# US 2019/0375709 A1 · Yap1 inhibitors that target the interaction of yap1 with oct4

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- Number: US 2019/0375709 A1
- Document ID: US20190375709A1
- Status: Published application
- Kind: A1
- Application number: 16/334,087
- Filed: 2017-09-18
- Published: 2019-12-12
- Earliest claimed: 2016-09-18
- Assignees: H.Lee Moffitt Cancer and Research Institute, Inc.
- Applicants: H.Lee Moffitt Cancer and Research Institute, Inc.
- Inventors: Srikumar CHELLAPAN; Nicholas J. LAWRENCE; Sujeewa Ranatunga Mahanthe MUDIYANSELAGE
- Web page: https://patentgrep.com/patent/US20190375709A1

## CPC

- C07D 211/60: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- A61P 35/00: Antineoplastic agents
- C07C 237/14: the carbon skeleton being saturated and containing rings
- C07C 237/22: having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated (peptides C07K)
- C07C 251/24: having carbon atoms of imino groups bound to carbon atoms of six-membered aromatic rings
- C07C 255/57: containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
- C07C 271/24: with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07D 207/16: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 211/14: with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
- C07D 211/32: by oxygen atoms
- C07D 211/34: with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 211/56: Nitrogen atoms (nitro radicals C07D211/38)
- C07D 211/58: attached in position 4
- C07D 211/96: Sulfur atom
- C07D 233/64: with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
- C07D 233/92: attached in position 4 or 5
- C07D 241/04: having no double bonds between ring members or between ring members and non-ring members
- C07D 257/04: Five-membered rings
- C07D 263/32: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 401/10: linked by a carbon chain containing aromatic rings
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 405/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07C 2601/14: The ring being saturated
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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)

## Abstract

Binding of the transcriptional co-activator, YAP1, to the transcription factor Oct4, induces Sox2. which is a transcription actor necessary for the self-renewal of stem-like cells from non-small cell lung cancer. The WW domain of YAP1 binds to the PPxY motif of Oct4 to induce Sox2. Delivering a peptide corresponding to the WAV domain could prevent the induction of Sox2 and stemness. Similarly, peptides and mimetics of the PPxY motif would be able to inhibit stemness. Disclosed arc compounds that affect the Yap1:Oct4 interaction.

