# US 2023/0054767 A1 · Combinations

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- Number: US 2023/0054767 A1
- Document ID: US20230054767A1
- Status: Published application
- Kind: A1
- Application number: 17/757,514
- 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; Hooman Izadi; Peter Qinhua Huang; Sayee Gajanan Hegde; Joseph Robert Pinchman; Kevin Duane Bunker; Fernando Donate
- Web page: https://patentgrep.com/patent/US20230054767A1

## CPC

- 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 31/438: The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- 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 a Bcl-2 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) has the structure:
wherein:
R1a is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 haloalkyl, a substituted or unsubstituted C3-C6 cycloalkyl, a substituted or unsubstituted C1-C6 alkoxy, an unsubstituted mono-C1-C6 alkylamine and an unsubstituted di-C1-C6 alkylamine;
each R2a is independently selected from the group consisting of halogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 haloalkyl and a substituted or unsubstituted C3-C6 cycloalkyl; or
when m-a is 2 or 3, each R2a is independently selected from the group consisting of halogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 haloalkyl and a substituted or unsubstituted C3-C6 cycloalkyl, or two R2a groups taken together with the atom(s) to which they are attached form a substituted or unsubstituted C3-C6 cycloalkyl or a substituted or unsubstituted 3 to 6 membered heterocyclyl;
R4a is selected from the group consisting of NO2, S(O)R6a, SO2R6a, halogen, cyano and an unsubstituted C1-C6 haloalkyl;
R5a is —X1a-(Alk1a)n-a-R7a;
Alk1a is selected from an unsubstituted C1-C4 alkylene and a C1-C4 alkylene substituted with 1, 2 or 3 substituents independently selected from fluoro, chloro, an unsubstituted C1-C3 alkyl and an unsubstituted C1-C3 haloalkyl;
R6a is selected from the group consisting of a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 haloalkyl and a substituted or unsubstituted C3-C6 cycloalkyl;
R7a is selected from a substituted or unsubstituted C1-C6 alkoxy, a substituted or unsubstituted C3-C10 cycloalkyl, a substituted or unsubstituted 3 to 10 membered heterocyclyl, hydroxy, amino, a substituted or unsubstituted mono-substituted amine group, a substituted or unsubstituted di-substituted amine group, a substituted or unsubstituted N-carbamyl, a substituted or unsubstituted C-amido and a substituted or unsubstituted N-amido;
m-a is 0, 1, 2 or 3;
n-a is selected from the group consisting of 0 and 1; and
X1a is selected from the group consisting of —O—, —S— and —NH—.

### Claim 2

Use of a combination of compounds for treating a disease or condition, wherein the combination includes an effective amount of Compound (C) and an effective amount of one or more of Compound (B), or a pharmaceutically acceptable salt thereof, wherein:
the Compound (C) has the structure:
and
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;
R11is 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; and
the one or more of Compound (B) has the structure
wherein:
R1a is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 haloalkyl, a substituted or unsubstituted C3-C6 cycloalkyl, a substituted or unsubstituted C1-C6 alkoxy, an unsubstituted mono-C1-C6 alkylamine and an unsubstituted di-C1-C6 alkylamine;
each R2a is independently selected from the group consisting of halogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 haloalkyl and a substituted or unsubstituted C3-C6 cycloalkyl; or
when m-a is 2 or 3, each R2a is independently selected from the group consisting of halogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 haloalkyl and a substituted or unsubstituted C3-C6 cycloalkyl, or two R2a groups taken together with the atom(s) to which they are attached form a substituted or unsubstituted C3-C6 cycloalkyl or a substituted or unsubstituted 3 to 6 membered heterocyclyl;
R4a is selected from the group consisting of NO2, S(O)R6a, SO2R6a, halogen, cyano and an unsubstituted C1-C6 haloalkyl;
R5a is—X1a-(Alk1a)n R7a; Alk1a is selected from an unsubstituted C1-C4 alkylene and a C1-C4 alkylene substituted with 1, 2 or 3 substituents independently selected from fluoro, chloro, an unsubstituted C1-C3 alkyl and an unsubstituted C1-C3 haloalkyl;
R6a is selected from the group consisting of a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 haloalkyl and a substituted or unsubstituted C3-C6 cycloalkyl;
R7a is selected from a substituted or unsubstituted C1-C6 alkoxy, a substituted or unsubstituted C3-C10 cycloalkyl, a substituted or unsubstituted 3 to 10 membered heterocyclyl, hydroxy, amino, a substituted or unsubstituted mono-substituted amine group, a substituted or unsubstituted di-substituted amine group, a substituted or unsubstituted N-carbamyl, a substituted or unsubstituted C-amido and a substituted or unsubstituted N-amido;
m-a is 0, 1, 2 or 3;
n-a is selected from the group consisting of 0 and 1;
X1a is selected from the group consisting of —O—, —S— and —NH—; and
provided that the Compound (C) cannot be
or a pharmaceutically acceptable salt thereof.

