# US 2024/0199622 A1 · Crystal Forms of (S)-4-(8-amino-3-(1-(but-2-ynoyl)-pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-n-(pyridin-2-yl)benzamide

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- Number: US 2024/0199622 A1
- Document ID: US20240199622A1
- Status: Published application
- Kind: A1
- Application number: 18/487,254
- Filed: 2023-10-16
- Published: 2024-06-20
- Earliest claimed: 2015-07-02
- Assignees: Acerta Pharma B.V.
- Applicants: Acerta Pharma B.V.
- Inventors: Fritz Blatter; Tim Ingallinera; Tjeerd Barf; Edwin Aret; Cecile Krejsa; Jerry Evarts
- Web page: https://patentgrep.com/patent/US20240199622A1

## CPC

- C07D 487/04: Ortho-condensed systems
- A61K 31/4985: Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/36: Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 13/08: of the prostate
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/04: Antipruritics
- A61P 17/06: Antipsoriatics
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 31/18: for HIV
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/02: Immunomodulators
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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)
- 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

In some embodiments, the invention relates to crystalline solid forms, including hydrates, polymorphs, and salt forms, of (S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-α]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide. In some embodiments, the invention relates to amorphous solid forms of (S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-α]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide. In some embodiments, the invention also relates to pharmaceutical compositions containing the solid forms, and methods for treating conditions or disorders by administering to a subject a pharmaceutical composition that includes the forms, including pharmaceutical compositions and methods for overcoming the effects of acid reducing agents.

## Claims

### Claim 1

A composition comprising crystalline (S)-4-(8-amino-3-(1-(but-2-ynoyll)pyrrolidin-2-yl)imidazo[1,5-α]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide free base.

### Claim 2 (depends on 1)

The composition of claim 1, wherein the crystalline (S)-4-(8-amino-3-(1-(but-2-ynoyll)pyrrolidin-2-yl)imidazo[1,5-α]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide free base is characterized by a transmission X-ray powder diffraction pattern comprising peaks at 6.4, 8.6, 10.5, 11.6, and 15.7° 20 0.2 °2θ.

### Claim 3 (depends on 2)

The composition of claim 2, wherein the crystalline (S)-4-(8-amino-3-(1-(but-2-ynoyll)pyrrolidin-2-yl)imidazo[1,5-α]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide free base is characterized by a transmission X-ray powder diffraction pattern further comprising peaks at 10.9, 12.7, 13.4, 14.3, 14.9, and 18.2 °2θ±0.2°2θ.

### Claim 4 (depends on 1)

The composition of claim 1, wherein the crystalline (S)-4-(8-amino-3-(1-(but-2-ynoyll)pyrrolidin-2-yl)imidazo[1,5-α]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide free base is characterized by a transmission X-ray powder diffraction pattern further comprising one or more peaks selected from the group consisting of 11.3, 15.1, 15.7, 16.1, 17.3, 19.2, 19.4, 19.8, 20.7, 21.1, 21.4, 21.6, 21.9, 22.6, 23.3, 23.6, 24.9, 25.2, 25.4, 25.7, 26.1, 26.4, 26.8, 26.9, 27.7, 28.6, 29.1, 29.4, 30.1, 30.5, 31.7, 31.9, 32.2, 32.6, 33.1, 33.4, 34.5, 35.9, 36.1, 36.8, 37.4, 38.1, 38.9, and 39.5° 2θ 0.2° 2θ.

### Claim 5 (depends on 1)

The composition of claim 1, wherein the crystalline (S)-4-(8-amino-3-(1-(but-2-ynoyll)pyrrolidin-2-yl)imidazo[1,5-α]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide free base is characterized by a transmission X-ray powder diffraction pattern substantially the same as the representative X-ray powder diffraction pattern shown in FIG. 2.

### Claim 6 (depends on 1)

The composition of claim 1, wherein the crystalline (S)-4-(8-amino-3-(1-(but-2-ynoyll)pyrrolidin-2-yl)imidazo[1,5-α]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide free base is characterized by a Raman spectrum comprising peaks at 1620, 1609, 1547, 1514 and 1495 cm−1 4 cm−1.

### Claim 7 (depends on 6)

The composition of claim 6, wherein the crystalline (S)-4-(8-amino-3-(1-(but-2-ynoyll)pyrrolidin-2-yl)imidazo[1,5-α]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide free base is fcharacterized by a Raman spectrum further comprising one or more peaks selected from the group consisting of 1680, 1620, 1609, 1574, 1547, 1514, 1495, 1454, 1433, 1351, 1312, 1255, 1232, 1187, 1046, 995, 706, 406, and 280 cm−1±2 cm−1.

### Claim 8 (depends on 1)

The composition of claim 1, wherein the crystalline (S)-4-(8-amino-3-(1-(but-2-ynoyll)pyrrolidin-2-yl)imidazo[1,5-α]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide free base is characterized by a Raman spectrum substantially the same as the representative Raman spectrum shown in FIG. 2.

