# US 11,078,191 B2 · 1-(4-amino-5-bromo-6-(1H-pyrazol-1-yl)pyrimidin-2-yl)-1H-pyrazol-4-ol and use thereof in the treatment of cancer

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- Number: US 11,078,191 B2
- Document ID: US11078191B2
- Status: Granted
- Kind: B2
- Application number: 16/484,183
- Filed: 2018-02-08
- Published: 2019-11-28
- Granted: 2021-08-03
- Earliest claimed: 2017-02-10
- Assignees: Novartis AG; Palobiofarma, S.L.
- Applicants: Novartis AG; Palobiofarma S.L.
- Inventors: Sanela Bilic; Juan Alberto Camacho Gomez; John Scott Cameron; Julio Cesar Castro-Palomino Laria; Danny Roland Howard, Jr.
- Web page: https://patentgrep.com/patent/US11078191B2

## CPC

- C07D 403/14: containing three or more hetero rings
- A61K 39/395: Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61P 35/00: Antineoplastic agents
- C07K 16/2818: {against CD28 or CD152}
- C07K 16/2827: {against B7 molecules, e.g. CD80, CD86}
- C07K 2317/565: Complementarity determining region [CDR]
- 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
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

This invention relates to an active metabolite of 5-bromo-2,6-di(1H-pyrazol-1-yl)pyrimindin-4-amine that modulates the activity of adenosine A2a receptor. In particular, the present invention relates to pharmaceutical compositions comprising 1-(4-amino-5-bromo-6-(1H-pyrazol-1-yl)-pyrimidin-2-yl)-1H-pyrazol-4-ol, as well as processes for its preparation and its use in the treatment of cancer alone of in combination with one or more immunotherapeutic agents.

## Claims

### Claim 1

A metabolite of 5-bromo-2,6-di(1H-pyrazol-1-yl)pyrimindin-4-amine, which is compound:
or a pharmaceutically acceptable salt thereof.

### Claim 2

The compound 1-(4-amino-5-bromo-6-(1H-pyrazol-1-yl)-pyrimidin-2-yl)-1H-pyrazol-4-ol, in an isolated form.

### Claim 3

A pharmaceutical composition comprising, 1-(4-amino-5-bromo-6-(1H-pyrazol-1-yl)-pyrimidin-2-yl)-1H-pyrazol-4-ol, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient for simultaneous, concurrent, or sequential use.

### Claim 4

A combination, comprising a therapeutically effective amount of 1-(4-amino-5-bromo-6-(1H-pyrazol-1-yl)-pyrimidin-2-yl)-1H-pyrazol-4-ol, or a pharmaceutically acceptable salt thereof and one or more immunotherapeutic agents.

### Claim 5

A method of treating cancer, in a subject in need of such treatment, the method comprising: administering to a subject in need thereof, a therapeutically effective amount of 1-(4-amino-5-bromo-6-(1H-pyrazol-1-yl)-pyrimidin-2-yl)-1H-pyrazol-4-ol , or a pharmaceutically acceptable salt thereof; alone or in combination with one or more immunotherapeutic agents wherein the cancer is selected from a lung cancer, a melanoma, a renal cancer, a liver cancer, a myeloma, a prostate cancer, a breast cancer, a colorectal cancer, a pancreatic cancer, a head and neck cancer, anal cancer, gastro-esophageal cancer, thyroid cancer, cervical cancer, a lymphoproliferative disease or a hematological cancer, T-cell lymphoma, B-cell lymphoma, a non-Hogdkin lymphoma, or a leukemia.

### Claim 6 (depends on 1, 3)

A method of inhibiting adenosine A2a receptor in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the 1-(4-amino-5-bromo-6-(1H-pyrazol-1-yl)-pyrimidin-2-yl)-1H-pyrazol-4-ol according to claim 1; or administering a pharmaceutical composition according to claim 3 to a subject.

### Claim 7 (depends on 5)

The method of claim 5, wherein the cancer is lung cancer.

### Claim 8 (depends on 5)

The method of claim 5, wherein one or more immunotherapeutic agents are selected from the group consisting of anti-CTLA4 antibodies, anti-PD-1 antibodies and anti-PD-L1 antibodies.

