# US 11,116,767 B2 · 3,5-disubstituted pyrazoles useful as checkpoint kinase 1 (Chk1) inhibitors, and their preparations and applications

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- Number: US 11,116,767 B2
- Document ID: US11116767B2
- Status: Granted
- Kind: B2
- Application number: 16/074,195
- Filed: 2016-02-04
- Published: 2021-05-13
- Granted: 2021-09-14
- Earliest claimed: 2016-02-04
- Assignees: Pharmaengine, Inc.
- Applicants: Pharmaengine, Inc.
- Inventors: Xiong Cai; Changgeng Qian; Yanong Daniel Wang
- Web page: https://patentgrep.com/patent/US11116767B2

## CPC

- A61K 31/497: containing further heterocyclic rings
- A61K 31/138: Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine (atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377)
- A61K 31/4196: 1,2,4-Triazoles
- A61K 31/436: the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61K 31/4402: only substituted in position 2, e.g. pheniramine, bisacodyl
- A61K 31/4745: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48)
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/565: not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention provides compounds of formula (I) which are potent inhibitors of Chk1 and have the structural formula below: wherein R1, R2, R3, R4, and R5 are as defined herein. Pharmaceutical compositions comprising the compounds, uses thereof and their preparation process are also provided.

## Claims

### Claim 1

A compound of formula (I):
wherein:
R1 is halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted aryl, —NO2, —OH, —C(O)R, —C(O)OR, —C(O)N(R′)(R″), or —N(R′)(R″);
R2 and R3 are each independently —H, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted alkoxy, —NO2, —OH, or —N(R′)(R″), or R2 and R3 together with the carbon atom to which they are attached form an unsubstituted or substituted carbon cyclic or heterocyclic ring;
R4 is —H, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted aryl, —OH, —C(O)R, —C(O)OR, —C(O)N(R′)(R″), or —N(R′)(R″);
R5 is —CN, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted alkoxy, —NO2, —OH, or —N(R′)(R″);
R is unsubstituted or substituted alkyl; and
R′ and R″ are each independently —H or unsubstituted or substituted alkyl, or a pharmaceutically acceptable salt, geometric isomer, enantiomer, distereomer, racemate, prodrug, solvate, or hydrate thereof.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein:
R1 is halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted alkoxy, —NO2, —OH, —C(O)OR, —C(O)N(R′)(R″), or —N(R′)(R″);
R is unsubstituted or substituted alkyl; and
R′ and R″ are each independently —H or unsubstituted or substituted alkyl.

### Claim 3 (depends on 2)

The compound according to claim 2, wherein:
R1 is halogen, unsubstituted alkyl, unsubstituted alkoxy, —OH, —CF3, or hydroxyalkyl.

### Claim 4 (depends on 3)

The compound according to claim 3, wherein:
R1 is —F, —Cl, —Br, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, —OH, —CF3, or hydroxymethyl.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein:
R2 and R3 are each independently —H, —OH, halogen, unsubstituted or substituted alkyl, or —N(R′)(R″), or R2 and R3 together with the carbon atom to which they are attached form an unsubstituted or substituted carbon cyclic or heterocyclic ring; and
R′ and R″ are each independently —H or unsubstituted or substituted alkyl.

### Claim 6 (depends on 5)

The compound according to claim 5, wherein:
R2 and R3 are each independently —H, —OH, halogen, unsubstituted alkyl, or hydroxyalkyl, or R2 and R3 together with the carbon atom to which they are attached form an unsubstituted carbon cyclic ring or heterocyclic ring.

### Claim 7 (depends on 6)

The compound according to claim 6, wherein:
R2 and R3 are each independently —H, —OH, —F, —Cl, methyl, ethyl, or hydroxymethyl, or R2 and R3 together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, oxirane, aziridine, or azetidine.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein:
R4 is —H, unsubstituted or substituted alkyl, —C(O)OR, or —C(O)R; and
R is unsubstituted or substituted alkyl.

### Claim 9 (depends on 8)

The compound according to claim 8, wherein:
R4 is —H, methyl, ethyl, propyl, acetyl, aminoacetyl, methoxycarbonyl, 1-(1-oxo-2-methylpropoxy)ethoxycarbonyl, or ethoxycarbonyl.

### Claim 10 (depends on 1)

The compound according to claim 1, wherein:
R5 is —CN, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, or unsubstituted or substituted alkynyl.

