# US 2017/0283418 A1 · Solid forms of (1s,4s)-4-(2-(((3s,4r)-3-fluorotetrahydro-2h-pyran-4-yl)amino)-8-((2,4,6-trichlorophenyl)amino)-9h-purin-9-yl)-1-methylcyclohexane-1-carboxamide and methods of their use

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- Number: US 2017/0283418 A1
- Document ID: US20170283418A1
- Status: Published application
- Kind: A1
- Application number: 15/475,836
- Filed: 2017-03-31
- Published: 2017-10-05
- Earliest claimed: 2016-04-01
- Assignees: Signal Pharmaceuticals, LLC
- Applicants: Signal Pharmaceuticals, LLC
- Inventors: Zheng Chen; Paul F. Fernandez; Tracy L. Gaebele; Lianfeng Huang; Matthew J. Jackson; Matthew M. Kreilein; Xiaoling Lu; Wenju Wu; Jean Xu
- Web page: https://patentgrep.com/patent/US20170283418A1

## CPC

- C07D 473/32: Nitrogen atom
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- 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

Provided herein are formulations, solid forms and methods of use relating to (1s,4s)-4-(2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-8-((2,4, 6-trichlorophenyl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide.

## Claims

### Claim 1

A crystal form comprising Compound 1, or a tautomer thereof:
which has an X-ray powder diffraction pattern comprising peaks at 7.3, 8.5, 18.2, and 21.3° 2θ (±0.2° 2θ).

### Claim at position 2

-9. (canceled)

### Claim 10

A crystal form comprising a citrate salt of Compound 1, or a tautomer thereof:
which has an X-ray powder diffraction pattern comprising peaks at 4.8, 9.6, 18.9, and 19.2° 2θ (±0.2° 2θ).

### Claim at position 4

-12. (canceled)

### Claim 13

A crystal form comprising a hydrochloride salt of Compound 1, or a tautomer thereof:
which has an X-ray powder diffraction pattern comprising peaks at 9.0, 9.8, 9.9, and 16.7° 2θ (±0.2° 2θ).

### Claim at position 6

-20. (canceled)

### Claim 21 (depends on 1)

A pharmaceutical composition comprising said solid form of claim 1, and a pharmaceutical carrier.

### Claim 22 (depends on 1)

A method for treating or preventing a cancer, comprising administering to a subject in need thereof an effective amount a solid form of claim 1, wherein the cancer is a solid tumor or a hematological cancer.

### Claim 23 (depends on 22)

The method of claim 22, wherein the solid tumor is melanoma, colorectal cancer, stomach cancer, head and neck cancer, thyroid cancer, bladder cancer, CNS cancer, lung cancer, pancreatic cancer, or soft tissue cancer.

### Claim 24 (depends on 22)

The method of claim 22, wherein the cancer is bladder cancer, breast cancer, CNS cancer, colon cancer, gastrointestinal cancer, endocrine cancer, female genitoureal cancer, head and neck cancer, hematopoietic cancer, kidney cancer, liver cancer, lung cancer, melanoma, pancreas cancer, prostate cancer, or soft tissue cancer.

### Claim 25 (depends on 22)

The method of claim 22, wherein the cancer is glioma, neuroblastoma, stomach cancer, thyroid cancer, adrenal gland cancer, cancer of the uterus, cervix, ovary clear cell, or vulva, leukemia, myeloma, NSCLC, SCLC, sarcoma or osteosarcoma.

### Claim 26 (depends on 1)

A method for treating or preventing hepatocellular carcinoma (HCC), comprising administering to a subject in need thereof an effective amount a solid form of claim 1.

### Claim 27 (depends on 1)

A method for treating or preventing colorectal cancer (CRC), melanoma, gastric cancer, HCC, lung cancer, pancreatic cancer, leukemia, or multiple myeloma), comprising administering to a subject in need thereof an effective amount a solid form of claim 1.

### Claim 28 (depends on 1)

A method for treating or preventing a cancer expressing PD-L1, comprising administering to a subject in need thereof an effective amount a solid form of claim 1.