### Claim 9 (depends on 5)

The method of claim 5, wherein the immunotherapeutic agent is selected from the group consisting of: Ipilimumab, Tremelimumab, Nivolumab, Pembrolizumab, Pidilizumab (CT-011), AMP-224, AMP-514 (MEDI0680), MPDL3280A, MEDI4736, MSB0010718C, YW243.55.S70 and MDX-1105.

### Claim 10 (depends on 5)

The method of claim 5, wherein the immunotherapeutic agents is an anti-PD-1 antibody.

### Claim 11 (depends on 10)

The method, the use or the combination for use according to claim 10, wherein the anti-PD-1 antibody comprises:
(a) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 4, a VHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ ID NO: 14, and a VLCDR3 amino acid sequence of SEQ ID NO: 15;
(b) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 1; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 10, a VLCDR2 amino acid sequence of SEQ ID NO: 11, and a VLCDR3 amino acid sequence of SEQ ID NO: 12;
(c) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 41, a VHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ ID NO: 14, and a VLCDR3 amino acid sequence of SEQ ID NO: 15; or
(d) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 41; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 10, a VLCDR2 amino acid sequence of SEQ ID NO: 11, and a VLCDR3 amino acid sequence of SEQ ID NO: 12.

### Claim 12 (depends on 10)

The method, according to claim 10, wherein the anti-PD-1 comprises a VH comprising the amino acid sequence of SEQ ID NO: 6 and a VL comprising the amino acid sequence of SEQ ID NO: 20.

### Claim 13

The method, according to embodiment 10, wherein the anti-PD-1 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 8 and a light chain comprising the amino acid sequence of SEQ ID NO: 22.

### Claim 14

The method, according to embodiment 10, wherein the anti-PD-1 antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 6 and a VL comprising the amino acid sequence of SEQ ID NO: 16.

### Claim 15

The method, according to embodiment 10, wherein the anti-PD-1 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 8 and a light chain comprising the amino acid sequence of SEQ ID NO: 18.

### Claim 16 (depends on 10)

The method, according to claim 10, wherein the anti-PD-1 antibody molecule is administered at a dose of about 300 mg once every three weeks.

### Claim 17 (depends on 10)

The method, according to claim 10, wherein the anti-PD-1 antibody molecule is administered at a dose of about 400 mg once every four weeks.

### Claim 18 (depends on 5)

The method of claim 5, wherein the immunotherapeutic agents is an anti-PD-L1 antibody.

### Claim 19 (depends on 18)

The method, according to claim 18, wherein the anti PD-L1 antibody molecule comprises:
(a) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 47, a VHCDR2 amino acid sequence of SEQ ID NO: 48, and a VHCDR3 amino acid sequence of SEQ ID NO: 46; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 52, a VLCDR2 amino acid sequence of SEQ ID NO: 53, and a VLCDR3 amino acid sequence of SEQ ID NO: 54;
(b) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 44; a VHCDR2 amino acid sequence of SEQ ID NO: 45; and a VHCDR3 amino acid sequence of SEQ ID NO: 46; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 49, a VLCDR2 amino acid sequence of SEQ ID NO: 50, and a VLCDR3 amino acid sequence of SEQ ID NO: 51;
(c) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 63, a VHCDR2 amino acid sequence of SEQ ID NO: 48, and a VHCDR3 amino acid sequence of SEQ ID NO: 46; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 52, a VLCDR2 amino acid sequence of SEQ ID NO: 53, and a VLCDR3 amino acid sequence of SEQ ID NO: 54; or
(d) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 63; a VHCDR2 amino acid sequence of SEQ ID NO: 45; and a VHCDR3 amino acid sequence of SEQ ID NO: 46; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 49, a VLCDR2 amino acid sequence of SEQ ID NO: 50, and a VLCDR3 amino acid sequence of SEQ ID NO: 51.

### Claim 20 (depends on 18)

The method, according to claim 18, wherein the anti PD-L1 antibody molecule comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 55 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 58.

### Claim 21 (depends on 8)

The method, according to claim 8, wherein immunotherapeutic agent is administered together in a single composition or administered separately in two or more different compositions forms.

### Claim 22 (depends on 8)

The method, according to claim 8, wherein the immunotherapeutic agent is administered concurrently with, prior to, or subsequent to, the compound: -(4-amino-5-bromo-6-(1H-pyrazol-1-yl)-pyrimidin-2-yl)-1H-pyrazol-4-ol.

### Claim 23 (depends on 7)

The method according to claim 7, wherein the lung cancer is non-small cell lung cancer.