### Claim 11 (depends on 10)

The compound according to claim 10, wherein:
R5 is —CN, halogen, or unsubstituted alkyl.

### Claim 12 (depends on 11)

The compound according to claim 11, wherein:
R5 is —CN, —F, —Cl, —Br, methyl, ethyl, propyl, or isopropyl.

### Claim 13 (depends on 1)

The compound according to claim 1, which is a compound of formula (II):
wherein:
R1 is —F, —Cl, —Br, methyl, or methoxy;
R2 and R3 are each independently —H or —OH, or R2 and R3 together with the carbon atom to which they are attached form cyclopropyl;
R4 is —H, methyl, aminoacetyl, 1-(1-oxo-2-methylpropoxy)ethoxycarbonyl, or ethoxycarbonyl; and
R5 is —CN, methyl, or —Cl, or a pharmaceutically acceptable salt, geometric isomer, enantiomer, distereomer, racemate, prodrug, solvate, or hydrate thereof.

### Claim 14

A compound, which is selected from:
5-(5-(2-(3-aminopropoxy)-3-fluoro-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
5-((5-(6-(3-aminopropoxy)-3-fluoro-2-methoxyphenyl)-1H-pyrazol-3-yl)amino) pyrazine-2-carbonitrile;
5-(5-(2-(3-aminopropoxy)-4-fluoro-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
5-(5-(2-(3-aminopropoxy)-4-chloro-6-methoxyphenyl)-1H-pyrazol-3-yl amino)pyrazine-2-carbonitrile;
5-(5-(2-(3-aminopropoxy)-4-bromo-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
5-(5-(2-(3-aminopropoxy)-6-methoxy-4-methylphenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
5-(5-(2-(3-aminopropoxy)-4,6-dimethoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
5-(5-(2-(3-methylaminopropoxy)-4-fluoro-6-methoxyphenyl)-1H-pyrazol-3-ylamino) pyrazine-2-carbonitrile;
5-(5-(2-(3-methylaminoprop oxy)-4-chloro-6-methoxyphenyl)-1H-pyrazol-3-ylamino) pyrazine-2-carbonitrile;
5-(5-(2-(3-methylaminopropoxy)-4-bromo-6-methoxyphenyl)-1H-pyrazol-3-ylamino) pyrazine-2-carbonitrile;
5-(5-(2-(3-methylaminopropoxy)-4-methyl-6-methoxyphenyl)-1H-pyrazol-3-ylamino) pyrazine-2-carbonitrile;
5-(5-(2-(3-methylaminopropoxy)-4, 6-dimethoxyphenyl)-1H-pyrazol-3-ylamino) pyrazine-2-carbonitrile;
5-(5-(2-((1-(aminomethyl)cyclopropyl)methoxy)-4-fluoro-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
5-(5-(2-((1-(aminomethyl)cyclopropyl)methoxy)-4-chloro-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
5-(5-(2-((1-(aminomethyl)cyclopropyl)methoxy)-4-bromo-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
5-(5-(2-((1-(aminomethyl)cyclopropyl)methoxy)-6-methoxy-4-methylphenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
5-(5-(2-((1-(aminomethyl)cyclopropyl)methoxy)-4,6-dimethoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
5-(5-(3-fluoro-6-methoxy-2-((1-((methylamino)methyl)cyclopropyl)methoxy)phenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
5-((5-(3-fluoro-2-methoxy-6-((1-((methylamino)methyl)cyclopropyl)methoxy)phenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile;
5-(5-(4-fluoro-2-methoxy-6-((1-((methylamino)methyl)cyclopropyl)methoxy)phenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
5-((5-(4-chloro-2-methoxy-6-((1-((methylamino)methyl)cyclopropyl)methoxy)phenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile;
5-((5-(4-bromo-2-methoxy-6-((1-((methylamino)methyl)cyclopropyl)methoxy)phenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile;
5-((5-(2-methoxy-4-methyl-6-((1-((methylamino)methyl)cyclopropyl)methoxy)phenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile;
5-((5-(2,4-dim ethoxy-6-((1-((methyl amino)methyl)cyclopropyl)methoxy)phenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile;
5-(5-(2-(2-hydroxy-3-aminopropoxy)-4-fluoro-6-methoxyphenyl)-1H-pyrazol-3-yl amino)pyrazine-2-carbonitrile;
5-(5-(2-(2-hydroxy-3-aminopropoxy)-4-methyl-6-methoxyphenyl)-1H-pyrazol-3-yl amino)pyrazine-2-carbonitrile;
5-(5-(2-(2-hydroxy-3-aminopropoxy)-4,6-dimethoxyphenyl)-1H-pyrazol-3-yl amino)pyrazine-2-carbonitrile;
2-methyl-5-(5-(2-(3-aminopropoxy)-4-fluoro-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine;
2-chloro-5-(5-(2-(3-aminopropoxy)-4-fluoro-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine;
2-methyl-5-(5-(2-(3-methylaminopropoxy)-4-fluoro-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine;
2-chloro-5-(5-(2-(3-methylaminopropoxy)-4-fluoro-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine;
2-methyl-5-(5-(2-((1-(aminomethyl)cyclopropyl)methoxy)-4-fluoro-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine;
2-chloro-5-(5-(2-((1-(aminomethyl)cyclopropyl)methoxy)-4-fluoro-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine;
2-methyl-5-(5-(2-((1-(aminomethyl)cyclopropyl)methoxy)-4-fluoro-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine;
2-chloro-5-(5-(2-((1-(aminomethyl)cyclopropyl)methoxy)-4-fluoro-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine;
2-methyl-5-(5-(2-(2-hydroxy-3-aminopropoxy)-4-fluoro-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine;
2-chloro-5-(5-(2-(2-hydroxy-3-aminopropoxy)-4-fluoro-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine;
ethyl 3-(2-(3-(5-cyanopyrazin-2-ylamino)-1H-pyrazol-5-yl)-5-fluoro-3-methoxy phenoxy)propylcarbamate;
2-amino-N-(3-(2-(3-((5-cyanopyrazin-2-yl)amino)-1H-pyrazol-5-yl)-5-fluoro-3-methoxyphenoxy)propyl)acetamide; or
1-(((3-(2-(3-((5-cyanopyrazin-2-yl)amino)-1H-pyrazol-5-yl)-5-fluoro-3-methoxy phenoxy)propyl)carbamoyl)oxy)ethylisobutyrate;
or a pharmaceutically acceptable salt, geometric isomer, enantiomer, distereomer, racemate, prodrug, solvate, or hydrate thereof.