### Claim 29 (depends on 28)

The method of claim 28, wherein the PD-L1 expressing cancer is melanoma, lung cancer, renal cell carcinoma (RCC), or HCC.

### Claim 30 (depends on 1)

A method for treating or preventing a cancer characterized by a BRAF mutation, comprising administering to a subject in need thereof an effective amount a solid form of claim 1.

### Claim 31 (depends on 30)

The method of claim 30, wherein the cancer characterized by a BRAF mutation is CRC, thyroid cancer, melanoma or lung cancer.

### Claim 32

(canceled)

### Claim 33 (depends on 1)

A method for treating or preventing a cancer characterized by an NRAS mutation, comprising administering to a subject in need thereof an effective amount a solid form of claim 1.

### Claim 34 (depends on 33)

The method of claim 33, wherein the cancer characterized by an NRAS mutation is melanoma.

### Claim 35 (depends on 1)

A method for treating or preventing a cancer characterized by a KRAS mutation, comprising administering to a subject in need thereof an effective amount a solid form of claim 1.

### Claim 36 (depends on 35)

The method of claim 35, wherein the cancer characterized by a KRAS mutation is CRC, pancreas cancer or lung cancer.

### Claim 37 (depends on 1)

A method for treating or preventing a cancer characterized by a beta-catenin mutation, comprising administering to a subject in need thereof an effective amount a solid form of claim 1.

### Claim 38 (depends on 37)

The method of claim 37, wherein the beta-catenin mutation is one or more of beta-catenin S33Y, G34E, S45del, or S33C.

### Claim 39 (depends on 37, 38)

The method of claim 37 or 38, wherein the HCC is characterized by a beta-catenin mutation and/or increased YAP expression.

### Claim 40 (depends on 37)

The method of claim 37, further comprising an EGFR mutation or increased EGFR activity.

### Claim 41

(canceled)

### Claim 42 (depends on 37)

The method of claim 37, further comprising a BRAF mutation.

### Claim at position 29

-45. (canceled)

### Claim 46 (depends on 37)

The method of claim 37, wherein the cancer characterized by a beta-catenin mutation is CRC, stomach cancer, HCC or sarcoma.

### Claim 47 (depends on 1)

A method for treating or preventing a cancer characterized by an activated beta-catenin pathway, comprising administering to a subject in need thereof an effective amount a solid form of claim 1.

### Claim 48 (depends on 47)

The method of claim 47, wherein the cancer is CRC, stomach cancer, HCC or sarcoma.

### Claim 49

(canceled)

### Claim 50 (depends on 1)

A method for treating or preventing gastric cancer, comprising administering to a subject in need thereof an effective amount a solid form of claim 1.

### Claim at position 35

-52. (canceled)

### Claim 53 (depends on 50)

The method of claim 50, wherein the gastric cancer is characterized by a beta-catenin mutation, or by an activated beta-catenin pathway.

### Claim 54

(canceled)

### Claim 55 (depends on 1)

A method for treating or preventing melanoma, comprising administering to a subject in need thereof an effective amount a solid form of claim 1.

### Claim 56 (depends on 55)

The method of claim 55, wherein the melanoma is characterized by a BRAF mutation and/or NRAS mutation.

### Claim 57 (depends on 1)

A method for modulating the levels of a biomarker in a subject having a cancer, comprising administering to said subject an effective amount of a solid form of claim 1.

### Claim 58

(canceled)

### Claim 59 (depends on 57)

The method of claim 57, wherein the biomarker is ERK, RSK1, DUSP4, DUSP5, DUSP6, BMF, EFNA1, EGR1, ETV5, FOS, FOSL1, GJA1, IL-8, cMyc, Cyclin D1, YAP, SPRY2, SPRY4, Axin2, CTGF, AREG, CYR61, CXCL1, HAS2, HES1, MAFF, CITED2, ELF3, or PD-L1.

### Claim 60 (depends on 57)

The method of claim 57, wherein the modulation is measured by measurement of the reduction of phosphorylation levels of one or more of ERK and RSK1.

### Claim at position 44

-62. (canceled)

### Claim 63 (depends on 22)

The method of claim 22, wherein the solid form of Compound 1 is administered as a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient.