# US 2023/0054741 A1 · Therapeutic compounds and methods of use

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

- Number: US 2023/0054741 A1
- Document ID: US20230054741A1
- Status: Published application
- Kind: A1
- Application number: 17/383,422
- Filed: 2021-07-22
- Published: 2023-02-23
- Earliest claimed: 2020-07-24
- Assignees: Genentech, Inc.
- Applicants: Genentech, Inc.
- Inventors: Jason R. Zbieg; Paul Powell Beroza
- Web page: https://patentgrep.com/patent/US20230054741A1

## CPC

- C07D 307/79: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D 307/81: Radicals substituted by nitrogen atoms not forming part of a nitro radical
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- C07D 213/74: Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
- C07D 277/64: with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/10: linked by a carbon chain containing aromatic rings
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D 409/10: linked by a carbon chain containing aromatic rings
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D 417/10: linked by a carbon chain containing aromatic rings
- C07D 491/048: the oxygen-containing ring being five-membered
- C07F 5/025: {Boronic and borinic acid compounds}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

The invention relates to compounds and methods of using said compounds, as well as pharmaceutical compositions containing such compounds, for treating diseases and conditions mediated by TEAD, such as cancer.

## Claims

### Claim 1

A compound of formula (I):
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
X1 is N or C—R5, wherein each R5 is independently selected from the group consisting of H, cyano, halo, C(O)NH2, N(Re)(Rf), C3-10cycloalkyl, C1-6alkoxy, C6-20aryl, and C1-6alkyl, wherein the C1-6alkyl of R5 is optionally substituted with hydroxyl or N(Re)(Rf), or
the R5 of X1 is taken together with R3, and the atoms to which they are attached, to form a 5-membered heterocyclyl or a 5-membered heteroaryl, wherein the 5-membered heterocyclyl or 5-membered heteroaryl is optionally substituted with one or more C1-6alkyl;
X2 is N or C—R5, wherein each R5 is independently selected from the group consisting of H, cyano, halo, C(O)NH2, N(Re)(Rf), C3-10cycloalkyl, C1-6alkoxy, C6-20aryl, and C1-6alkyl, wherein the C1-6alkyl of R5 is optionally substituted with hydroxyl or N(Re)(Rf);
X3 is N or C—H;
R1 is:
(i) a 3-5 membered saturated heterocyclyl comprising at least one annular oxygen atom, wherein the 3-5 membered saturated heterocyclyl is optionally substituted with one or more C1-6alkyl, or
(ii) N(Re)(Rf), or
wherein Ra, Rb, and Rc are each independently selected from the group consisting of H, halo, cyano, hydroxyl, B(OH)2, C(O)—OH, C(O)—N(Re)(Rf), C(O)—C1-6alkoxy, C(O)—C1-6alkyl, C1-6alkyl, C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, C5-13spirocyclyl, and 5-20 membered heteroaryl, wherein the C1-6alkyl is further optionally substituted with hydroxyl, or
wherein Rd is selected from the group consisting of H, halo, cyano, hydroxyl, B(OH)2, C(O)—OH, C(O)—N(Re)(Rf), C(O)—C1-6alkoxy, C(O)—C1-6alkyl, C1-6alkyl, C3-10cycloalkyl, C6-20 aryl, 3-10 membered heterocyclyl, C5-13spirocyclyl, and 5-20 membered heteroaryl, wherein the C1-6alkyl is further optionally substituted with hydroxyl;
L is absent or is selected from the group consisting of —O—, *—CH2—O—**, *—O—CH2—**, —CH═CH—, and —C≡C—, wherein ** indicates the attachment point to the R2 moiety and * indicates the attachment point to the remainder of the molecule;
R2 is C1-12alkyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, C5-13spirocyclyl, C6-20aryl, or 5-20 membered heteroaryl,
wherein the C1-12alkyl, C3-10cycloalkyl, 3-10 membered saturated heterocyclyl, C5-13spirocyclyl, C6-20 aryl, or 5-20 membered heteroaryl of R2 is independently optionally substituted with one or more substituents selected from the group consisting of cyano, halo, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, NO2, N(Re)(Rf), and O(Re),
provided that, when R2 is C1-12alkyl, wherein the C1-12alkyl of R2 is independently optionally substituted with one or more substituents selected from the group consisting of cyano, halo, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, NO2, N(Re)(Rf), and O(Re), then L is —CH═CH— or —C≡C—;
R3 is cyano, C1-6alkyl, C1-4alkoxy, or C2-4alkenyl, wherein the C2-4alkenyl is optionally substituted with N(Re)(Rf), or
R3 is taken together with R5 of X1, and the atoms to which they are attached, to form a 5-membered heterocyclyl or a 5-membered heteroaryl, wherein the 5-membered heterocyclyl or 5-membered heteroaryl is optionally substituted with one or more C1-6alkyl, or
R3 is taken together with the carbon atom of *—CH2—O—** of L, and the atoms to which they are attached, to form a C6aryl or a 6-membered heteroaryl;
R4 is H or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with hydroxyl; and
Re and Rf are, independently of each other and independently at each occurrence, selected from the group consisting of H, cyano, hydroxyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C1-6alkyl-C3-10cycloalkyl, 3-10 membered heterocyclyl, C5-13spirocyclyl, C6-20aryl, and 3-20 membered heteroaryl, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C1-6alkyl-C3-10cycloalkyl, 3-10 membered heterocyclyl, C5-13spirocyclyl, C6-20aryl, and 3-20 membered heteroaryl of Re and Rf are each independently optionally substituted with one or more substituents selected from the group consisting of C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, oxo, cyano, halo, NO2, and hydroxyl.

