# US 2023/0053946 A1 · Combinations

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 2023/0053946 A1
- Document ID: US20230053946A1
- Status: Published application
- Kind: A1
- Application number: 17/757,485
- Filed: 2020-12-16
- Published: 2023-02-23
- Earliest claimed: 2019-12-20
- Assignees: Recurium IP Holdings, LLC
- Applicants: Recurium IP Holdings, LLC
- Inventors: Ahmed Abdi Samatar; Jiali Li; Jianhui Ma; Peter Qinhua Huang; Sayee Gajanan Hegde; Kevin Duane Bunker; Fernando Donate
- Web page: https://patentgrep.com/patent/US20230053946A1

## CPC

- A61K 31/4353: ortho- or peri-condensed with heterocyclic ring systems
- 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 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/513: having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K 31/565: not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- 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

Disclosed herein are combinations of compounds for treating a disease or condition, such as cancer. A combination of compounds for treating a disease or condition can include a SERD inhibitor and another inhibitor (such as a CDK4/6 inhibitor, a selective aromatase inhibitor, a non-selective aromatase inhibitor, a mTOR inhibitor, a PI3K inhibitor, an ERK or a MEK inhibitor, AKT inhibitor, a BET inhibitor and an Aurora inhibitor), along with pharmaceutically acceptable salts of any of the foregoing.

## Claims

### Claim 1

Use of a combination of compounds for treating a disease or condition, wherein the combination includes an effective amount of Compound (A), or a pharmaceutically acceptable salt thereof, and an effective amount of one or more of Compound (B), or a pharmaceutically acceptable salt thereof, wherein:
the Compound (A) has the structure:
and
the one or more of Compound (B) is selected from the group consisting of a CDK4/6 inhibitor, a selective aromatase inhibitor, a non-selective aromatase inhibitor, a mTOR inhibitor, a PI3K inhibitor, an ERK or a MEK inhibitor, AKT inhibitor, a BET inhibitor and an Aurora inhibitor, or a pharmaceutically acceptable salt of any of the foregoing;
wherein the CDK4/6 inhibitor is selected from the group consisting of
or a pharmaceutically acceptable salt of any of the foregoing;
wherein the selective aromatase inhibitor is selected from the group consisting of
or a pharmaceutically acceptable salt of any of the foregoing;
wherein the non-selective aromatase inhibitor is selected from the group consisting of
or a pharmaceutically acceptable salt of any of the foregoing;
wherein the mTOR inhibitor is selected from the group consisting of
or a pharmaceutically acceptable salt of any of the foregoing;
wherein the PI3K inhibitor is selected from the group consisting of
or a pharmaceutically acceptable salt of any of the foregoing;
wherein the ERK or the MEK inhibitor is selected from the group consisting of
or a pharmaceutically acceptable salt of any of the foregoing;
wherein the AKT inhibitor is selected from the group consisting of
or a pharmaceutically acceptable salt of any of the foregoing;
wherein the BET inhibitor is selected from the group consisting of
or a pharmaceutically acceptable salt of any of the foregoing; and
wherein the Aurora inhibitor is selected from the group consisting of
or a pharmaceutically acceptable salt of any of the foregoing.