### Claim 9 (depends on 1)

The composition of claim 1, wherein the crystalline (S)-4-(8-amino-3-(1-(but-2-ynoyll)pyrrolidin-2-yl)imidazo[1,5-α]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide free base is characterized by an infrared (IR) spectrum comprising peaks at 1621, 1608, 1403, 1303, and 764 cm−1±4 cm−1.

### Claim 10 (depends on 9)

The composition of claim 9, wherein the crystalline (S)-4-(8-amino-3-(1-(but-2-ynoyll)pyrrolidin-2-yl)imidazo[1,5-α]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide free base is characterized by an IR spectrum further comprising one or more peaks selected from the group consisting of 3367, 3089, 2246, 1682, 1621, 1608, 1574, 1514, 1504, 1454, 1428, 1403, 1345, 1303, 1248, 1194, 1177, 1149, 1109, 1049, 1023, 1003, 947, 900, 858, 842, 816, 764, 734, 729, 701, 689, 665, 623, and 612 cm−1 4 cm−1.

### Claim 11 (depends on 1)

The composition of claim 1, wherein the crystalline (S)-4-(8-amino-3-(1-(but-2-ynoyll)pyrrolidin-2-yl)imidazo[1,5-α]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide free base is characterized by an IR spectrum substantially the same as the representative IR spectrum shown in FIG. 3.

### Claim 12 (depends on 2)

The composition of claim 2, wherein the crystalline (S)-4-(8-amino-3-(1-(but-2-ynoyll)pyrrolidin-2-yl)imidazo[1,5-α]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide free base is further characterized by the absence of water in the crystal structure.

### Claim 13 (depends on 1)

The composition of claim 1, further comprising an extragranular acidulant.

### Claim 14 (depends on 13)

The composition of claim 13, wherein the extragranular acidulant is selected from the group consisting of fumaric acid, succinic acid, D-tartaric acid, L-tartaric acid, racemic tartaric acid, ascorbic acid, isoascorbic acid (also known as erythorbic acid and D-araboascorbic acid), alginic acid, or a salt thereof, Protacid F 120 NM, Protacid AR 1112 (also known as Kelacid NF), and Carbopol 971P (carboxypolymethylene), and combinations thereof.

### Claim 15 (depends on 13)

The composition of claim 13, wherein the extragranular acidulant is alginic acid, or a sodium or potassium salt thereof, at a concentration of between about 5% to about 33% by weight.

### Claim 16 (depends on 1)

The composition of claim 1, wherein the composition further comprises at least one pharmaceutically-acceptable excipient.

### Claim 17 (depends on 21)

A method of treating a hyperproliferative disease, comprising the step of administering a therapeutically effective amount of the composition of claim 21, wherein the hyperproliferative disease is selected from the group consisting of chronic lymphocytic leukemia, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, B-cell lymphoproliferative disease, B cell acute lymphoblastic leukemia, Waldenstrom's macroglobulinemia, Burkitt's leukemia, Hodgkin's disease, multiple myeloma, acute myeloid leukemia, juvenile myelomonocytic leukemia, hairy cell leukemia, mast cell leukemia, mastocytosis, myeloproliferative disorders (MPDs), myeloproliferative neoplasms, polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), myelodysplastic syndrome, chronic myelogenous leukemia (BCR-ABL1-positive), chronic neutrophilic leukemia, chronic eosinophilic leukemia, primary central nervous system (CNS) lymphoma, primary multifocal lymphoma of peripheral nervous system (PNS), thymus cancer, brain cancer, glioblastoma, lung cancer, squamous cell cancer, skin cancer (e.g., melanoma), eye cancer, retinoblastoma, intraocular melanoma, oral cavity and oropharyngeal cancers, bladder cancer, gastric cancer, stomach cancer, pancreatic cancer, breast cancer, cervical cancer, head and neck cancer, renal cancer, kidney cancer, liver cancer, ovarian cancer, prostate cancer, colorectal cancer, bone cancer (e.g., metastatic bone cancer), esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, epidermoid cancer, AIDS-related cancer (e.g., lymphoma), viral-induced cervical carcinoma (human papillomavirus), nasopharyngeal carcinoma (Epstein-Barr virus), Kaposi's sarcoma, primary effusion lymphoma (Kaposi's sarcoma herpesvirus), hepatocellular carcinoma (hepatitis B and hepatitis C viruses), T-cell leukemias (Human T-cell leukemia virus-1), benign hyperplasia of the skin, restenosis, benign prostatic hypertrophy, tumor angiogenesis, chronic inflammatory disease, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, ulcerative colitis, atopic dermatitis, pouchitis, spondylarthritis, uveitis, Behcet's disease, polymyalgia rheumatica, giant-cell arteritis, sarcoidosis, Kawasaki disease, juvenile idiopathic arthritis, hidratenitis suppurativa, Sjögren's syndrome, psoriatic arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, lupus, and lupus nephritis.

### Claim 18 (depends on 17)

The method of claim 17, further comprising the step of administering a therapeutically effective amount of an acid-reducing agent.