### Claim 15 (depends on 14)

The compound according to claim 14, which is selected from:
5-(5-(2-(3-aminopropoxy)-3-fluoro-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
5-((5-(6-(3-aminopropoxy)-3-fluoro-2-methoxyphenyl)-1H-pyrazol-3-yl)amino) pyrazine-2-carbonitrile;
5-(5-(2-(3-aminopropoxy)-4-fluoro-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
5-(5-(2-(3-aminopropoxy)-4-chloro-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
5-(5-(2-(3-aminopropoxy)-4-bromo-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
5-(5-(2-(3-aminopropoxy)-6-methoxy-4-methylphenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
5-(5-(2-(3-aminopropoxy)-4,6-dimethoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
5-(5-(2-((1-(aminomethyl)cyclopropyl)methoxy)-4-fluoro-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
5-(5-(2-((1-(aminomethyl)cyclopropyl)methoxy)-4-chloro-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
5-(5-(2-((1-(aminomethyl)cyclopropyl)methoxy)-4-bromo-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
5-(5-(2-((1-(aminomethyl)cyclopropyl)methoxy)-6-methoxy-4-methylphenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
5-(5-(2-((1-(aminomethyl)cyclopropyl)methoxy)-4,6-dimethoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
5-(5-(3-fluoro-6-methoxy-2-((1-((methylamino)methyl)cyclopropyl)methoxy)phenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
5-((5-(3-fluoro-2-methoxy-6-((1-((methyl amino)methyl)cyclopropyl)methoxy)phenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile;
5-(5-(4-fluoro-2-methoxy-6-((1-((methylamino)methyl)cyclopropyl)methoxy)phenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile; and
ethyl 3-(2-(3-(5-cyanopyrazin-2-ylamino)-1H-pyrazol-5-yl)-5-fluoro-3-methoxyphenoxy)propylcarbamate,
or a pharmaceutically acceptable salt, geometric isomer, enantiomer, distereomer, racemate, prodrug, solvate, or hydrate thereof.

### Claim 16 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt, geometric isomer, enantiomer, distereomer, racemate, prodrug, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.

### Claim 17 (depends on 14)

A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 14 or a pharmaceutically acceptable salt, geometric isomer, enantiomer, distereomer, racemate, prodrug, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.

