# US 12,180,214 B2 · Crystalline forms of (s)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazine-7-yl)ethyl)amino)pyrimidine-5-carbonitrile as inhibitors of phosphatidylinositol-3-kinase

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- Number: US 12,180,214 B2
- Document ID: US12180214B2
- Status: Granted
- Kind: B2
- Application number: 18/150,623
- Filed: 2023-01-05
- Published: 2023-05-18
- Granted: 2024-12-31
- Earliest claimed: 2018-04-20
- Assignees: Hutchison Medipharma Limited
- Applicants: Hutchison Medipharma Limited
- Inventors: Zhenping Wu; Wenji Li; Ling Feng
- Web page: https://patentgrep.com/patent/US12180214B2

## CPC

- A61K 31/506: not condensed and containing further heterocyclic rings
- C07D 487/04: Ortho-condensed systems
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The present invention belongs to the pharmaceutical field, and provides crystalline forms, solvates and the crystalline forms thereof of the compound (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazin-7-yl)ethyl)amino)pyrimidine-5-carbonitrile of the formula shown below, and the pharmaceutical compositions comprising the same as well as the methods of preparing the same and the use thereof.

## Claims

### Claim 1

A crystalline form of (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazin-7-yl)ethyl)amino)pyrimidine-5-carbonitrile of the Formula A:
wherein the crystalline form is Form V; and
wherein crystalline Form V is characterized by an X-ray powder diffractogram comprising characteristic peaks at diffraction angles (°2θ) of 7.3°±0.2°2θ, 11.60±0.2°2θ, 14.60±0.2°2θ, 19.3°±0.2° 2θ, and 23.4°±0.2°2θ.

### Claim 2 (depends on 1)

The crystalline form of claim 1, wherein the crystalline form is further characterized by an X-ray powder diffractogram comprising additional characteristic peaks at diffraction angles (°2θ) of 4.6°±0.2°2θ, 8.9°±0.2°2θ, 13.5°±0.2°2θ, 15.5°±0.2°±2θ, and 18.0°±0.2°2θ.

### Claim 3 (depends on 1)

The crystalline form of claim 1, wherein the crystalline form has less than 40% by weight of other crystalline forms of (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazine-7-yl)ethyl)amino)pyrimidine-5-carbonitrile.

### Claim 4 (depends on 1)

The crystalline form of claim 1, wherein the crystalline form has less than 30% by weight of other crystalline forms of (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazine-7-yl)ethyl)amino)pyrimidine-5-carbonitrile.

### Claim 5 (depends on 1)

The crystalline form of claim 1, wherein the crystalline form has less than 20% by weight of other crystalline forms of (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazine-7-yl)ethyl)amino)pyrimidine-5-carbonitrile.

### Claim 6 (depends on 1)

The crystalline form of claim 1, wherein the crystalline form has less than 10% by weight of other crystalline forms of (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazine-7-yl)ethyl)amino)pyrimidine-5-carbonitrile.

### Claim 7 (depends on 1)

The crystalline form of claim 1, wherein the crystalline form has less than 5% by weight of other crystalline forms of (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazine-7-yl)ethyl)amino)pyrimidine-5-carbonitrile.

### Claim 8 (depends on 1)

The crystalline form of claim 1, wherein the crystalline form has less than 1% by weight of other crystalline forms of (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazine-7-yl)ethyl)amino)pyrimidine-5-carbonitrile.

### Claim 9 (depends on 1)

A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and an effective amount of the crystalline form of claim 1.

### Claim 10 (depends on 1)

A method for inhibiting phosphatidylinositol-3 kinase (PI3K) activity in a subject, wherein the method comprises administering to the subject in need thereof an effective amount of the crystalline form of claim 1.

### Claim 11 (depends on 10)

The method of claim 10, wherein the subject has a disease associated with phosphatidylinositol-3 kinase (PI3K) activity selected from the group consisting of an autoimmune disease, an inflammatory disease, and cancer.

### Claim 12 (depends on 11)

The method of claim 11, wherein the autoimmune disease, inflammatory disease, or cancer is selected from the group consisting of allergic rhinitis, asthma, chronic obstructive pulmonary disease, leukemia, lymphoma, multiple myeloma, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and Waldenstrom's macroglobulinemia.

### Claim 13 (depends on 12)

The method of claim 12, wherein the leukemia is selected from the group consisting of acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and chronic myelogenous leukemia.

### Claim 14 (depends on 12)

The method of claim 12, wherein the lymphoma is selected from the group consisting of B-cell lymphoma, Burkitt lymphoma, follicular lymphoma, Hodgkin's lymphoma, mantle cell lymphoma, marginal zone lymphoma, natural killer (NK) cell lymphoma, non-Hodgkin's lymphoma, small lymphocytic lymphoma, and T-cell lymphoma.

### Claim 15 (depends on 14)

The method of claim 14, wherein the B-cell lymphoma is diffuse large B-cell lymphoma.

### Claim 16 (depends on 11)

The method of claim 11, wherein the cancer is a hematological malignancy.

### Claim 17 (depends on 16)

A process for preparing crystalline Form V of (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazin-7-yl)ethyl)amino)pyrimidine-5-carbonitrile of the Formula A of claim 16:
wherein the process comprises the following steps:
(1) mixing (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazin-7-yl)ethyl)amino)pyrimidine-5-carbonitrile with:
(a) at least one dissolution solvent selected from the group consisting of (i) acetonitrile; (ii) a mixture of acetonitrile and acetic acid; (iii) a mixture of acetonitrile and butanone; (iv) a mixture of acetonitrile and ethanol; (v) a mixture of acetonitrile and ethyl acetate; and (vi) a mixture of acetonitrile and tetrahydrofuran; or
(b) a mixture of acetonitrile and water; and
heating the mixture to reflux, to obtain a solution;
(2) cooling the solution obtained in step (1) above until (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazin-7-yl)ethyl)amino)pyrimidine-5-carbonitrile precipitates;
(3) isolating Form V of (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazin-7-yl)ethyl)amino)pyrimidine-5-carbonitrile of the Formula A; and
(4) optionally drying Form V of (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazin-7-yl)ethyl)amino)pyrimidine-5-carbonitrile of the Formula A obtained in step (3) above.

### Claim 18 (depends on 16)

A process for preparing crystalline Form V of (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazin-7-yl)ethyl)amino)pyrimidine-5-carbonitrile of the Formula A of claim 16:
wherein the process comprises the following steps:
(1) suspending (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazin-7-yl)ethyl)amino)pyrimidine-5-carbonitrile in acetonitrile;
(2) stirring the suspension obtained in step (1) above;
(3) isolating Form V of (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazin-7-yl)ethyl)amino)pyrimidine-5-carbonitrile of the Formula A; and
(4) optionally drying Form V of (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazin-7-yl)ethyl)amino)pyrimidine-5-carbonitrile of the Formula A obtained in step (3) above.