## Claims

### Claim 1

A compound having Formula I
wherein,
X is C(O), S(O), or SO2;
Y is CH, CR6, or N;
Z is CH2, CR6R7, or NH;
R1 is C1-C8 alkyl, C1-C8 alkenyl, C1-C8 alkynyl, C1-C8 alkoxyl, C1-C8 heteroalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, or heteroaryl, any of which is optionally substituted with one or more carbonyl (C═O), C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, amino, —NR6R7, —C(O)NR6R7, C1-C6 alkylhydroxy, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, heteroaryl, halo, hydroxyl, thiol, cyano, nitro, or radiolabeled isotope;
R2 is amino, hydroxyl, C1-C8 alkyl, C1-C8 alkenyl, C1-C8 alkynyl, C1-C8 alkoxyl, C1-C8 heteroalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, or heteroaryl, any of which is optionally substituted with one or more carbonyl (C═O), carboxyl (—CO2—), ester (CO2R6), C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, amino, —NR6R7, —C(O)NR6R7, C1-C6 alkylC3-6 cycloalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, heteroaryl, C1-6 alkylaryl, halo, hydroxyl, thiol, cyano, nitro, or radiolabeled isotope;
each R3 is, independently, hydrogen, halogen, OH, C1-C8 alkyl, C1-C8 alkoxyl, aryl, O-aryl, heteroaryl, O-heteroaryl, 0-CH2aryl, or O-CH2heteroaryl; and
R6 and R7 are independently selected from hydrogen, C1-C8 alkyl, C1-C8 alkenyl, C1-C8 alkynyl, C1-C8 alkoxide, C1-C8 carboxylate, C1-C8 haloalkyl, C1-C8 haloalkenyl, C1-C8 haloalkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, C1-C3 alkylheteroaryl, or heteroaryl; any of which is optionally substituted with a halogen; and n is 1-5.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the compound has Formula II
wherein,
R1 is hydrogen, C1-C8 alkyl, C1-C8 alkenyl, C1-C8 alkynyl, C1-C8 alkoxyl, C1-C8 heteroalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, or heteroaryl, any of which is optionally substituted with one or more carbonyl (C═O), C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, amino, —NR6R7, —C(O)NR6R7, C1-C6 alkylhydroxy, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, heteroaryl, halo, hydroxyl, thiol, cyano, nitro, or radiolabeled isotope;
R2 is amino, hydroxyl, C1-C8 alkyl, C1-C8 alkenyl, C1-C8 alkynyl, C1-C8 alkoxyl, C1-C8 heteroalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, or heteroaryl, any of which is optionally substituted with one or more carbonyl (C═O), carboxyl (—CO2—), ester (CO2R6), C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, amino, —NR6R7, —C(O)NR6R7, C1-C6 alkylC3-6 cycloalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, heteroaryl, C1-6 alkylaryl, halo, hydroxyl, thiol, cyano, nitro, or radiolabeled isotope;
each R3 is, independently, hydrogen, halogen, OH, C1-C8 alkyl, C1-C8 alkoxyl, aryl, O-aryl, heteroaryl, O-heteroaryl, O-CH2aryl, or O-CH2heteroaryl; and
R6 and R7 are independently selected from hydrogen, C1-C8 alkyl, C1-C8 alkenyl, C1-C8 alkynyl, C1-C8 alkoxide, C1-C8 carboxylate, C1-C8 haloalkyl, C1-C8 haloalkenyl, C1-C8 haloalkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, C1-C3 alkylheteroaryl, or heteroaryl; any of which is optionally substituted with a halogen; and n is 1-5.

### Claim 3

A compound having Formula III
wherein,
X is C(O), S(O), or SO2;
Y is CH, CR6, or N;
Z is CH2, CR6R7, or NH;
W is cyano, C2-C4 alkyne, or a triazole, tetrazole or oxaxole optionally substituted with one or more carbonyl (C═O), C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, amino, —NR6R7, —C(O)NR6R7, C1-C6 alkylhydroxy, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, heteroaryl, halo, hydroxyl, thiol, cyano, nitro, or radiolabeled isotope;
R1 is C1-C8 alkyl, C1-C8 alkenyl, C1-C8 alkynyl, C1-C8 alkoxyl, C1-C8 heteroalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, or heteroaryl, any of which is optionally substituted with one or more carbonyl (C═O), C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, amino, —NR6R7, —C(O)NR6R7, C1-C6 alkylhydroxy, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, heteroaryl, halo, hydroxyl, thiol, cyano, nitro, or radiolabeled isotope;
R2 is amino, hydroxyl, C1-C8 alkyl, C1-C8 alkenyl, C1-C8 alkynyl, C1-C8 alkoxyl, C1-C8 heteroalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, or heteroaryl, any of which is optionally substituted with one or more carbonyl (C═O), carboxyl (—CO2—), ester (CO2R6), C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, amino, —NR6R7, —C(O)NR6R7, C1-C6 alkylC3-6 cycloalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, heteroaryl, C1-6alkylaryl, halo, hydroxyl, thiol, cyano, nitro, or radiolabeled isotope;
each R3 is, independently, hydrogen, halogen, OH, C1-C8 alkyl, C1-C8 alkoxyl, aryl, O-aryl, heteroaryl, O-heteroaryl, O-CH2aryl, or O-CH2heteroaryl; and
R6 and R7 are independently selected from hydrogen, C1-C8 alkyl, C1-C8 alkenyl, C1-C8 alkynyl, C1-C8 alkoxide, C1-C8 carboxylate, C1-C8 haloalkyl, C1-C8 haloalkenyl, C1-C8 haloalkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, C1-C3 alkylheteroaryl, or heteroaryl; any of which is optionally substituted with a halogen; and n is 1-5.

