# US 12,215,113 B2 · Crystalline forms of N[4[4-(4-Morpholinyl)-7H-Pyrrolo[2-3-D]Pyrimidin-6-yl]Phenyl]-4-[[3(R)-[(1-Oxo-2-Protein-1-yl)Amino]-1-Piperidinyl]Methyl]2-Pyridinecarboxamide]

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- Number: US 12,215,113 B2
- Document ID: US12215113B2
- Status: Granted
- Kind: B2
- Application number: 18/427,226
- Filed: 2024-01-30
- Published: 2024-09-12
- Granted: 2025-02-04
- Earliest claimed: 2023-01-18
- Assignees: Biomea Fusion, Inc.
- Applicants: Biomea Fusion, Inc.
- Inventors: Satish Goud Puppali; James T. Palmer; Thorsten A. Kirschberg; Angelina Sau Man Wong; Heow Meng Tan; Jay Li; Jing Lin; Ming Gao; Junlu Ding; Shuang Li; Yuyao Gu; Hongyan He; Bo Zheng; Yanjing Zhou; Mei You
- Web page: https://patentgrep.com/patent/US12215113B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61K 9/1623: {Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules}
- A61K 9/1635: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/1652: {Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin (homeopathic globules A61K9/1623)}
- A61K 9/2009: {Inorganic compounds}
- A61K 9/2013: {Organic compounds, e.g. phospholipids, fats}
- A61K 9/2018: {Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates}
- A61K 9/2027: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/2054: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 9/2059: {Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin}
- A61K 9/4825: {Proteins, e.g. gelatin (gelatin capsule shells with substantial amounts of other macromolecular substances A61K9/4816)}
- A61K 9/485: {Inorganic compounds}
- A61K 9/4858: {Organic compounds}
- A61K 9/4866: {Organic macromolecular compounds}
- A61K 31/155: Amidines ([IMAGE cpc-sch-A61K-1029.gif]), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
- A61K 31/277: having a ring, e.g. verapamil
- A61K 31/40: having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/497: containing further heterocyclic rings
- A61K 31/5025: ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/53: having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495})
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/70: Carbohydrates; Sugars; Derivatives thereof (sorbitol A61K31/047)
- A61K 31/7034: attached to a carbocyclic compound, e.g. phloridzin
- A61K 31/704: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)}
- A61K 31/7042: Compounds having saccharide radicals and heterocyclic rings
- A61K 31/7048: having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin {, digitoxin or digoxin}
- A61K 31/7056: containing five-membered rings with nitrogen as a ring hetero atom
- A61K 31/706: containing six-membered rings with nitrogen as a ring hetero atom
- A61K 31/7064: containing condensed or non-condensed pyrimidines
- A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K 38/16: Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof {(enzyme inhibitors A61K38/005)}
- A61K 38/193: {Colony stimulating factors [CSF]}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- 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

## Abstract

Described herein is N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (Compound A) (Formula I), including crystalline forms, solvates, and pharmaceutically acceptable salts thereof. Also disclosed are pharmaceutical compositions or pharmaceutical formulations that include the compound, as well as methods of using the compound, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, diabetes, and inflammatory diseases or conditions.

## Claims

### Claim 1

A crystalline Form K of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (Compound A) of formula (I):
wherein the crystalline Form K is characterized by an X-ray powder diffraction pattern comprising at least two characteristic peaks at angles (° 2θ) selected from the group consisting of 10.483°±0.2° 2θ, 12.756°±0.2° 2θ, and 19.071°±0.2° 2θ.

### Claim 2 (depends on 1)

The crystalline Form K according to claim 1, wherein the crystalline Form K is further characterized by an X-ray powder diffraction pattern comprising one additional characteristic peak at an angle (° 2θ) of 24.254±0.2° 2θ.

### Claim 3 (depends on 1)

The crystalline Form K according to claim 1, wherein the crystalline Form K is further characterized by an X-ray powder diffraction pattern as shown in FIG. 9.

