# US 11,026,949 B2 · Combination therapy for treating cancer

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- Number: US 11,026,949 B2
- Document ID: US11026949B2
- Status: Granted
- Kind: B2
- Application number: 16/562,683
- Filed: 2019-09-06
- Published: 2020-04-02
- Granted: 2021-06-08
- Earliest claimed: 2015-04-20
- Assignees: Epizyme, Inc.; Health Research, Inc.
- Applicants: Epizyme, Inc.; Health Research, Inc.
- Inventors: Heike Keilhack; Roberto Pili
- Web page: https://patentgrep.com/patent/US11026949B2

## CPC

- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/404: Indoles, e.g. pindolol
- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61K 31/4412: having oxo groups directly attached to the heterocyclic ring
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/517: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- 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

The present disclosure relates to compositions comprising inhibitors of human histone methyltransferase EZH2 and one or more other therapeutic agents (such as tyrosine kinase inhibitors or VEGF/VEGFR inhibitors), particularly anticancer agents such as sunitinib, and methods of combination therapy for administering to subjects in need thereof for the treatment of cancer.

## Claims

### Claim 1

A method for treating clear cell renal cell carcinoma in a patient in need thereof comprising administering a therapeutically effective amount of an EZH2 inhibitor and one or more tyrosine kinase inhibitors, wherein the EZH2 inhibitor is GSK-126 having the following formula:
or a pharmaceutically acceptable salt thereof;
or
a compound of Formula (I):
or a pharmaceutically acceptable salt thereof;
wherein:
R701 is H, F, OR707, NHR707, —(C≡C)—(CH2)n7-R708, phenyl, 5- or 6-membered heteroaryl, C3-8 cycloalkyl, or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the phenyl, 5- or 6-membered heteroaryl, C3-8 cycloalkyl or 4-7 membered heterocycloalkyl each independently is optionally substituted with one or more groups selected from halo, C1-3 alkyl, OH, O—C1-6 alkyl, NH—C1-6 alkyl, and, C1-3 alkyl substituted with C3-8 cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein each of the O—C1-6 alkyl and NH—C1-6 alkyl is optionally substituted with hydroxyl, O—C1-3 alkyl or NH—C1-3 alkyl, each of the O—C1-3 alkyl and NH—C1-3 alkyl being optionally further substituted with O—C1-3 alkyl or NH—C1-3 alkyl alkyl;
each of R702 and R703, independently is H, halo, C1-4 alkyl, C1-6 alkoxyl or C6-C10 aryloxy, each optionally substituted with one or more halo;
each of R704 and R705, independently is C1-4 alkyl;
R706 is cyclohexyl substituted by N(C1-4 alkyl)2 wherein one or both of the C1-4 alkyl is substituted with C1-6 alkoxy; or R706 is tetrahydropyranyl;
R707 is C1-4 alkyl optionally substituted with one or more groups selected from hydroxyl, C1-4 alkoxy, amino, mono- or di-C1-4 alkylamino, C3-8 cycloalkyl, and 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the C3-8 cycloalkyl or 4-7 membered heterocycloalkyl each independently is further optionally substituted with C1-3 alkyl;
R708 is C1-4 alkyl optionally substituted with one or more groups selected from OH, halo, and C1-4 alkoxy, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, or O—C1-6 alkyl, wherein the 4-7 membered heterocycloalkyl can be optionally further substituted with OH or C1-6 alkyl; and
n7 is 0, 1 or 2.

### Claim 2 (depends on 1)

The method of claim 1, wherein the clear cell renal cell carcinoma is resistant to tyrosine kinase inhibitor treatment.

### Claim 3 (depends on 2)

The method of claim 2, wherein the one or more tyrosine kinase inhibitors are VEGF/VEGFR inhibitors.

