# US 2021/0277002 A1 · Compounds, pharmaceutical compositions, and methods of preparing compounds and of their use as atr kinase inhibitors

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

- Number: US 2021/0277002 A1
- Document ID: US20210277002A1
- Status: Published application
- Kind: A1
- Application number: 17/245,574
- Filed: 2021-04-30
- Published: 2021-09-09
- Earliest claimed: 2018-10-30
- Assignees: Repare Therapeutics Inc.
- Applicants: Repare Therapeutics Inc.
- Inventors: Sheldon N. CRANE; Vouy Linh TRUONG; Abbas ABDOLI; Jean-François TRUCHON; Cameron BLACK; Stéphane DORICH; Lee FADER; Stéphanie LANOIX; Paul JONES; Miguel ST-ONGE; Audrey PICARD; Cyrus M. LACBAY
- Web page: https://patentgrep.com/patent/US20210277002A1

## CPC

- A61P 35/00: Antineoplastic agents
- C07D 471/04: Ortho-condensed systems
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07B 2200/05: Isotopically modified compounds, e.g. labelled
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

Disclosed are compounds and pharmaceutically acceptable salts thereof that may be used in the treatment of subjects in need thereof. The compounds disclosed herein may be inhibitors of Ataxia-telangiectasia and RAD-3-related protein kinase (ATR). Also disclosed are pharmaceutical compositions containing the compounds or pharmaceutically acceptable salts thereof and methods of their preparation and use.

## Claims

### Claim 1

A compound of formula (I):
or a pharmaceutically acceptable salt thereof,
wherein
is a double bond, and each Y is independently N or CR4; or is a single bond, and each Y is independently NRY, carbonyl, or C(RY)2; wherein each RY is independently H or optionally substituted C1-6 alkyl;
R1 is optionally substituted C1-6 alkyl or H;
R2 is optionally substituted C2-9 heterocyclyl, optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, halogen, —N(R5)2, —OR5, —CON(R6)2, —SO2N(R6)2,—SO2R5A, or -Q-R5B;
R3 is optionally substituted C1-9 heteroaryl or optionally substituted C1-9 heteroaryl C1-6 alkyl;
each R4 is independently hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl;
each R5 is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, or —SO2R5A; or both R5, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl;
each R5A is independently optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, or optionally substituted C6-10 aryl;
R5B is hydroxyl, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, —N(R5)2, —CON(R6)2, —SO2N(R6)2, —SO2R5A, or optionally substituted alkoxy;
each R6 is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkoxyalkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C1-9 heteroaryl; or both R6, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl;
Q is optionally substituted C2-9 heterocyclylene, optionally substituted C3-8 cycloalkylene, optionally substituted C1-9 heteroarylene, or optionally substituted C6-10 arylene; and
X is hydrogen or halogen.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the compound is a compound of formula (II):
or a pharmaceutically acceptable salt thereof,
wherein
each Y is independently N or CR4;
R1 is optionally substituted C1-6 alkyl or H;
R2 is optionally substituted C2-9 heterocyclyl, optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, halogen, —N(R5)2, —OR5, —CON(R6)2, —SO2N(R6)2,—SO2R5A, or -Q-R5B;
R3 is optionally substituted C1-9 heteroaryl or optionally substituted C1-9 heteroaryl C1-6 alkyl;
each R4 is independently hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl;
each R5 is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, or —SO2R5A; or both R5, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl;
each R5A is independently optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, or optionally substituted C6-10 aryl;
R5B is hydroxyl, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, —N(R5)2, —CON(R6)2, —SO2N(R6)2, —SO2R5A, or optionally substituted alkoxy;
each R6 is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkoxyalkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C1-9 heteroaryl; or both R6, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl;
Q is optionally substituted C2-9 heterocyclylene, optionally substituted C3-8 cycloalkylene, optionally substituted C1-9 heteroarylene, or optionally substituted C6-10 arylene; and
X is hydrogen or halogen.

