# US 12,760,013 B2 · Heteroaryl derivative, method for preparation thereof, and pharmaceutical composition comprising same as active ingredient

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- Number: US 12,760,013 B2
- Document ID: US12760013B2
- Status: Granted
- Kind: B2
- Application number: 18/026,793
- Filed: 2021-09-18
- Published: 2023-10-12
- Granted: 2026-10-13
- Earliest claimed: 2020-09-18
- Assignees: Voronoi Inc.
- Applicants: Voronoi Inc.
- Inventors: Younho Lee; Juhee Kang; Yikyung Ko; Jung Beom Son; Eunhwa Ko; Sung Hwan Kim; Nam Doo Kim; Hwan Geun Choi
- Web page: https://patentgrep.com/patent/US12760013B2

## CPC

- C07D 413/14: containing three or more hetero rings
- A61P 35/00: Antineoplastic agents
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 498/08: Bridged systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to a pharmaceutical composition comprising a compound of the present invention, an isomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient for prevention or treatment of cancer. The compound exhibits high inhibitory activity against epidermal growth factor receptor (EGFR) mutants or at least one of the wild-type or mutant ErbB2 and ErbB4 and as such, can be advantageously used for treatment of the cancer expressing same.

## Claims

### Claim 1

A compound of Formula 1, or a pharmaceutically acceptable salt thereof:
wherein:
E1 is N;
R1 is hydrogen, C1-5 alkoxy, or alkoxy substituted by halogen;
X1 is CH, N, O or S;
wherein when X1 is CH,
R2 and R3 form, together with a bonded C, a 3 to 12 atom heteroaryl comprising at least one N, and the 3 to 12 atom heteroaryl is substituted or unsubstituted by a C1-5 straight chain or branched chain alkyl or a 3 to 12 atom heterocycloalkyl,
wherein when X1 is N,
R2 and R3 are each independently selected from the group consisting of: hydrogen and C1-5 straight chain or branched chain alkyl, or
R2 and R3 form, together with a bonded N, a 3 to 12 atom heterocycloalkyl, wherein the 3 to 12 atom heterocycloalkyl comprises one or more heteroatoms, and wherein each heteroatom of the one or more heteroatoms is selected from the group consisting of: N, O and S, wherein the C1-5 straight chain or branched chain alkyl is substituted or unsubstituted by a C1-5 alkylamino, wherein the 3 to 12 atom heterocycloalkyl comprises one or more heteroatoms, each heteroatom of the one or more heteroatoms being selected from the group consisting of: N, O and S, is substituted or unsubstituted by one or more substituents A,
wherein each substituent A of the one or more substituents A is selected from the group consisting of: C1-5 straight chain or branched chain alkyl, C3-6 cycloalkyl, C1-5 alkylamino, allyl, oxo, C1-3 alkylcarbonyl, and 3 to 12 atom heterocycloalkyl, wherein the 3 to 12 atom heterocycloalkyl comprises one or more heteroatoms, wherein each heteroatom of the one or more heteroatoms is selected from the group consisting of: N and O, wherein the C1-5 straight chain or branched chain alkyl is additionally substituted or unsubstituted by a C3-6 cycloalkyl, a C1-5 alkylamino, or a 3 to 12 atom heterocycloalkyl that comprises at least one N, wherein the 3 to 12 atom heterocycloalkyl is substituted or unsubstituted by a substituent B,
wherein the substituent B is selected from the group consisting of: C1-5 straight chain or branched chain alkyl, C3-6 cycloalkyl, C1-5 alkylcarbonyl, a 3 to 12 atom heterocycloalkyl that includes one or more heteroatoms, and oxo, and wherein each heteroatom of the one or more heteroatoms is selected from the group consisting of: N and O, wherein the 3 to 12 atom heterocycloalkyl is additionally substituted or unsubstituted by a C1-5 straight chain or branched chain alkyl or a C3-6 cycloalkyl;
wherein when X1 is S or O,
R2 does not exist and R3 is C1-5 alkyl substituted by C1-5 alkylamino; and R4 and R5 are each independently selected from the group consisting of: hydrogen, halogen, and haloalkyl, or R4 and R5 form, together with a benzene, a 7 to 12 atom heteroaryl that includes one or more heteroatoms, wherein each heteroatom of the one or more heteroatoms is selected from the group consisting of: N, O and S, and wherein the 7 to 12 atom heteroaryl is substituted or unsubstituted by a C1-5 straight chain or branched chain alkyl.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
R1 is hydrogen, methoxy, difluoromethoxy, or trifluoroethoxy;
X1 is N;
R2 is methyl, and R3 is dimethylaminoethyl or methylaminoethyl; or
R2 and R3 form, together with a N bonded thereto, a morpholino, a piperazine, or a piperidine, wherein the morpholino, the piperazine, or the piperidine is substituted or unsubstituted by one or more substituents E, wherein each substituent E of the one or more substituents E is selected from the group consisting of: methyl, piperazinyl, morpholino, and oxazabicycloheptane, and wherein when E is piperazinyl, the piperazinyl is additionally substituted or unsubstituted by a methyl or a cyclopropyl; and
R4 and R5 are each independently hydrogen, fluoro, or trifluoromethyl.