### Claim 4 (depends on 1)

The compound of claim 1, wherein Z is CH2.

### Claim 5 (depends on 1)

The compound of claim 1, wherein Z is NH.

### Claim 6 (depends on 1)

The compound of claim 1, wherein Y is CH2.

### Claim 7 (depends on 1)

The compound of claim 1, wherein Y is N.

### Claim 8 (depends on 1)

The compound of claim 1, wherein X is C(O).

### Claim 9 (depends on 1)

The compound of claim 1, wherein X is SO2.

### Claim 10 (depends on 1)

The compound of claim 1, wherein R1 is C1-C8 alkoxyl.

### Claim 11 (depends on 1)

The compound of claim 1, wherein R1 is phenyl.

### Claim 12 (depends on 1)

The compound of claim 1, wherein R1 is C1-3 alkyl substituted with aryl, wherein the aryl is optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, amino, halo, hydroxyl, thiol, cyano, nitro, or radiolabeled isotope.

### Claim 13 (depends on 1)

The compound of claim 1, wherein R1 is CH2CH2Ph, CH2CH2CH2Ph, CH(CH2)Ph, C(CH3)2Ph, or CH2CH(Ph)2.

### Claim 14 (depends on 1)

The compound of claim 1, wherein R1 is CH2CH2Ph, where the phenyl is substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, amino, halo, hydroxyl, thiol, cyano, nitro, or radiolabeled isotope.

### Claim 15 (depends on 1)

The compound of claim 1, wherein R1 is a C1-3 alkyl substituted with a phenyl substituted with one or more halogen, methoxyl, ethoxyl, propoxyl, cyano, and CF3, or R1 is a C1-3 alkyl substituted with a phenyl substituted with a dioxole.

### Claim 16 (depends on 1)

The compound of claim 1, wherein R1 is C1-3 alkenyl substituted with aryl, wherein the aryl is optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, amino, halo, hydroxyl, thiol, cyano, nitro, or radiolabeled isotope.

### Claim 17 (depends on 1)

The compound of claim 1, wherein R1 is CH═CHPh, where the phenyl is substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, amino, halo, hydroxyl, thiol, cyano, nitro, or radiolabeled isotope.

### Claim 18 (depends on 1)

The compound of claim 1, wherein R1 is C1-C8 heteroalkyl, C3-C6 heterocycloalkyl, which is optionally substituted with one or more C═O, C1-6 alkyl, and aryl.

### Claim 19 (depends on 1)

The compound of claim 1, wherein R1 is pyrrolidine substituted with C(O)CH3.

### Claim 20 (depends on 1)

The compound of claim 1, wherein R2 is OMe or OH.

### Claim 21 (depends on 1)

The compound of claim 1, wherein R2 is unsubstituted amino, amino substituted with C1-C6 alkyl, amino substituted with with C3-C6 cycloalkyl, or amino substituted with C1-C6 alkyl C3-6 cycloalkyl.

### Claim 22 (depends on 1)

The compound of claim 1, wherein R3 is hydrogen or OH.

### Claim 23 (depends on 1)

The compound of claim 1, wherein R3 is Obenzyl.

### Claim 24 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutical carrier and optional anticancer or anti-inflammatory agent.

### Claim 25 (depends on 1)

A method of treating cancer in a subject in need thereof, comprising: administering to the subject the compound of claim 1.

### Claim 26 (depends on 25)

The method of claim 25, wherein the cancer is selected from bladder cancer, brain cancer, breast cancer, colorectal cancer, cervical cancer, gastrointestinal cancer, genitourinary cancer, head and neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer, and testicular cancer

### Claim 27 (depends on 25)

The method of claim 25, wherein the cancer is lung cancer.

### Claim 28 (depends on 1)

A method of killing a tumor cell in a subject, comprising contacting the cell with the compound of claim 1.