### Claim 2 (depends on 1)

The compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X1 is C—R5, X2 is C—R5, and X3 is C—H.

### Claim 3 (depends on 1)

The compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X1 is C—R5, X2 is C—R5, and X3 is N.

### Claim 4 (depends on 1)

The compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X1 is C—R5, X2 is N, and X3 is C—H.

### Claim 5 (depends on 1)

The compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X1 is C—R5, X2 is N, and X3 is N.

### Claim 6 (depends on 1)

The compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X1 is C—R5, and R3 is taken together with the R5 of X1, and the atoms to which they are attached, to form a 5-membered heterocyclyl or a 5-membered heteroaryl, wherein the 5-membered heterocyclyl or 5-membered heteroaryl is optionally substituted with one or more C1-6alkyl.

### Claim 7 (depends on 6)

The compound of claim 6, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X1 is C—R5 and R3 is taken together with the R5 of X1, and the atoms to which they are attached, to form a 5-membered heterocyclyl.

### Claim 8 (depends on 7)

The compound of claim 7, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X1 is C—R5, and R3 is taken together with the R5 of X1, and the atoms to which they are attached, to form a 5-membered heterocyclyl, such that the compound of formula (I) is a compound of formula (IA):
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 8)

The compound of claim 8, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L is absent.

### Claim 10 (depends on 8)

The compound of claim 8, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound of formula (IA) is a compound of formula (IA-1):
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 8)

The compound of claim 8, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X2 is C—R5, wherein the R5 of X2 is H, cyano, halo, or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more hydroxyl.

### Claim 12 (depends on 8)

The compound of claim 8, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the R5 of X2 is cyano.

### Claim 13 (depends on 10)

The compound of claim 10, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 8)

The compound of any one of claim 8, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R2 is C3-10cycloalkyl or C6-20aryl, wherein the C3-10cycloalkyl or C6-20aryl of R2 is independently optionally substituted with one or more O(Re) or C1-6alkyl, wherein the C1-6alkyl is further optionally substituted with one or more halo.

### Claim 15 (depends on 1)

The compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R2 is C6-20aryl, wherein the C6-20aryl of R2 is independently optionally substituted with one or more C1-6alkyl.

### Claim 16 (depends on 8)

The compound of claim 8, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (IB):
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 16)

The compound of claim 16, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound of formula (IB) is selected from the group consisting
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

### Claim 18 (depends on 1)

The compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R1 is

### Claim 19 (depends on 18)

The compound of claim 18, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (IC):
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

### Claim 20 (depends on 18)

The compound of claim 18, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein at least two of Ra, Rb, and Rc are H.

### Claim 21 (depends on 18)

The compound of claim 18, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein exactly two of Ra, Rb, and Rc are H, and exactly one of Ra, Rb, and Rc is B(OH)2, C(O)—OH, C(O)—N(Re)(Rf), C(O)—C1-6alkoxy, or C(O)—C1-6alkyl.

### Claim 22 (depends on 21)

The compound of claim 21, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the Re and Rf of C(O)—N(Re)(Rf) are each independently H, C1-6alkyl, or hydroxyl.

### Claim 23 (depends on 18)

The compound of any one of claim 18, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein exactly two of Ra, Rb, and Rc are H, and exactly one of Ra, Rb, and Rc is C(O)—OH.

### Claim 24 (depends on 18)

The compound of claim 18, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Ra and Rb are each H, and Rc is C(O)—OH.

### Claim 25 (depends on 22)

The compound of claim 22, wherein the compound of formula (IC), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, is selected from the group consisting of
or a stereosiomer, tautomer, or pharmaceutically acceptable salt thereof.

### Claim 26 (depends on 1)

The compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R4 is H.

### Claim 27

A compound, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, selected from the group consisting of
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

### Claim 28

A compound, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, selected from the group consisting of
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

### Claim 29 (depends on 1)

The compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X1 is N, X2 is C—R5, and X3 is C—H.

### Claim 30 (depends on 1)

A pharmaceutical composition, comprising (i) a compound as described in any one of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable carrier, diluent, or excipient.

### Claim at position 31

31-32. (canceled)

### Claim 33 (depends on 1)

A method for treating cancer in a mammal, comprising administering a compound as described in any one of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, to the mammal.

### Claim at position 33

34-37. (canceled)

### Claim 38 (depends on 33)

The use of claim 33, wherein the disease or condition is acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor.

### Claim 39 (depends on 1)

A method for modulating TEAD activity, comprising contacting TEAD with a compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

### Claim 40 (depends on 1)

A method for treating a disease or condition mediated by TEAD activity in a mammal, comprising administering a compound of claim 1, or a pharmaceutically acceptable salt thereof, to the mammal.

### Claim 41 (depends on 40)

The method of claim 40, wherein the disease or condition is acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor.

### Claim at position 38

42-44. (canceled)

### Claim 45

A process for preparing a compound of formula (I):
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, comprising
wherein Boc is a tert-butyloxycarbonyl group, and halo is halogen.

### Claim 46 (depends on 45)

A compound, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, prepared by the process of claim 45.

### Claim 47

(canceled)