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

The use of claim 1 or 2, wherein the Compound (C) is selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing.

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

The use of any one of claims 1-3, wherein the Compound (B) 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 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 bladder cancer, a brain cancer, a bone marrow cancer, a colorectal cancer, an esophageal cancer, a hepatocellular cancer, a lymphoblastic leukemia, a follicular lymphoma, a lymphoid malignancy of T-cell or B-cell origin, a melanoma, a myelogenous leukemia, a Hodgkin's lymphoma, a Non-Hodgkin's lymphoma, a head and neck cancer (including oral cancer), a non-small cell lung cancer, a chronic lymphocytic leukemia, a myeloma, a prostate cancer, a small cell lung cancer, a spleen cancer, a polycythemia vera, a thyroid cancer, an endometrial cancer, a stomach cancer, a gallbladder cancer, a bile duct cancer, a testicular cancer, a neuroblastoma, an osteosarcoma, an Ewings's tumor and a Wilm's tumor.

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

The use of any one of claims 1-4, 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, and a vulvar cancer.

### Claim 7 (depends on 6)

The use of claim 6, wherein the disease or condition is a breast cancer.

### Claim 8 (depends on 5, 6, 7)

The use of any one of claims 5-7, wherein the breast cancer that does not include any point mutations ER mutations.

### Claim 9 (depends on 5, 6, 7)

The use of any one of claims 5-7, 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 (ERα), 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 10 (depends on 5, 6, 7, 8, 9)

The use of any one of claims 5-9, wherein the breast cancer is ER positive breast cancer.

### Claim 11 (depends on 5, 6, 7, 8, 9)

The use of any one of claims 5-9, wherein the breast cancer is ER positive/HER2-negative breast cancer.

### Claim 12 (depends on 5, 6, 7, 8, 9, 10, 11)

The use of any one of claims 5-11, wherein the breast cancer is local breast cancer.

### Claim 13 (depends on 5, 6, 7, 8, 9, 10, 11)

The use of any one of claims 5-11, wherein the breast cancer is metastatic breast cancer.

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

The use of any one of claims 5-13, wherein the breast cancer is recurrent breast cancer.

### Claim 15 (depends on 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)

The use of any one of claims 5-14, wherein the breast cancer has been previously treated with an endocrine therapy.

### Claim 16 (depends on 15)

The use of claim 15, wherein the treatment was with a selective ER modulator (SERM).

### Claim 17 (depends on 16)

The use of claim 16, 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 18 (depends on 15)

The use of claim 15, wherein the treatment was with a selective ER degrader (SERD).

### Claim 19 (depends on 18)

The use of claim 18, 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-yl)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-l-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]indol-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 20 (depends on 15)

The use of claim 15, wherein the treatment was with an aromatase inhibitor.

### Claim 21 (depends on 20)

The use of claim 20, wherein the aromatase inhibitor is a steroidal aromatase inhibitor.

### Claim 22 (depends on 21)

The use of claim 21, 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 23 (depends on 20)

The use of claim 20, wherein the aromatase inhibitor is a non-steroidal aromatase inhibitor.

### Claim 24 (depends on 23)

The use of claim 23, 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 25 (depends on 5, 6, 7, 8, 9, 10, 11, 12, 13)

The use of any one of claims 5-13, wherein the breast cancer has not been previously treated.

### Claim 26 (depends on 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25)

The use of any one of claim 5-25, wherein the breast cancer is present in a woman.

### Claim 27 (depends on 26)

The use of claim 26, wherein the subject is a premenopausal woman.

### Claim 28 (depends on 26)

The use of claim 26, wherein the subject is a perimenopausal woman.

### Claim 29 (depends on 26)

The use of claim 26, wherein the subject is a menopausal woman.

### Claim 30 (depends on 26)

The use of claim 26, wherein the breast cancer is present in a postmenopausal woman.

### Claim 31 (depends on 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25)

The use of any one of claim 5-25, wherein the breast cancer is present a man.

### Claim 32 (depends on 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31)

The use of any one of claim 5-31, 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 33 (depends on 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31)

The use of any one of claim 5-31, wherein the breast cancer is present in a subject that has a serum estradiol level ≤15 pg/mL.

### Claim 34 (depends on 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31)

The use of any one of claim 5-31, wherein the breast cancer is present in a subject that has a serum estradiol level ≤10 pg/mL.