### Claim 18 (depends on 15)

A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 15 or a pharmaceutically acceptable salt, geometric isomer, enantiomer, distereomer, racemate, prodrug, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.

### Claim 19 (depends on 1)

A method for treating cancer in a subject in need thereof comprising administrating a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt, geometric isomer, enantiomer, distereomer, racemate, prodrug, solvate, or hydrate thereof to the subject.

### Claim 20 (depends on 19)

The method according to claim 19, comprising further administrating to the subject a second anticancer agent, a surgical therapy, an ionizing radiation, or a combination thereof.

### Claim 21 (depends on 20)

The method according to claim 20, wherein the second anticancer agent is selected from: targeted cancer drugs, such as trastuzumab, ramucirumab, vismodegib, sonidegib, bevacizumab, everolimus, tamoxifen, toremifene, fulvestrant, anastrozole, exemestane, lapatinib, letrozole, pertuzumab, ado-trastuzumab emtansine, palbociclib, cetuximab, panitumumab, ziv-aflibercept, regorafenib, lmatinib mesylate, lanreotide acetate, sunitinib, regorafenib, denosumab, alitretinoin, sorafenib, pazopanib, temsirolimus, everolimus, tretinoin, dasatinib, nilotinib, bosutinib, rituximab, alemtuzumab, ofatumumab, obinutuxumab, ibrutinib, idelalisib, blinatumomab, soragenib, crizotinib, erlotinib, gefitinib, afatinib dimaleate, ceritnib, ramucirumab, nivolumab, pembrolizumab, osimertinib, and necitumumab; an alkylating agent, such as busulfan, chlorambucil, cyclophosphamide, iphosphamide, melphalan, nitrogen mustard, streptozocin, thiotepa, uracil nitrogen mustard, triethylenemelamine, temozolomide, and 2-chloroethyl-3-sarcosinamide-l-nitrosourea (SarCNU); an antibiotic or plant alkaloid, such as actinomycin-D, bleomycin, cryptophycins, daunorubicin, doxorubicin, idarubicin, irinotecan, L-asparaginase, mitomycin-C, mitramycin, navelbine, paclitaxel, docetaxel, topotecan, vinblastine, vincristine, teniposide (VM-26), and etoposide (VP-16); a hormone or steroid, such as 5α-reductase inhibitor, aminoglutethimide, anastrozole, bicalutamide, chlorotrianisene, diethyl stilbestrol (DES), dromostanolone, estramustine, ethinyl estradiol, flutamide, fluoxymesterone, goserelin, hydroxyprogesterone, letrozole, leuprolide, medroxyprogesterone acetate, megestrol acetate, methyl prednisolone, methyltestosterone, mitotane, nilutamide, prednisolone, arzoxifene (SERM-3), tamoxifen, testolactone, testosterone, triamicnolone, and zoladex; a synthetic, such as all-trans retinoic acid, carmustine (BCNU), carboplatin (CBDCA), lomustine (CCNU), cis-diaminedichloroplatinum (cisplatin), dacarbazine, gliadel, hexamethylmelamine, hydroxyurea, levamisole, mitoxantrone, o, p′-dichlorodiphenyldichloroethane (o,p′-DDD) (also known as lysodren or mitotane), oxaliplatin, porfimer sodium, procarbazine, and imatinib mesylate; an antimetabolite, such as chlorodeoxyadenosine, cytosine arabinoside, 2′-deoxycoformycin, fludarabine phosphate, 5-fluorouracil (5-FU), 5-fluoro-2′-deoxyuridine (5-FUdR), gemcitabine, camptothecin, 6-mercaptopurine, methotrexate, 4-methylthioamphetamine (4-MTA), and thioguanine; and a biologic, such as alpha interferon, BCG (Bacillus Calmette-Guerin), granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2, and herceptin.

### Claim 22 (depends on 21)

The method according to claim 21, wherein the second anticancer agent is irinotecan.

### Claim 23 (depends on 19)

The method according to claim 19, wherein the cancer is breast cancer, squamous cell carcinoma, lung cancer, oesophagus cancer, liver cancer, gastric cancer, colorectal cancer, bladder cancer, ovary carcinoma, prostate cancer, giloblastoma, pancreatic cancer, or leukemia.

### Claim 24 (depends on 14)

A method for treating cancer in a subject in need thereof comprising administrating a therapeutically effective amount of a compound of claim 14 or a pharmaceutically acceptable salt, geometric isomer, enantiomer, distereomer, racemate, prodrug, solvate, or hydrate thereof to the subject.