### Claim 2

Use of a combination of compounds for treating a disease or condition, wherein the combination includes an effective amount of Compound (C), or a pharmaceutically acceptable salt thereof, and an effective amount of one or more of Compound (B), or a pharmaceutically acceptable salt thereof, wherein: the Compound (C) has the structure:
wherein:
X1, Y1 and Z1 are each independently C or N;
with the first proviso that at least one of X1, Y1 and Z1 is N;
with the second proviso that each of X1, Y1 and Z1 is uncharged;
with third proviso that two of the dotted lines indicate double bonds;
with the fourth proviso that the valencies of X1, Y1 and Z1 can be each independently satisfied by attachment to a substituent selected from H and R12;
X2 is O;
A1 is selected from the group consisting of an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted heterocyclyl;
R1 is selected from the group consisting of an optionally substituted C1-6 alkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted cycloalkyl(C1-6 alkyl), an optionally substituted cycloalkenyl(C1-6 alkyl), an optionally substituted aryl(C1-6 alkyl), an optionally substituted heteroaryl(C1-6 alkyl) and an optionally substituted heterocyclyl(C1-6 alkyl);
R2 and R3 are each independently selected from the group consisting of hydrogen, halogen, an optionally substituted C1-6 alkyl and an optionally substituted C1-6 haloalkyl; or R2 and R3 together with the carbon to which R2 and R3 are attached form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl or an optionally substituted heterocyclyl;
R4 and R5 are each independently selected from the group consisting of hydrogen, halogen, an optionally substituted C1-6 alkyl and an optionally substituted C1-6 haloalkyl; or R4 and R5 together with the carbon to which R4 and R5 are attached form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl or an optionally substituted heterocyclyl;
R6, R7, R8 and R9 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted haloalkyl, an optionally substituted mono-substituted amine, and an optionally substituted di-substituted amine;
R10 is hydrogen, halogen, an optionally substituted alkyl, or an optionally substituted cycloalkyl;
R11 is hydrogen; and
R12 is hydrogen, halogen, an optionally substituted C1-3 alkyl, an optionally substituted C1-3 haloalkyl or an optionally substituted C1-3 alkoxy;
provided that the Compound (C) cannot be
or a pharmaceutically acceptable salt thereof; and
the one or more of Compound (B) is selected from the group consisting of a CDK4/6 inhibitor, a selective aromatase inhibitor, a non-selective aromatase inhibitor, a mTOR inhibitor, a PI3K inhibitor, an ERK or a MEK inhibitor, AKT inhibitor, BET inhibitor and Aurora inhibitor, or a pharmaceutically acceptable salt of any of the foregoing;
wherein the CDK4/6 inhibitor is selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing;
wherein the selective aromatase inhibitor is selected from the group consisting of
or a pharmaceutically acceptable salt of any of the foregoing;
wherein the non-selective aromatase inhibitor is selected from the group consisting of
or a pharmaceutically acceptable salt of any of the foregoing;
wherein the mTOR inhibitor is selected from the group consisting of
or a pharmaceutically acceptable salt of any of the foregoing;
wherein the PI3K inhibitor is selected from the group consisting of
or a pharmaceuticallyacceptable salt of any of the foregoing;
wherein the ERK or the MEK inhibitor is selected from the group consisting of
or a pharmaceutically acceptable salt of any of the foregoing;
wherein the AKT inhibitor is selected from the group consisting of
or a pharmaceutically acceptable salt of any of the foregoing;
wherein the BET inhibitor is selected from the group consisting of
or a pharmaceutically acceptable salt of any of the foregoing; and
wherein the Aurora inhibitor is selected from the group consisting of
or a pharmaceutically acceptable salt of any of the foregoing.

### Claim 3 (depends on 2)

The use of claim 2, wherein for the Compound (C) when X1 is NH; Y1 and Z1 are each C; A1 is a phenyl, 2-fluorophenyl or 2,6-difluorophenyl; R2 and R3 are each methyl or one of R2 and R3 is hydrogen and the other of R2 and R3 is methyl; and R4, R5, R6, R7, R8, R9 and R10 are each hydrogen; then R1 cannot be 2-hydroxyethyl, 2-methylpropyl, 2-fluoro-2-methylpropyl, 3-fluoro-2-methylpropyl, 3-hydroxy-2-methylpropyl or 2-fluoro-3-hydroxy-2-methylpropyl.

### Claim 4 (depends on 2, 3)

The use of claim 2 or 3, wherein the Compound (C) is selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing.

### Claim 5 (depends on 1, 2, 3, 4)

The use of any one of claims 1-4, wherein the Compound (B) is selected from the group consisting of
or a pharmaceutically acceptable salt of any of the foregoing.

### Claim 6 (depends on 1, 2, 3, 4)

The use of any one of claims 1-4, wherein the Compound (B) is selected from the group consisting of
or a pharmaceutically acceptable salt of any of the foregoing.

### Claim 7 (depends on 1, 2, 3, 4)

The use of any one of claims 1-4, wherein the Compound (B) is selected from the group consisting of
or a pharmaceutically acceptable salt of any of the foregoing.

### Claim 8 (depends on 1, 2, 3, 4)

The use of any one of claims 1-4, wherein the Compound (B) is selected from the group consisting of
or a pharmaceutically acceptable salt of any of the foregoing.