### Claim 4 (depends on 1)

The crystalline Form K according to claim 1, wherein the crystalline Form K is further characterized by an infrared (IR) spectrum comprising one, two, three, four, five, six, seven, or eight characteristic peaks selected from the group consisting of 3676 cm−1, 3332 cm−1, 2970 cm−1, 1581 cm−1, 1515 cm−1, 1340 cm−1, 1279 cm−1, and 1110 cm−1.

### Claim 5 (depends on 1)

The crystalline Form K according to claim 1, wherein the crystalline Form K is further characterized by an infrared (IR) spectrum as shown in FIG. 5.

### Claim 6 (depends on 1)

The crystalline Form K according to claim 1, wherein the crystalline Form K is further characterized by a melting temperature in the range of 275° C. to 277° C.

### Claim 7 (depends on 1)

The crystalline Form K according to claim 1, wherein the crystalline Form K is further characterized by a thermogravimetric analysis (TGA) thermogram as shown in FIG. 6.

### Claim 8 (depends on 1)

The crystalline Form K according to claim 1, wherein the crystalline Form K is further characterized by a differential scanning calorimetry (DSC) thermogram with an endotherm having an onset at 275.4° C. and a peak at 277° C.

### Claim 9 (depends on 1)

The crystalline Form K according to claim 1, wherein the crystalline Form K is further characterized by a differential scanning calorimetry (DSC) thermogram as shown in FIG. 7.

### Claim 10

A pharmaceutical formulation comprising one or more diluents and crystalline Form K of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (Compound A) of formula (I):
wherein the crystalline Form K is characterized by an X-ray powder diffraction pattern comprising at least two characteristic peaks at angles (° 2θ) selected from the group consisting of 10.483°±0.2° 2θ, 12.756°±0.2° 2θ, and 19.071°±0.2° 2θ.

### Claim 11 (depends on 10)

The pharmaceutical formulation according to claim 10, wherein the crystalline Form K is further characterized by an X-ray powder diffraction pattern as shown in FIG. 9.

### Claim 12 (depends on 10)

The pharmaceutical formulation according to claim 10, wherein the pharmaceutical formulation further comprises at least one of (a), (b), (c), (d), and (e):
(a) 5 wt % to 70 wt % of Compound A;
(b) 25 wt % to 80 wt % of one or more diluents;
(c) 1 wt % to 10 wt % of one or more disintegrating agents;
(d) 0.2 wt % to 3 wt % of one or more glidants; and
(e) 0.2 wt % to 1.0 wt % of one or more lubricants.

### Claim 13 (depends on 12)

The pharmaceutical formulation according to claim 12, wherein the pharmaceutical formulation further comprises 10 mg to 500 mg of Compound A.

### Claim 14 (depends on 12)

The pharmaceutical formulation according to claim 12, wherein at least one diluent is selected from the group consisting of calcium phosphate, calcium sulfate, a cyclodextrin, a dextrate, dextrose, lactose, maltodextrin, mannitol, microcellulose, microcrystalline cellulose, sorbitol, sucrose, xylitol, a starch, modified starches, and talc.

### Claim 15 (depends on 14)

The pharmaceutical formulation according to claim 14, wherein the starch is a modified starch.

### Claim 16 (depends on 12)

The pharmaceutical formulation according to claim 12, wherein at least one diluent is lactose or a pregelatinized maize starch.

### Claim 17 (depends on 12)

The pharmaceutical formulation according to claim 12, wherein at least one disintegrating agent is selected from the group consisting of croscarmellose, croscarmellose sodium, cross-linked carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, methyl cellulose, methylcrystalline cellulose, a cross-linked starch, a natural starch, a pregelatinized starch, and a sodium starch.

### Claim 18 (depends on 17)

The pharmaceutical formulation according to claim 17, wherein the croscarmellose is cross-linked croscarmellose.

### Claim 19 (depends on 17)

The pharmaceutical formulation according to claim 17, wherein the cross-linked starch is a cross-linked polymer or sodium starch glycolate.

