# US 2021/0275522 A1 · Pharmaceutical compositions and use thereof

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- Number: US 2021/0275522 A1
- Document ID: US20210275522A1
- Status: Published application
- Kind: A1
- Application number: 16/966,736
- Filed: 2019-11-22
- Published: 2021-09-09
- Earliest claimed: 2018-11-23
- Applicants: Ascentage Pharma (Suzhou) Co., Ltd.; Ascentage Pharma Group Corp Limited
- Inventors: Dajun YANG; Yifan ZHAI; Douglas Dong FANG; Ran TAO
- Web page: https://patentgrep.com/patent/US20210275522A1

## CPC

- A61K 31/416: condensed with carbocyclic ring systems, e.g. indazole
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/4184: condensed with carbocyclic rings, e.g. benzimidazoles
- 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 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/453: containing a six-membered ring with oxygen as a ring hetero atom
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/635: having a heterocyclic ring, e.g. sulfadiazine
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- 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 is a pharmaceutical composition comprising (i) a compound of formula (I) or a pharmaceutically acceptable salt thereof; (ii) a CDK inhibitor or a pharmaceutically acceptable salt thereof, for the prevention and/or treatment of a disease mediated by Bcl-2 and/or CDK activity.

## Claims

### Claim 1

A pharmaceutical composition comprising
(i) a compound of formula (I) or a pharmaceutically acceptable salt thereof;
(ii) a CDK inhibitor or a pharmaceutically acceptable salt thereof;
wherein, A is selected from the group consisting of
E is a carbon atom and is a double bond; or
E is a —C(H)— and is a single bond, or
E is a nitrogen atom and is a single bond;
X1, X2, and X3 are each independently selected from the group consisting of —CR8═ and —N═;
R1a and R1b taken together with the carbon atom to which they are attached form a 3-, 4-, or 5-membered optionally substituted cycloalkyl; or
R1a and R1b taken together with the carbon atom to which they are attached form a 4- or 5-membered optionally substituted heterocyclo;
each of R2 is independently selected from the group consisting of —NO2, —SO2CH3, and —SO2CF3;
each of R2a is independently selected from the group consisting of hydrogen and halogen;
R3 is selected from the group consisting of hydrogen, —CN, —C≡CH, and —N(R4a)(R4b);
R4a is selected from the group consisting of optionally substituted C1-6 alkyl, optionally substituted C3-6 cycloalkyl, heterocyclo, heteroalkyl, (cycloalkyl)alkyl, and (heterocyclo)alkyl;
R4b is selected from the group consisting of hydrogen and C1-4 alkyl;
R5 is selected from the group consisting of optionally substituted C1-6 alkyl, heterocyclo, heteroalkyl, (cycloalkyl)alkyl, and (heterocyclo)alkyl;
R6a, R6c, R6e, R6f, and R6g are each independently selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, heterocyclo, heteroalkyl, (cycloalkyl)alkyl, and (heterocyclo)alkyl;
R6b and R6d are each independently selected from the group consisting of hydrogen, C1-4 alkyl, and halogen;
R7 is selected from the group consisting of optionally substituted C1-6 alkyl, heterocyclo, heteroalkyl, (cycloalkyl)alkyl, and (heterocyclo)alkyl; and
R8 is selected from the group consisting of hydrogen and halogen.

### Claim 2 (depends on 1)

The pharmaceutical composition as defined in claim 1, wherein,
the compound of formula (I) is selected from the group consisting of
and/or, R4a is selected from the group consisting of

### Claim 3 (depends on 1)

The pharmaceutical composition as defined in claim 1, wherein, the compound of formula (I) is selected from

### Claim 4 (depends on 1)

The pharmaceutical composition as defined in claim 1, wherein, the compound of formula (I) is (R)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide, (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide, (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-fluoro-5-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide, or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

The pharmaceutical composition as defined in claim 1, wherein, the compound of formula (I) is (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-fluoro-5-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide.

### Claim 6 (depends on 1)

The pharmaceutical composition as defined in claim 1, wherein, the CDK inhibitor is selected from the group consisting of kenpaullone, PKC-412, butyrolactone I, alvocidib, N9-isopropyl-olomoucine, indirubin-3′-monoxime, NU2058, olomoucine II, 9-cyanopaullone, 5-iodo-indirubin-3′-monoxime, NU6102, oxindole I, SU 9516, roscovitine, RO-3306, 10Z-hymenialdisine, AZD 5438, AT7519, dinaciclib, R547, CGP 74514A, SNS-032, BMS-265246, JNJ-7706621, PHA-793887, P276-00, PHA-767491, milciclib, NU6027, LDC000067, ribociclib, palbociclib, abemaciclib, Senexin A, Atuveciclib, LY2857785, and dinaciclib.

### Claim 7 (depends on 1)

The pharmaceutical composition as defined in claim 1, wherein, the CDK inhibitor is a CDK9 inhibitor or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

The pharmaceutical composition as defined in claim 1, wherein, the CDK inhibitor is compound 2
Compound 2, compound 3 Compound 3, or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

The pharmaceutical composition as defined in claim 1, wherein, the compound of formula (I) is (R)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide, (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide, (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-fluoro-5-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide, or a pharmaceutically acceptable salt thereof;
and, the CDK inhibitor is compound 2
compound 3
or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 1)

The pharmaceutical composition as defined in claim 1, wherein, the compound of formula (I) is (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-fluoro-5-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide or a pharmaceutically acceptable salt thereof, and the CDK inhibitor is
or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 1)

The pharmaceutical composition as defined in claim 1, wherein, the weight ratio of the compound of formula (I) to the CDK inhibitor is 50:1 to 1:50.