### Claim 3 (depends on 1)

The compound of claim 1, wherein the compound is a compound of formula (IB):
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

The compound of claim 1, wherein the compound is a compound of formula (IB-a):
or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

The compound of claim 1, wherein the compound is a compound of formula (I-a):
or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

The compound of claim 1, wherein the compound is a compound of formula (IA):
or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

The compound of claim 1, wherein the compound is a compound of formula (IA-a):
or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

The compound of claim 1, wherein the compound is a compound of formula (IC):
or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

The compound of claim 1, wherein the compound is a compound of formula (IC-a):
or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 1)

The compound of claim 1, wherein R1 is methyl.

### Claim 11 (depends on 1)

The compound of claim 1, wherein R2 is optionally substituted C2-9 heterocyclyl, optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, —N(R5)2, —CON(R6)2, —SO2N(R6)2, or —SO2R5A.

### Claim 12 (depends on 1)

The compound of claim 1, wherein each R5A is independently optionally substituted C1-6 alkyl or optionally substituted C3-8 cycloalkyl.

### Claim 13 (depends on 1)

The compound of claim 1, wherein each R6 is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C6-10 aryl, or optionally substituted C1-9 heteroaryl; or both R6, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl.

### Claim 14 (depends on 1)

The compound of claim 1, wherein R2 is:

### Claim 15 (depends on 1)

The compound of claim 1, wherein R3 is optionally substituted, monocyclic C1-9 heteroaryl comprising at least one nitrogen atom.

### Claim 16 (depends on 1)

The compound of claim 1, wherein R3 is:

### Claim 17 (depends on 1)

The compound of claim 1, wherein R4 is hydrogen.

### Claim 18 (depends on 1)

The compound of claim 1, wherein X is hydrogen.

### Claim 19

A compound selected from the group consisting of compounds 1-152 and pharmaceutically acceptable salts thereof.

### Claim 20 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)

A pharmaceutical composition comprising the compound of any one of claims 1 to 19 and a pharmaceutically acceptable excipient.

### Claim 21 (depends on 20)

The pharmaceutical composition of claim 20, wherein the composition is isotopically enriched in deuterium.

### Claim 22 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)

A method of inhibiting ATR kinase in a cell expressing ATR kinase, the method comprising contacting the cell with the compound of any one of claims 1 to 19.

### Claim 23 (depends on 22)

The method of claim 22, wherein the cell is in a subject.

### Claim 24 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)

A method of treating a subject in need thereof comprising administering to the subject the compound of any one of claims 1 to 19.

### Claim 25 (depends on 24)

The method of claim 24, wherein the subject is suffering from, and is in need of a treatment for, a disease or condition having the symptom of cell hyperproliferation.

### Claim 26 (depends on 25)

The method of claim 25, wherein the disease or condition is a cancer.

### Claim 27 (depends on 26)

The method of claim 26, wherein the cancer is a carcinoma, sarcoma, adenocarcinoma, leukemia, or melanoma.

### Claim 28 (depends on 26)

The method of claim 26, wherein the cancer is a carcinoma selected from the group consisting of medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, Schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, and carcinoma villosum.

### Claim 29 (depends on 26)

The method of claim 26, wherein the cancer is a sarcoma selected from the group consisting of chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, and telangiectaltic sarcoma.

### Claim 30 (depends on 26)

The method of claim 26, wherein the cancer is a leukemia selected from the group consisting of nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Riedercell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, and undifferentiated cell leukemia.

### Claim 31 (depends on 26)

The method of claim 26, wherein the cancer is a melanoma selected from the group consisting of acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, and superficial spreading melanoma.

### Claim 32 (depends on 26)

The method of claim 26, wherein the cancer is prostate cancer, thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervix cancer, colon cancer, head & neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, stomach cancer, uterus cancer, medulloblastoma, ampullary cancer, colorectal cancer, or pancreatic cancer.

### Claim 33 (depends on 26)

The method of claim 26, wherein the cancer is Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulinoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.

### Claim 34 (depends on 25)

The method of claim 25, wherein the subject is suffering from, and is in need of a treatment for, a pre-malignant condition.