### Claim 25 (depends on 24)

The method according to claim 24, comprising further administrating to the subject a second anticancer agent, a surgical therapy, an ionizing radiation, or a combination thereof.

### Claim 26 (depends on 25)

The method according to claim 25, wherein the second anticancer agent is selected from: targeted cancer drugs, such as trastuzumab, ramucirumab, vismodegib, sonidegib, bevacizumab, everolimus, tamoxifen, toremifene, fulvestrant, anastrozole, exemestane, lapatinib, letrozole, pertuzumab, ado-trastuzumab emtansine, palbociclib, cetuximab, panitumumab, ziv-aflibercept, regorafenib, lmatinib mesylate, lanreotide acetate, sunitinib, regorafenib, denosumab, alitretinoin, sorafenib, pazopanib, temsirolimus, everolimus, tretinoin, dasatinib, nilotinib, bosutinib, rituximab, alemtuzumab, ofatumumab, obinutuxumab, ibrutinib, idelalisib, blinatumomab, soragenib, crizotinib, erlotinib, gefitinib, afatinib dimaleate, ceritnib, ramucirumab, nivolumab, pembrolizumab, osimertinib, and necitumumab; an alkylating agent, such as busulfan, chlorambucil, cyclophosphamide, iphosphamide, melphalan, nitrogen mustard, streptozocin, thiotepa, uracil nitrogen mustard, triethylenemelamine, temozolomide, and 2-chloroethyl-3-sarcosinamide-l-nitrosourea (SarCNU); an antibiotic or plant alkaloid, such as actinomycin-D, bleomycin, cryptophycins, daunorubicin, doxorubicin, idarubicin, irinotecan, L-asparaginase, mitomycin-C, mitramycin, navelbine, paclitaxel, docetaxel, topotecan, vinblastine, vincristine, teniposide (VM-26), and etoposide (VP-16); a hormone or steroid, such as 5α-reductase inhibitor, aminoglutethimide, anastrozole, bicalutamide, chlorotrianisene, diethyl stilbestrol (DES), dromostanolone, estramustine, ethinyl estradiol, flutamide, fluoxymesterone, goserelin, hydroxyprogesterone, letrozole, leuprolide, medroxyprogesterone acetate, megestrol acetate, methyl prednisolone, methyltestosterone, mitotane, nilutamide, prednisolone, arzoxifene (SERM-3), tamoxifen, testolactone, testosterone, triamicnolone, and zoladex; a synthetic, such as all-trans retinoic acid, carmustine (BCNU), carboplatin (CBDCA), lomustine (CCNU), cis-diaminedichloroplatinum (cisplatin), dacarbazine, gliadel, hexamethylmelamine, hydroxyurea, levamisole, mitoxantrone, o, p′-dichlorodi phenyl di chloroethane (o,p′-DDD) (also known as lysodren or mitotane), oxaliplatin, porfimer sodium, procarbazine, and imatinib mesylate; an antimetabolite, such as chlorodeoxyadenosine, cytosine arabinoside, 2′-deoxycoformycin, fludarabine phosphate, 5-fluorouracil (5-FU), 5-fluoro-2′-deoxyuridine (5-FUdR), gemcitabine, camptothecin, 6-mercaptopurine, methotrexate, 4-methylthioamphetamine (4-MTA), and thioguanine; and a biologic, such as alpha interferon, BCG (Bacillus Calmette-Guerin), granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2, and herceptin.

### Claim 27 (depends on 26)

The method according to claim 26, wherein the second anticancer agent is irinotecan.

### Claim 28 (depends on 24)

The method according to claim 24, wherein the cancer is breast cancer, squamous cell carcinoma, lung cancer, oesophagus cancer, liver cancer, gastric cancer, colorectal cancer, bladder cancer, ovary carcinoma, prostate cancer, giloblastoma, pancreatic cancer, or leukemia.

### Claim 29 (depends on 15)

A method for treating cancer in a subject in need thereof comprising administrating a therapeutically effective amount of a compound of claim 15 or a pharmaceutically acceptable salt, geometric isomer, enantiomer, distereomer, racemate, prodrug, solvate, or hydrate thereof to the subject.

### Claim 30 (depends on 29)

The method according to claim 29, comprising further administrating to the subject a second anticancer agent, a surgical therapy, an ionizing radiation, or a combination thereof.