### Claim 20 (depends on 19)

The pharmaceutical formulation according to claim 19, wherein the cross-linked polymer is selected from the group consisting of a clay, crospovidone, cross-linked polyvinylpyrrolidone, a gum, and sodium alginate.

### Claim 21 (depends on 12)

The pharmaceutical formulation according to claim 12, wherein at least one glidant is selected from the group consisting of ascorbyl palmitate, calcium palmitate, fumed silica, magnesium stearate, a starch, and talc.

### Claim 22 (depends on 12)

The pharmaceutical formulation according to claim 12, wherein at least one lubricant is selected from the group consisting of calcium hydroxide, corn starch, magnesium stearate, sodium stearyl fumarate, sodium stearate, stearic acid, talc, a wax, and zinc stearate.

### Claim 23 (depends on 12)

The pharmaceutical formulation according to claim 12, wherein the pharmaceutical formulation further comprises one or more binders.

### Claim 24 (depends on 23)

The pharmaceutical formulation according to claim 23, wherein at least one binder is hydroxypropyl cellulose.

### Claim 25 (depends on 12)

The pharmaceutical formulation according to claim 12, wherein the pharmaceutical formulation further comprises one or more surfactants.

### Claim 26 (depends on 25)

The pharmaceutical formulation according to claim 25, wherein at least one surfactant is cremophore or Poloxamer 407.

### Claim 27 (depends on 10)

The pharmaceutical formulation according to claim 10, wherein the pharmaceutical formulation is formulated for a route of administration selected from the group consisting of buccal administration, nasal administration, oral administration, parenteral administration, rectal administration, and topical administration.

### Claim 28

A method for treating diabetes in a mammal, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of crystalline Form K of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (Compound A) of formula (I):
wherein the crystalline Form K is characterized by an X-ray powder diffraction pattern comprising at least two characteristic peaks at angles (° 2θ) selected from the group consisting of 10.483°±0.2° 28, 12.756°±0.2° 2θ, and 19.071°±0.2° 2θ.

### Claim 29 (depends on 28)

The method according to claim 28, wherein the crystalline Form K is further characterized by an X-ray powder diffraction pattern as shown in FIG. 9.

### Claim 30

A method for treating diabetes in a mammal, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a pharmaceutical formulation comprising one or more diluents and crystalline Form K of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (Compound A) of formula (I):
wherein the crystalline Form K is characterized by an X-ray powder diffraction pattern comprising at least two characteristic peaks at angles (° 2θ) selected from the group consisting of 10.483°±0.2°2θ, 12.756°±0.2°2θ, and 19.071°±0.2°2θ.

### Claim 31 (depends on 30)

The method according to claim 30, wherein the crystalline Form K is further characterized by an X-ray powder diffraction pattern as shown in FIG. 9.

### Claim 32

A method for treating cancer in a mammal, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of crystalline Form K of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (Compound A) of formula (I):
wherein the crystalline Form K is characterized by an X-ray powder diffraction pattern comprising at least two characteristic peaks at angles (° 2θ) selected from the group consisting of 10.483°±0.2° 2θ, 12.756°±0.2° 2θ, and 19.071°±0.2° 2θ.

### Claim 33 (depends on 32)

The method according to claim 32, wherein the crystalline Form K is further characterized by an X-ray powder diffraction pattern as shown in FIG. 9.

### Claim 34

A method for treating cancer in a mammal, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a pharmaceutical formulation comprising one or more diluents and crystalline Form K of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (Compound A) of formula (I):
wherein the crystalline Form K is characterized by an X-ray powder diffraction pattern comprising at least two characteristic peaks at angles (° 2θ) selected from the group consisting of 10.483°±0.2°2θ, 12.756°±0.2° 2θ, and 19.071°±0.2° 2θ.

### Claim 35 (depends on 34)

The method according to claim 34, wherein the crystalline Form K is further characterized by an X-ray powder diffraction pattern as shown in FIG. 9.