### Claim 3

A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
(R)—N-(5-((6-(3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)-6-methoxy-2-(4-methylpiperazine-1-yl)pyridine-3-yl)acrylamide;
(R)—N-(5-((6-(3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)-2-(4-methylpiperazine-1-yl)-6-(2,2,2-trifluoroethoxy)pyridine-3-yl)acrylamide;
(R)—N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-(3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)-6-methoxypyridine-3-yl)acrylamide;
(R)—N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidine-1-yl)-5-((6-(3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)-6-methoxypyridine-3-yl)acrylamide;
(R)—N-(6-(difluoromethoxy)-5-((6-(3-(2-fluoro-3-(trifluoromethyl)phenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)-2-(4-methylpiperazine-1-yl)pyridine-3-yl)acrylamide;
(R)—N-(5-((6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-6-methoxypyridine-3-yl)acrylamide;
(R)—N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidine-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)-6-methoxypyridine-3-yl)acrylamide;
(R)—N-(5-((6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)-6-methoxy-2-(4-methylpiperazine-1-yl)pyridine-3-yl)acrylamide;
(R)—N-(5-((6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)-6-methoxy-2-morpholinopyridine-3-yl)acrylamide;
N-(2-(4-((S)-4-cyclopropyl-3-methylpiperazine-1-yl)piperidine-1-yl)-5-((6-((R)-3-(3,5-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)-6-methoxypyridine-3-yl)acrylamide;
N-(2-(4-((R)-4-cyclopropyl-3-methylpiperazine-1-yl)piperidine-1-yl)-5-((6-((R)-3-(3,5-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)-6-methoxypyridine-3-yl)acrylamide;
N-(2-(4-((S)-4-cyclopropyl-3-methylpiperazine-1-yl)piperidine-1-yl)-5-((6-((R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)-6-methoxypyridine-3-yl)acrylamide;
N-(2-(4-((S)-4-cyclopropyl-3-methylpiperazine-1-yl)piperidine-1-yl)-6-methoxy-5-((6-((R)-3-(3-(trifluoromethyl)phenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)pyridine-3-yl)acrylamide;
N-(2-(4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)piperidine-1-yl)-5-((6-((R)-3-(3,5-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)-6-methoxypyridine-3-yl)acrylamide; and
N-(2-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)piperidine-1-yl)-5-((6-((R)-3-(3,5-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)-6-methoxypyridine-3-yl)acrylamide.

### Claim 4

A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
(R)—N-(5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-2-(4-methylpiperazin-1-yl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)acrylamide; and
(R)—N-(5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)acrylamide.

### Claim 5 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

### Claim 6 (depends on 1)

A method of treating cancer in a subject, the method comprising administering to the subject a compound of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 6)

The method of claim 6, wherein the cancer comprises one or more EGFR mutations, wherein each EGFR mutation of the one or more EGFR mutations is selected from the group consisting of EGFR (E746-A750del), EGFR (G719C), EGFR (G719S), EGFR (L747-E749del, A750P), EGFR (L747-S752del, P753S), EGFR (L747-T751del, Sins), EGFR (L858R), EGFR (L858R, T790M), EGFR (L861Q), EGFR (S752-I759del), EGFR (T790M), EGFR Del19, EGFR Del19/T790M, EGFR L858RMT790M/C797S, EGFR Del19/T790M/C797S, EGFR Exon20 ins NPH, and EGFR Exon20 ins SVD.

### Claim 8 (depends on 6)

The method of claim 6, wherein the cancer is selected from the group consisting of: pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testis cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphocytic leukemia, basal cell carcinoma, epithelial ovarian cancer, ovarian seminoma, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, cholangiocarcinoma, colorectal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampullar of Vater cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal and paranasal cavity cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvis cancer, renal cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoid, gastrointestinal stromal tumor, Wilms' tumor, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational choriocarcinoma, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid, vaginal cancer, spinal cancer, vestibular schwannoma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsillar cancer, squamous cell cancer, adenocarcinoma of lung, lung cancer, squamous cell lung cancer, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleura cancer, hematologic malignancy, thymic cancer, and non-small cell lung cancer.

### Claim 9 (depends on 8)

The method of claim 8, wherein the cancer is non-small cell lung cancer.