### Claim 4

A method for treating renal cell carcinoma in a patient in need thereof comprising administering a therapeutically effective amount of an EZH2 inhibitor and one or more VEGF/VEGFR inhibitors, wherein the EZH2 inhibitor is GSK-126 having the following formula:
or a pharmaceutically acceptable salt thereof;
or
a compound of Formula (I):
or a pharmaceutically acceptable salt thereof;
wherein:
R701 is H, F, OR707, NHR707,—(C≡C)—(CH2)n7-R708, phenyl, 5- or 6-membered heteroaryl, C3-8 cycloalkyl, or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the phenyl, 5- or 6-membered heteroaryl, C3-8 cycloalkyl or 4-7 membered heterocycloalkyl each independently is optionally substituted with one or more groups selected from halo, C1-3 alkyl, OH, O—C1-6 alkyl, NH—C1-6 alkyl, and, C1-3 alkyl substituted with C3-8 cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein each of the O—C1-6 alkyl and NH—C1-6 alkyl is optionally substituted with hydroxyl, O—C1-3 alkyl or NH—C1-3 alkyl, each of the O—C1-3 alkyl and NH—C1-3 alkyl being optionally further substituted with O—C1-3 alkyl or NH—C1-3 alkyl;
each of R702 and R703, independently is H, halo, C1-4 alkyl, C1-6 alkoxyl or C6-C10 aryloxy, each optionally substituted with one or more halo;
each of R704 and R705, independently is C1-4 alkyl;
R706 is cyclohexyl substituted by N(C1-4 alkyl)2 wherein one or both of the C1-4 alkyl is substituted with C1-6 alkoxy; or R706 is tetrahydropyranyl;
R707 is C1-4 alkyl optionally substituted with one or more groups selected from hydroxyl, C1-4 alkoxy, amino, mono- or di-C1-4 alkylamino, C3-8 cycloalkyl, and 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the C3-8 cycloalkyl or 4-7 membered heterocycloalkyl each independently is further optionally substituted with C1-3 alkyl;
R708 is C1-4 alkyl optionally substituted with one or more groups selected from OH, halo, and C1-4 alkoxy, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, or O—C1-6 alkyl, wherein the 4-7 membered heterocycloalkyl can be optionally further substituted with OH or C1-6 alkyl; and
n7 is 0, 1 or 2.

### Claim 5 (depends on 4)

The method of claim 4, wherein the renal cell carcinoma is resistant to VEGF/VEGFR inhibitor treatment.

### Claim 6 (depends on 1)

The method of claim 1, wherein the EZH2 inhibitor is Compound 44 having the following formula:
or pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

The method of claim 1, wherein the EZH2 inhibitor is:
or pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

The method of claim 1, wherein the EZH2 inhibitor is GSK-126.

### Claim 9 (depends on 1)

The method of claim 1, wherein the one or more tyrosine kinase inhibitors are selected from erlotinib (Tarceva); gefitinib (Iressa); imatinib (Gleevec); sorafenib (Nexavar); sunitinib (Sutent); trastuzumab (Herceptin); bevacizumab (Avastin); rituximab (Rituxan); lapatinib (Tykerb); cetuximab (Erbitux); panitumumab (Vectibix); everolimus (Afinitor); alemtuzumab (Campath); gemtuzumab (Mylotarg); temsirolimus (Torisel); pazopanib (Votrient); dasatinib (Sprycel); nilotinib (Tasigna); vatalanib (Ptk787; ZK222584); CEP-701; SU5614; MLN518; XL999; VX-322; Azd0530; BMS-354825; SKI-606 CP-690; AG-490; WHI-P154; WHI-P131; AC-220; and AMG888.

### Claim 10 (depends on 1)

The method of claim 1, wherein the one or more tyrosine kinase inhibitors include sunitinib.

### Claim 11 (depends on 4)

The method of claim 4, wherein the one or more VEGF/VEGFR inhibitors are selected from bevacizumab (Avastin); sorafenib (Nexavar);
sunitinib (Sutent); ranibizumab; pegaptanib; vandetinib; E7080; Zd6474; PKC-412; Vatalanib (Ptk787 or ZK222584); and motesanib diphosphate.

### Claim 12 (depends on 4)

The method of claim 4, wherein the one or more VEGF/VEGFR inhibitors include sunitinib.

### Claim 13 (depends on 1)

The method of claim 1, wherein the EZH2 inhibitor and the one or more tyrosine kinase inhibitors are administered simultaneously or sequentially.

### Claim 14 (depends on 1)

The method of claim 1, wherein the EZH2 inhibitor is administered prior to administration of the one or more tyrosine kinase inhibitors.

### Claim 15 (depends on 4)

The method of claim 4, wherein the EZH2 inhibitor and the one or more VEGF/VEGFR inhibitors are administered simultaneously or sequentially.

### Claim 16 (depends on 4)

The method of claim 4, wherein the EZH2 inhibitor is administered prior to administration of the one or more VEGF/VEGFR inhibitors.

### Claim 17 (depends on 4)

The method of claim 4, wherein the renal cell carcinoma is clear cell renal cell carcinoma.

### Claim 18 (depends on 4)

The method of claim 4, wherein the EZH2 inhibitor is Compound 44 having the following formula:
or pharmaceutically acceptable salt thereof.

### Claim 19 (depends on 4)

The method of claim 4, wherein the EZH2 inhibitor is:
or pharmaceutically acceptable salt thereof.

### Claim 20 (depends on 4)

The method of claim 4, wherein the EZH2 inhibitor is GSK-126.