### Claim 31 (depends on 30)

The method according to claim 30, wherein the second anticancer agent is selected from: targeted cancer drugs, such as trastuzumab, ramucirumab, vismodegib, sonidegib, bevacizumab, everolimus, tamoxifen, toremifene, fulvestrant, anastrozole, exemestane, lapatinib, letrozole, pertuzumab, ado-trastuzumab emtansine, palbociclib, cetuximab, panitumumab, ziv-aflibercept, regorafenib, lmatinib mesylate, lanreotide acetate, sunitinib, regorafenib, denosumab, alitretinoin, sorafenib, pazopanib, temsirolimus, everolimus, tretinoin, dasatinib, nilotinib, bosutinib, rituximab, alemtuzumab, ofatumumab, obinutuxumab, ibrutinib, idelalisib, blinatumomab, soragenib, crizotinib, erlotinib, gefitinib, afatinib dimaleate, ceritnib, ramucirumab, nivolumab, pembrolizumab, osimertinib, and necitumumab; an alkylating agent, such as busulfan, chlorambucil, cyclophosphamide, iphosphamide, melphalan, nitrogen mustard, streptozocin, thiotepa, uracil nitrogen mustard, triethylenemelamine, temozolomide, and 2-chloroethyl-3-sarcosinamide-l-nitrosourea (SarCNU); an antibiotic or plant alkaloid, such as actinomycin-D, bleomycin, cryptophycins, daunorubicin, doxorubicin, idarubicin, irinotecan, L-asparaginase, mitomycin-C, mitramycin, navelbine, paclitaxel, docetaxel, topotecan, vinblastine, vincristine, teniposide (VM-26), and etoposide (VP-16); a hormone or steroid, such as 5a-reductase inhibitor, aminoglutethimide, anastrozole, bicalutamide, chlorotrianisene, diethyl stilbestrol (DES), dromostanolone, estramustine, ethinyl estradiol, flutamide, fluoxymesterone, goserelin, hydroxyprogesterone, letrozole, leuprolide, medroxyprogesterone acetate, megestrol acetate, methyl prednisolone, methyltestosterone, mitotane, nilutamide, prednisolone, arzoxifene (SERM-3), tamoxifen, testolactone, testosterone, triamicnolone, and zoladex; a synthetic, such as all-trans retinoic acid, carmustine (BCNU), carboplatin (CBDCA), lomustine (CCNU), cis-diaminedichloroplatinum (cisplatin), dacarbazine, gliadel, hexamethylmelamine, hydroxyurea, levamisole, mitoxantrone, o, p′-dichlorodiphenyldichloroethane (o,p′-DDD) (also known as lysodren or mitotane), oxaliplatin, porfimer sodium, procarbazine, and imatinib mesylate; an antimetabolite, such as chlorodeoxyadenosine, cytosine arabinoside, 2′-deoxycoformycin, fludarabine phosphate, 5-fluorouracil (5-FU), 5-fluoro-2′-deoxyuridine (5-FUdR), gemcitabine, camptothecin, 6-mercaptopurine, methotrexate, 4-methylthioamphetamine (4-MTA), and thioguanine; and a biologic, such as alpha interferon, BCG (Bacillus Calmette-Guerin), granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2, and herceptin.

### Claim 32 (depends on 31)

The method according to claim 31, wherein the second anticancer agent is irinotecan.

### Claim 33 (depends on 29)

The method according to claim 29, wherein the cancer is breast cancer, squamous cell carcinoma, lung cancer, oesophagus cancer, liver cancer, gastric cancer, colorectal cancer, bladder cancer, ovary carcinoma, prostate cancer, gilobla stoma, pancreatic cancer, or leukemia.

### Claim 34 (depends on 1)

A method for preparing a compound of claim 1, which comprises:
a. reacting a compound of formula (1)
with a hydrazine of formula H2N-NH2, wherein R1 and R5 are as defined in claim 1; R6 is a hydroxy protecting group; R7 is alkyl; in the presence of a solvent to obtain a compound of formula (2);
b. de-protecting the compound of formula (2), followed by reacting the de-protected compound with a compound of formula (3)
wherein R2, R3, and R4 are as defined in claim 1; and R9 is an amino protecting group, in the presence of a coupling agent and a solvent to obtain a compound of formula (4)
wherein R1, R2, R3, R4, R5 and R9 are as defined above; and
c. de-protecting the compound of formula (4) to obtain a compound of formula (I).