种作为BRD4抑制剂的式(1)所示化合物的固体形式、晶型及其制备方法,以及其在制备治疗BRD4相关疾病药物中的应用。(I)(A solid form and a crystal form of a compound shown as a formula (1) as a BRD4 inhibitor, a preparation method thereof, and application thereof in preparing medicines for treating BRD4 related diseases. (I))

A compound of formula (I) in solid form,

the compound of formula (I) in solid form according to claim 1, in crystalline form.

The compound of formula (I) in solid form according to claim 2, which is form a of compound of formula (I) having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 7.03 +/-0.2 degrees, 11.28 +/-0.2 degrees, 14.00 +/-0.2 degrees;

alternatively, the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 7.03 +/-0.2 degrees, 11.28 +/-0.2 degrees, 20.07 +/-0.2 degrees;

alternatively, the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 7.03 +/-0.2 degrees, 19.48 +/-0.2 degrees, 20.07 +/-0.2 degrees, 26.05 +/-0.2 degrees;

alternatively, the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 7.03 +/-0.2 degrees, 11.28 +/-0.2 degrees, 17.31 +/-0.2 degrees, 19.48 +/-0.2 degrees, 20.07 +/-0.2 degrees, 26.05 +/-0.2 degrees;

alternatively, the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 7.03 +/-0.2 degrees, 11.28 +/-0.2 degrees, 14.00 +/-0.2 degrees, 15.11 +/-0.2 degrees, 17.31 +/-0.2 degrees, 19.48 +/-0.2 degrees, 20.07 +/-0.2 degrees, 26.05 +/-0.2 degrees;

alternatively, the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 7.03 +/-0.2 degrees, 11.28 +/-0.2 degrees, 12.39 +/-0.2 degrees, 14.00 +/-0.2 degrees, 15.11 +/-0.2 degrees, 17.31 +/-0.2 degrees, 19.48 +/-0.2 degrees, 20.07 +/-0.2 degrees, 22.86 +/-0.2 degrees, 26.05 +/-0.2 degrees;

alternatively, the XRPD pattern is substantially as shown in figure 1.

A compound of formula (I) in solid form according to claim 3 having a differential scanning calorimetry curve which shows the onset of an endothermic peak at 289.22 ± 3 ℃.

The compound of formula (I) in solid form according to claim 4, having a DSC profile substantially as shown in figure 2.

The compound of formula (I) in solid form according to claim 3, having a thermogravimetric analysis curve with a weight loss of up to 1.626% at 300.00 ± 3 ℃.

The compound of formula (I) in solid form according to claim 6 having a TGA profile substantially as shown in figure 3.

The compound of formula (I) in solid form according to claim 2, in form B of formula (I) having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 5.50 +/-0.2 degrees, 8.36 +/-0.2 degrees, 11.87 +/-0.2 degrees;

alternatively, the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 5.50 plus or minus 0.2 degrees, 8.36 plus or minus 0.2 degrees, 12.66 plus or minus 0.2 degrees;

alternatively, the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 5.50 +/-0.2 degrees, 8.36 +/-0.2 degrees, 11.87 +/-0.2 degrees, 12.39 +/-0.2 degrees, 12.66 +/-0.2 degrees, 15.11 +/-0.2 degrees, 17.35 +/-0.2 degrees, 18.70 +/-0.2 degrees;

alternatively, the XRPD pattern is substantially as shown in figure 4.

A process for the preparation of a compound of formula (I) according to claim 3 in solid form, comprising:

(1) adding a compound shown as a formula (I) into a solvent to form a suspension or a solution;

preferably, the solvent is selected from C_1-4alkyl-O-C_1-4Alkyl radical, C_1-4Alkyl C (═ O) OC_1-4Alkyl radical, C_1-4alkyl-CN, C_1-4alkyl-OH or C_1-4Alkyl C (═ O) C_1-4A single solvent for the alkyl group; further preferably, the single solvent is methyl tert-butyl ether, ethyl acetate, acetonitrile, ethanol, acetone, methanol or methyl ethyl ketone;

alternatively, preferably, the solvent is C_1-4Alkyl C (═ O) C_1-4Alkyl and water, or C_1-4A mixed solvent of alkyl-OH and water; further preferably, said C_1-4Alkyl C (═ O) C_1-4In a mixed solvent of an alkyl group and water, C_{1- 4}Alkyl C (═ O) C_1-4The volume ratio of alkyl to water is 1-5: 1, preferably 2: 1; said C is_1-4In a mixed solvent of alkyl-OH and water, C_1-4The volume ratio of alkyl-OH to water is 1-5: 1, preferably 3: 1; further preferably, the mixed solvent is a mixed solvent composed of acetone and water, or ethanol and water; further preferably, the mixed solvent is acetone-water with a volume ratio of 2:1, or ethanol-water with a volume ratio of 3: 1;

or preferably, the weight-volume ratio of the compound to the solvent is 1g: 5-15 mL, preferably 1g: 5-12 mL;

(2) placing the suspension or the solution in a constant-temperature mixing instrument, stirring, separating and drying to obtain a crystal form A of the compound shown in the formula (I);

preferably, the stirring temperature is 25-45 ℃;

or preferably, the stirring time is 12 hours to 50 hours, preferably 12 hours to 48 hours;

or preferably, the separation in step (2) is centrifugation or filtration; further preferably, the separation in step (2) is centrifugation.

A process for the preparation of a compound of formula (I) according to claim 8 in solid form, comprising:

(1) adding a compound shown as a formula (I) into tetrahydrofuran to form a suspension or a solution; preferably, the weight-volume ratio of the compound to tetrahydrofuran is 1g:5-10 mL;

(2) placing the suspension or the solution in a constant-temperature mixing instrument, stirring, separating and drying to obtain a B crystal form of the compound shown in the formula (I); preferably, the stirring temperature is 25-45 ℃;

or preferably, the stirring time is 12 hours to 50 hours, preferably 12 hours to 48 hours;

or preferably, the separation in step (2) is centrifugation or filtration;

further preferably, the separation in step (2) is centrifugation.

A pharmaceutical composition comprising a compound of formula (I) or a crystalline mixture of any two or more thereof, in solid form according to any one of claims 1 to 8.

Use of a compound of formula (I) in solid form according to any one of claims 1 to 8 or a pharmaceutical composition according to claim 11 for the manufacture of a medicament for the treatment of a BRD 4-related disorder;

preferably, the BRD 4-related disorder includes a neoplastic disease;

more preferably, the tumors include hematological tumors and advanced solid tumors, wherein hematological tumors include leukemia, lymphoma, and myeloma, and advanced solid tumors include neuroblastoma, glioma, breast cancer, gastrointestinal tumor, and prostate cancer;

further preferably, the leukemia is acute lymphoblastic leukemia, or the lymphoma is acute myeloid lymphoma;

further preferably, the breast cancer is triple negative breast cancer, or the gastrointestinal tumor is colorectal cancer.