### Claim 9 (depends on 1, 2, 3, 4)

The use of any one of claims 1-4, wherein the Compound (B) is selected from the group consisting of
or a pharmaceutically acceptable salt of any of the foregoing.

### Claim 10 (depends on 1, 2, 3, 4)

The use of any one of claims 1-4, wherein the Compound (B) is selected from the group consisting of
or a pharmaceutically acceptable salt of any of the foregoing.

### Claim 11 (depends on 1, 2, 3, 4)

The use of any one of claims 1-4, wherein the Compound (B) is selected from the group consisting of
or a pharmaceutically acceptable salt of any of the foregoing.

### Claim 12 (depends on 1, 2, 3, 4)

The use of any one of claims 1-4, wherein the Compound (B) is selected from the group consisting of
or a pharmaceutically acceptable salt of any of the foregoing.

### Claim 13 (depends on 1, 2, 3, 4)

The use of any one of claims 1-4, wherein the Compound (B) is selected from the group consisting of
or a pharmaceutically acceptable salt of any of the foregoing.

### Claim 14 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13)

The use of any one of claims 1-13, wherein the disease or condition is selected from the group consisting of a breast cancer, a cervical cancer, an ovarian cancer, an uterine cancer, a vaginal cancer, a vulvar cancer, a brain cancer, a cervicocerebral cancer, an esophageal cancer, a thyroid cancer, a small cell cancer, a non-small cell cancer, a lung cancer, a stomach cancer, a gallbladder/bile duct cancer, a liver cancer, a pancreatic cancer, a colon cancer, a rectal cancer, a choriocarcinoma, an uterus body cancer, an uterocervical cancer, a renal pelvis/ureter cancer, a bladder cancer, a prostate cancer, a penis cancer, a testicular cancer, a fetal cancer, a Wilms' cancer, a skin cancer, a malignant melanoma, a neuroblastoma, an osteosarcoma, an Ewing's tumor, a soft part sarcoma, an acute leukemia, a chronic lymphatic leukemia, a chronic myelocytic leukemia, polycythemia vera, a malignant lymphoma, multiple myeloma, a Hodgkin's lymphoma, and a non-Hodgkin's lymphoma.

### Claim 15 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13)

The use of any one of claims 1-13, wherein the disease or condition is a breast cancer, a cervical cancer, an ovarian cancer, an uterine cancer, a vaginal cancer, and a vulvar cancer.

### Claim 16 (depends on 15)

The use of claim 15, wherein the disease or condition is a breast cancer.

### Claim 17 (depends on 14, 15, 16)

The use of any one of claims 14-16, wherein the breast cancer that does not include any point mutations ER mutations.

### Claim 18 (depends on 14, 15, 16)

The use of any one of claims 14-16, wherein the disease or condition is breast cancer that has at least one point mutation within the Estrogen Receptor 1 (ESR1) that encodes Estrogen receptor alpha (ERa), wherein the mutation is selected from the group consisting of: K303R, D538G, Y537S, E380Q, Y537C, Y537N, A283V, A546D, A546T, A58T, A593D, A65V, C530L, D411H, E279V, E471D, E471V, E523Q, E542G, F461V, F97L, G145D, G160D, G274R, G344D, G420D, G442R, G557R, H524L, K252N, K481N, K531E, L370F, L453F, L466Q, L497R, L536H, L536P, L536Q, L536R, L540Q, L549P, M388L, M396V, M421V, M437I, M522I, N156T, N532K, N69K, P147Q, P222S, P535H, R233G, R477Q, R503W, R555H, S282C, S329Y, S338G, S432L, S463P, S47T, S576L, V392I, V418E, V478L, V533M, V534E, Y537D and Y537H.

### Claim 19 (depends on 14, 15, 16, 17, 18)

The use of any one of claims 14-18, wherein the breast cancer is ER positive breast cancer.

### Claim 20 (depends on 14, 15, 16, 17, 18)

The use of any one of claims 14-18, wherein the breast cancer is ER positive/HER2-negative breast cancer.

### Claim 21 (depends on 14, 15, 16, 17, 18, 19, 20)

The use of any one of claims 14-20, wherein the breast cancer is local breast cancer.

### Claim 22 (depends on 14, 15, 16, 17, 18, 19, 20)

The use of any one of claims 14-20, wherein the breast cancer is metastatic breast cancer.