### Claim 12 (depends on 1)

A pharmaceutical combination comprising
(i) a compound of formula (I) or a pharmaceutically acceptable salt thereof, and
(ii) a CDK inhibitor or a pharmaceutically acceptable salt thereof,
wherein, the compound of formula (I) and the CDK inhibitor are defined as in claim 1.

### Claim 13

(canceled)

### Claim 14 (depends on 1)

A method for the prevention and/or treatment of a disease mediated by Bcl-2 and/or CDK activity, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a CDK inhibitor or a pharmaceutically acceptable salt thereof;
wherein, the compound of formula (I) and the CDK inhibitor are defined as claim 1.

### Claim 15 (depends on 14)

The method as defined in claim 14, wherein, the disease mediated by Bcl-2 and/or CDK activity is a cancer, the cancer can be selected from the group consisting of adrenal cortical cancer, advanced cancer, anal cancer, aplastic anemia, bile duct cancer, bladder cancer, bone cancer, bone metastasis, brain/CNS tumors in adults, brain/CNS tumors in children, breast cancer, breast cancer in men, cancer in children, cancer of unknown primary, Castleman disease, cervical cancer, colon/rectum cancer, endometrial cancer, esophagus cancer, Ewing family of tumors, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumor, gestational trophoblastic disease, Hodgkin disease, Kaposi sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, leukemia, liver cancer, lung cancer-non-small cell, lung cancer-small cell, lung carcinoid tumor, lymphoma of the skin, malignant mesothelioma, myelodysplastic syndrome, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroectodermal tumor, peritoneal cancer, human head and neck squamous cell carcinoma, non-Hodgkin lymphoma, non-Hodgkin lymphoma in children, Hodgkin lymphoma, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumors, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma-adult soft tissue cancer, skin cancer-basal and squamous cell, skin cancer-melanoma, small intestine cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, and Wilms Tumor;
or, the disease mediated by Bcl-2 and/or CDK activity is cardiac hypertrophy, dilated cardiomyopathy, atherosclerosis, muscle atrophy or obesity.

### Claim 16 (depends on 14)

The method as defined in claim 14, wherein, the disease mediated by Bcl-2 and/or CDK activity is non-Hodgkin lymphoma or leukemia, the non-Hodgkin lymphoma is preferably diffuse large B-cell lymphoma; the leukemia is preferably myelodysplastic syndrome, chronic lymphocytic leukemia or acute myeloid leukemia.

### Claim 17 (depends on 14)

The method as defined in claim 14, wherein, the compound of formula (I) and the CDK inhibitor are administered simultaneously or separately in any order;
and/or, the compound of formula (I) and the CDK inhibitor are administered to a subject in a weight ratio of 50:1 to 1:50.

### Claim 18

(canceled)

### Claim 19 (depends on 1)

A method for the prevention and/or treatment of a cancer, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a CDK inhibitor or a pharmaceutically acceptable salt thereof;
wherein, the compound of formula (I) and the CDK inhibitor are defined as claim 1.

### Claim 20 (depends on 19)

The method as defined in claim 19, wherein, the cancer is selected from the group consisting of adrenal cortical cancer, advanced cancer, anal cancer, aplastic anemia, bile duct cancer, bladder cancer, bone cancer, bone metastasis, brain/CNS tumors in adults, brain/CNS tumors in children, breast cancer, breast cancer in men, cancer in children, cancer of unknown primary, Castleman disease, cervical cancer, colon/rectum cancer, endometrial cancer, esophagus cancer, Ewing family of tumors, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumor, gestational trophoblastic disease, Hodgkin disease, Kaposi sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, leukemia, liver cancer, lung cancer-non-small cell, lung cancer-small cell, lung carcinoid tumor, lymphoma of the skin, malignant mesothelioma, myelodysplastic syndrome, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroectodermal tumor, peritoneal cancer, human head and neck squamous cell carcinoma, non-Hodgkin lymphoma, non-Hodgkin lymphoma in children, Hodgkin lymphoma, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumors, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma-adult soft tissue cancer, skin cancer-basal and squamous cell, skin cancer-melanoma, small intestine cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, and Wilms Tumor.

### Claim 21 (depends on 19)

The method as defined in claim 19, wherein, the cancer is non-Hodgkin lymphoma or leukemia, the non-Hodgkin lymphoma is preferably diffuse large B-cell lymphoma; the leukemia is preferably myelodysplastic syndrome, chronic lymphocytic leukemia or acute myeloid leukemia.

### Claim 22 (depends on 1)

A kit comprising in separate containers in a single package pharmaceutical compositions comprising in one container a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and in a second container a pharmaceutical composition comprising a CDK inhibitor or a pharmaceutically acceptable salt thereof,
wherein, the compound of formula (I) and the CDK inhibitor are defined as in claim 1.