### Claim 23 (depends on 14, 15, 16, 17, 18, 19, 20, 21, 22)

The use of any one of claims 14-22, wherein the breast cancer is recurrent breast cancer.

### Claim 24 (depends on 14, 15, 16, 17, 18, 19, 20, 21, 22, 23)

The use of any one of claims 14-23, wherein the breast cancer has been previously treated with an endocrine therapy.

### Claim 25 (depends on 24)

The use of claim 24, wherein the treatment was with a selective ER modulator (SERM).

### Claim 26 (depends on 25)

The use of claim 25, wherein the selective ER modulator is selected from the group consisting of tamoxifen, raloxifene, ospemifene, bazedoxifene, toremifene and lasofoxifene, or a pharmaceutically acceptable salt of any of the foregoing.

### Claim 27 (depends on 24)

The use of claim 24, wherein the treatment was with a selective ER degrader (SERD).

### Claim 28 (depends on 27)

The use of claim 27, wherein the selective ER degrader is selected from the group consisting of fulvestrant, (E)-3[3,5-Difluoro-4-[(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid (AZD9496), (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (elacestrant, RAD1901), (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1—(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid (Brilanestrant, ARN-810, GDC-0810), (E)-3-(4-((2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-y1)oxy)phenyl)acrylic acid (LSZ102), (E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)ethyl)amino)but-2-enamide (H3B -6545), (E)-3-(4-((2-(4-fluoro-2,6-dimethylbenzoyl)-6-hydroxybenzo [b]thiophen-3-yl)oxy)phenyl)acrylic acid (rintodestrant, G1T48), D-0502, SHR9549, ARV-471, 3-(1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indo1-2-yl)-2,2-difluoropropan-1-ol (giredestrant, GDC-9545), (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo [7]annulene-3-carboxylic acid (SAR439859), N-[1-(3-fluoropropyl)azetidin-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo [4,3-f]isoquinolin-6-yl]pyridin-3-amine (AZD9833), OP-1250 and LY3484356, or a pharmaceutically acceptable salt of any of the foregoing.

### Claim 29 (depends on 24)

The use of claim 24, wherein the treatment was with an aromatase inhibitor.

### Claim 30 (depends on 29)

The use of claim 29, wherein the aromatase inhibitor is a steroidal aromatase inhibitor.

### Claim 31 (depends on 30)

The use of claim 30, wherein the steroidal aromatase inhibitor is selected from the group consisting of exemestane and testolactone, or a pharmaceutically acceptable salt of any of the foregoing.

### Claim 32 (depends on 29)

The use of claim 29, wherein the aromatase inhibitor is a non-steroidal aromatase inhibitor.

### Claim 33 (depends on 32)

The use of claim 32, wherein the non-steroidal aromatase inhibitor is selected from the group consisting of anastazole and letrazole, or a pharmaceutically acceptable salt of any of the foregoing.

### Claim 34 (depends on 14, 15, 16, 17, 18, 19, 20, 21, 22)

The use of any one of claims 14-22, wherein the breast cancer has not been previously treated.

### Claim 35 (depends on 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34)

The use of any one of claim 14-34, wherein the breast cancer is present in a woman.

### Claim 36 (depends on 35)

The use of claim 35, wherein the subject is a premenopausal woman.

### Claim 37 (depends on 35)

The use of claim 35, wherein the subject is a perimenopausal woman.

### Claim 38 (depends on 35)

The use of claim 35, wherein the subject is a menopausal woman.

### Claim 39 (depends on 35)

The use of claim 35, wherein the breast cancer is present in a postmenopausal woman.

### Claim 40 (depends on 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34)

The use of any one of claim 14-34, wherein the breast cancer is present a man.

### Claim 41 (depends on 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40)

The use of any one of claim 14-40, wherein the breast cancer is present in a subject that has a serum estradiol level in the range of >15 pg/mL to 350 pg/mL.

### Claim 42 (depends on 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40)

The use of any one of claim 14-40, wherein the breast cancer is present in a subject that has a serum estradiol level ≤15 pg/mL.

### Claim 43 (depends on 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40)

The use of any one of claim 14-40, wherein the breast cancer is present in a subject that has a serum estradiol level ≤10 pg/mL.